RIKEN IMSAnnual Report 2022
RIKEN Center for Integrative Medical Sciences

RIKEN Center for Integrative Medical Sciences
Organization Chart

Director

Kazuhiko Yamamoto

Deputy Directors

Senior Advisor

Haruhiko Koseki
Harukazu Suzuki
Hiroshi Ohno

Shizuo Akira

Office of the Center Director

Motohide Yokota

Advisory Council
Max Cooper (chair)Mark Lathrop (vice chair)
Hiroyuki Aburatani
Rudi Balling
Ewan Birney
Riccardo Dalla-Favera
Michel Georges
Ronald N. Germain
Yukiko Gotoh
David A. Hafler
Yutaka Kawakami
Juha KerePaul W. Kincade
Bernard MalissenJohn O'Shea
Fiona Powrie
Shimon Sakaguchi
Sarah Teichmann
Arthur Weiss

Division of Genomic Medicine
Laboratory for Transcriptome Technology: Piero Carninci

Laboratory for Genotyping Development: Yukihide Momozawa

Laboratory for Cellular Function Conversion Technology: Harukazu Suzuki Laboratory for Statistical and Translational Genetics: Chikashi Terao
Laboratory for Genome Information Analysis: Chung-Chau Hon

Laboratory for Pharmacogenomics: Taisei Mushiroda

Laboratory for Applied Computational Genomics: Michiel de Hoon

Laboratory for International Alliance on Genomic Research: Taisei Mushiroda

Laboratory for Single Cell Technologies: Piero Carninci

Laboratory for Bone and Joint Diseases: Shiro Ikegawa

Laboratory for Large-Scale Biomedical Data Technology: Takeya Kasukawa Laboratory for Genomics of Diabetes and Metabolism: Momoko Horikoshi
Laboratory for Advanced Genomics Circuit: Jay W. Shin

Laboratory for Cardiovascular Genomics and Informatics: Kaoru ItoLaboratory for Cellular Epigenomics: Akiko Minoda

Laboratory for Systems Genetics: Yukinori Okada

Laboratory for Comprehensive Genomic Analysis: Yasushi Okazaki

Laboratory for Functional Non-coding Genomics: Yuka Iwasaki

RIKEN-IFOM Joint Laboratory for Cancer Genomics: Yasuhiro Murakawa Laboratory for Retrotransposon Dynamics: Tomoichiro Miyoshi

Division of Human Immunology
Laboratory for Autoimmune Diseases: Kazuhiko Yamamoto

Laboratory for Immune Homeostasis: Taishin Akiyama

Laboratory for Human Immunogenetics: Kazuyoshi Ishigaki

Laboratory for Immune Crosstalk: Hilde Cheroutre

Laboratory for Cell Signaling: Takashi Saito

Laboratory for Inflammatory Regulation: Takashi Tanaka

Laboratory for Lymphocyte Differentiation: Tomohiro Kurosaki

Laboratory for Cytokine Regulation: Masato Kubo

Laboratory for Transcriptional Regulation: Ichiro Taniuchi

Laboratory for Immunological Memory: Shiki Takamura

Laboratory for Immune Cell Systems: Shigeo Koyasu

Infectious Diseases Research Unit: Haruhiko Koseki

Laboratory for Innate Immune Systems: Kazuyo Moro

Division of Disease Systems Biology
Laboratory for Developmental Genetics: Haruhiko Koseki

Laboratory for Integrated Cellular Systems: Katsuyuki Yugi

Laboratory for Intestinal Ecosystem: Hiroshi Ohno

Laboratory for Metabolomics: Makoto Arita

Laboratory for Integrative Genomics: Jun Seita

Laboratory for Microbiome Sciences: Hiroshi Ohno

Laboratory for Mucosal Immunity: Sidonia Fagarasan

Laboratory for Metabolic Networks: Toshimori Kitami

Laboratory for Gut Homeostasis: Kenya Honda

Laboratory for Epigenome Inheritance: Azusa Inoue

Laboratory for Skin Homeostasis: Masayuki Amagai

Drug Discovery Antibody Platform Unit: Takashi Saito

Laboratory for Tissue Dynamics: Takaharu Okada

Division of Cancer Immunology
Laboratory for Medical Science Mathematics: Tatsuhiko Tsunoda

Laboratory for Human Disease Models: Fumihiko Ishikawa

Laboratory for Cancer Genomics: Hidewaki Nakagawa

Laboratory for Cancer Invasion and Metastasis: Kohei Miyazono

Laboratory for Immunotherapy: Shin-ichiro Fujii

aAVC Drug Translational Unit: Shin-ichiro Fujii

RIKEN Hakubi Research Team
Genome Immunobiology RIKEN Hakubi Research Team: Nicholas Parrish

Young Chief Investigator Program
YCI Laboratory for Immunological Transcriptomics: Hideyuki Yoshida

I

Contents

Organization.............................................................................. I
Contents.....................................................................................II

Director’s Report.................................................................... IVPart 1
Research Highlights
Broadening the relevance of BRCA........................................2
Revealing the reality of somatic recombination....................3
Delving deep and wide into SLE.............................................4
The final piece of the artificial embryo puzzle......................5

Beneficial bacterium breaks down trypsin............................6
Predicting treatment response in esophageal cancer............7Award Winners 2022................................................................8

Part 2Lab Activities
Division of Genomic Medicine......................................10
Laboratory for Transcriptome Technology....................11
Laboratory for Cellular Function Conversion
Technology...................................................................12
Laboratory for Genome Information Analyses.............13
Laboratory for Applied Computational Genomics......14
Laboratory for Large-Scale Biomedical Data
Technology...................................................................15
Laboratory for Advanced Genomics Circuit.................16
Laboratory for Cellular Epigenomics.............................17
Laboratory for Comprehensive Genomic Analyses.....18
RIKEN-IFOM Joint Laboratory for Cancer
Genomics.....................................................................19
Laboratory for Genotyping Development.....................20
Laboratory for Statistical and Translational
Genetics........................................................................21
Laboratory for Pharmacogenomics................................22
Laboratory for Bone and Joint Diseases.........................23
Laboratory for Genomics of Diabetes andMetabolism..................................................................24
Laboratory for Cardiovascular Genomics andInformatics...................................................................25
Laboratory for Systems Genetics....................................26
Laboratory for Functional Non-coding Genomics.......27
Laboratory for Retrotransposon Dynamics...................28
Division of Human Immunology.................................29
Laboratory for Autoimmune Diseases...........................30
Laboratory for Cell Signaling..........................................31
Laboratory for Lymphocyte Differentiation..................32
Laboratory for Transcriptional Regulation....................33

II

Laboratory for Immune Cell Systems.............................34
Laboratory for Innate Immune Systems........................35
Laboratory for Immune Homeostasis............................36
Laboratory for Immune Crosstalk..................................37
Laboratory for Inflammatory Regulation......................38
Laboratory for Cytokine Regulation...............................39
Laboratory for Human Immunogenetics.......................40
Laboratory for Immunological Memory........................41
Infectious Diseases Research Unit..................................42
Division of Disease Systems Biology..........................43
Laboratory for Developmental Genetics........................44
Laboratory for Intestinal Ecosystem...............................45
Laboratory for Integrative Genomics.............................46
Laboratory for Mucosal Immunity.................................47
Laboratory for Gut Homeostasis.....................................48
Laboratory for Skin Homeostasis....................................49
Laboratory for Tissue Dynamics.....................................50
Laboratory for Metabolomics..........................................51
Laboratory for Microbiome Sciences.............................52
Laboratory for Integrated Cellular Systems...................53
Laboratory for Metabolic Networks...............................54
Laboratory for Epigenome Inheritance..........................55
Drug Discovery Antibody Platform Unit......................56
Division of Cancer Immunology...................................57
Laboratory for Medical Science Mathematics...............58
Laboratory for Cancer Genomics...................................59
Laboratory for Immunotherapy......................................60
Laboratory for Human Disease Models.........................61
Laboratory for Cancer Invasion and Metastasis...........62

Special Program for Young Leaders...........................63
Genome Immunobiology RIKEN Hakubi ResearchTeam.............................................................................64
YCI Laboratory for ImmunologicalTranscriptomics...........................................................65
IMS Research and Infrastructure Platforms
FACS...................................................................................66
Imaging and Microscopes................................................66
Genome Platform and related activities.........................67

Animal Facility..................................................................67
Metabolomics (Lipidomics).............................................68
Information Infrastructure..............................................68
Other Programs
IMS Bioethics Working Group........................................69
RIKEN International Program Associate (IPA)............70
RIKEN Junior Research Associate (JRA) Program......70
RIKEN Special Postdoctoral Researcher (SPDR)
Program........................................................................70

Part 3
Research Projects
COVID-19 projects in IMS..............................................72
Human Cell Atlas..............................................................73
Keio-RIKEN IMS HuMED..............................................73
FANTOM Project..............................................................74
Human genome analysis..................................................74
SEAPharm for the establishment of stratified
medicine in Asia..........................................................75
eQTL project: Integration of genetic information
into immune functions...............................................75

Identifying gut microbiota-associated biomarkers that
aggravate insulin resistance (IR) andinsulin sensitivity (IS).................................................76
Atopic dermatitis...............................................................76
iPS Project..........................................................................77
Humanized Mice...............................................................77
Cancer Immunology.........................................................78
Linkage to RIKEN Program for Drug Discovery andMedical Technology Platforms (DMP)....................78

Part 4
EventsRIKEN IMS-Stanford ISCBRM Joint Symposium..............80
The 5th Tsinghua-RIKEN Joint Workshop..........................80
Keio-IMS Joint Symposium...................................................81
RIKEN-McGill Symposiums.................................................81
RIKEN-KI/SciLifeLab & Student Exchange........................82

Adjunct Professorship Programs...........................................82
Yokohama Campus Open Day 2022.....................................83
IMS Social Implementation Seminar Series........................83
Guest Lectures 2022................................................................84

Part 5
Data and Statistics
IMS PI Seminar.......................................................................86
IMS Researcher Seminar 2022...............................................86
Publications 2022....................................................................87

Budget, Personnel and Patents...............................................97
Original Photos of the Cover and Front Pages....................98
Access to RIKEN Yokohama Campus..................................99

III

Director’s ReportCompared to the past several years, 2022 brought a
greater sense of normalcy back to research life at IMS.
I thank the staff and scientists at the centre for their vigilance as we continue to navigate the changing face of the
SARS-CoV-2 virus, and for their hard work in contributing
to crucial scientific discoveries that will benefit society for
years to come.
The opening of Japan’s borders and easing of travel
restrictions allowed many IMS researchers to resume international activities, including attend international meetingsin person. I was fortunate to take part in several joint meetings between IMS and our collaborators overseas, such as
the IMS-Karolinska Institute-SciLifeLab symposium in
Stockholm and the IMS-McGill joint meeting in Montreal.
While I, like most others, have enjoyed the convenience of
online meetings over the past few years, I cannot deny thatthey often left me feeling slightly dissatisfied. I had missed
the in-depth discussions that can arise spontaneously
within and outside the formal conference setting-crucial
bonding opportunities that I was overjoyed to engage inagain when we finally met in person. I truly believe thatsuch interactions help solidify the mutual relationship between our centres.
Prior to the formal IMS-Karolinska Institute-SciLifeLabsymposium, 12 young researchers from IMS and the University of Tokyo also participated in a 9-day exchange
program with SciLifeLab as part of an ongoing goal in ourpartnership to promote scientific exchange of young talent between Japan and Sweden. Each participant had theopportunity to experience research life in an assigned hostlaboratory and learn bioinformatics-related skills they
could take home with them to enhance their own projects
at IMS. I believe the program is an exceptional experiencefor young researchers and look forward to continuing theIVinitiative in the future.
The COVID-19 pandemic has put infectious disease
outbreaks at the forefront of research and government
agendas around the world. At IMS, we have expanded ourbiosafety level 3 laboratory capabilities to facilitate future
research on infectious disease. Thanks to the institute’s
leading expertise in human immunology research, IMS
has been selected to support the government’s initiative toboost Japan’s preparedness for new infectious disease outbreaks over the next five years. We are proud to contributeto the proposed plan to enhance vaccine development
across a variety of infectious diseases, which will be led
by The Strategic Center of Biomedical Advanced Vaccine
Research and Development for Preparedness and Response(SCARDA).
IMS scientists continued to break new ground by producing high impact studies on a variety of topics in 2022.
One example is the study by Yukihide Momozawa’s team,which showed that BRCA1/2 genes are altered in as manyas seven types of cancers-not just the four widely recognized breast, ovarian, prostate and pancreatic cancers.
These findings could lead to the development of early-risk
markers for patients with these diseases. Another noteworthy example is the ambitious large-scale and detailed analysis of the transcriptome of 27 immune cell types in patientswith systemic lupus erythematosus conducted by Kazuyoshi Ishigaki’s team in collaboration with the University ofTokyo. The study highlights the importance of examining
disease activity and provides publically available data that
could evoke novel research questions about SLE.
In 2023, IMS laboratories will take part in the second
IMS Advisory Council meeting of this seven-year midterm. All laboratories will be evaluated on their researchconcept and performance by a distinguished panel of scientists. Although these evaluations are often daunting, I am
confident that the panel will recognize each team’s achievements and IMS’s strong standing in Japanese research andcrucial contribution to the evolving needs of society.

Kazuhiko Yamamoto
Director
RIKEN Center for Integrative Medical Sciences

Part 1
Research
Highlights

Broadening the relevance of BRCA

Yukihide Momozawa

Figure: Expansion of cancer risk profile for BRCA1and BRCA2 pathogenic variants

A case-control study of 63,828 patients with 14 common
cancer types and 37,086 controls revealed that pathogenic variants in BRCA1 were associated with biliary tract
cancer, those in BRCA2 with esophageal cancer, and thosein BRCA1/2 with gastric cancer. These findings indicatethat genetic testing for BRCA1/2 could have broader clinical relevance than previously thought.

IMS researchers link three new cancers to BRCA
genes, prompting an update of screening guidelines
and treatment indications.
In 2013, Hollywood actress Angelina Jolie stunned theworld when she announced that she had “a faulty BRCA1gene” and had undergone preventive surgery to minimize
her risk of developing breast cancer. Her account led to asurge in genetic testing for mutations in BRCA1 and its cousin BRCA2, which in addition to breast and ovarian cancer
have since also been linked to prostate and pancreatic cancer.
As a geneticist, Yukihide Momozawa, Team Leader ofthe Laboratory for Genotyping Development at IMS, foundvalidation in Jolie’s story. “It shows that you can use genetics to escape disease,” he said.
However, he wondered whether the known variants
associated with BRCA genes were applicable to Japanesepeople. This is because rare genetic variants such as thosefound in BRCA genes are population-specific.
“Unfortunately, most data has come from European
populations,” Momozawa said. “We hypothesized that if we
examined Japanese data, we may identify Japanese-specificrare variants.”
To test this theory, Momozawa and his team collaborated with one of the largest disease-based biobanks in theworld, Biobank Japan, to conduct the biggest-of-its-kindstudy on BRCA genes. The researchers included controls
and cases with 14 cancer types whose DNA and clinicalinformation were available in Biobank Japan. Published in
JAMA Oncology, the study ultimately examined data from
100,914 individuals.
The team harnessed their experience with large-scale
analysis to perform a combination of “wet” and “dry”
Original paper:
Momozawa Y, Sasai R, Usui Y, Shiraishi K, Iwasaki Y, Taniyama Y,
Parsons MT, Mizukami K, Sekine Y, Hirata M, Kamatani Y, Endo M,
Inai C, Takata S, Ito H, Kohno T, Matsuda K, Nakamura S, Sugano K,

2

experiments to sequence and then analyse the abundanceof DNA. This led them to identify 315 unique pathogenic
variants in BRCA1 and 2 genes.
With help from epidemiologists Keitaro Matsuo of Aichi
Cancer Center and Amanda Spurdle of QIMR Berghofer
Medical Research Institute, the team then classified thevariants and linked them to breast, ovarian, prostate, andpancreatic cancer as well as three additional cancers. They
showed that pathogenic variants in BRCA1 were associatedwith biliary tract cancer, those in BRCA2 with esophageal
cancer, and those in BRCA1/2 with gastric cancer.
These findings have important implications for bothscreening and treatment. According to Momozawa, a
representative from the Guidelines for Diagnosis andTreatment of Hereditary Breast and Ovarian Cancer has
already informed him that they will be adding biliary tract,esophageal and gastric cancer to their upcoming edition ofrecommendations. Meanwhile, drugs known as PARP inhibitors currently used to treat the main cancers associatedwith BRCA could also be useful remedies for the newly
identified cancers, although this will need to be confirmed
in clinical trials.
The team also examined potential regional differencesin BRCA variants across Japan and, to their surprise, foundvariations across 7 areas. Momozawa notes that this finding
has implications for genetics research. “It suggests that it
is very important to collect case and control samples fromthe same region,” he said.
Going forward, Momozawa also wants to incorporate
environmental factors into their analyses. Including variables such as smoking habit and history of viral and bacterial infections, he believes, could reveal further unknown
genetic links to cancer.

Yoshida T, Nakagawa H, Matsuo K, Murakami Y, Spurdle AB, Kubo M.
Expansion of Cancer Risk Profile for BRCA1 and BRCA2 Pathogenic
Variants. JAMA Oncol 8, 871-878 (2022)

Revealing the reality of somatic recombination

Piero Carninci
Research Highlights

Figure: Detecting recombination – mutations
generated by the fusion of repeat elements – inhealth and disease

IMS researchers discover that healthy people harbour widespread recombinations – mutations formed
from the fusion of repeated DNA sequences – paving
the way to understanding the mechanisms that differentiate health from disease.

3

Data and Statistics

repeat elements generates somatic complexity in human genomes.
Cell 185, 3025-3040.e6 (2022)

EventsOriginal paper:
Pascarella G, Hon CC, Hashimoto K, Busch A, Luginbühl J, Parr C,
Yip WH, Abe K, Kratz A, Bonetti A, Agostini F, Severin J, Murayama
S, Suzuki Y, Gustincich S, Frith M, Carninci P*. Recombination of

Projects

In comic books and movies, mutations such as DNA
recombination are portrayed to confer superpowers, like
Mystique’s shape-shifting abilities, or used by mad scientists
to generate new species, as in the mutant dinosaurs in theJurassic Park saga. In reality, recombination of the DNA in
our genomes is typically linked to disease and, with a few exceptions, has long been considered an extremely rare event.
However, Giovanni Pascarella, a Senior Research Scientist in the Laboratory for Transcriptome Technology at
IMS, found himself challenging this dogma while studying
sequences of DNA that are present in multiple copies in eachcell. These so-called repeat elements are known to participate
in recombinations that can change the shape and structure of
the DNA, leading to afflictions like cancer. Yet, despite theirknown connection to disease, Pascarella was struck by thesheer number of repeat elements in the healthy genome.
“I thought, there are more than one million of these sequences in the genome of each cell,” he said. “Is it possiblethat this process of recombination is also happening innormal cells, and does not always result in cancer?”In their study published in Cell, Pascarella and Team
Leader Piero Carninci tackled this question by focusing ona specific type of DNA recombination event that involves
the fusion of two repeat elements called Alu and L1. The
IMS team collaborated with researchers at the University ofTokyo to develop a bioinformatics pipeline to detect these
events in cells and tissues.

They then ran samples from healthy donors through thepipeline. To their surprise, they discovered extraordinarily
high numbers of these recombination events-much morethan previously thought.
“This particular type of recombination event has never beenstudied on such a vast scale before,” Carninci noted. “Thesefindings show that the genome can actually tolerate a very highnumber of mutations without turning into anything bad.”
To better understand the role of these events in healthy
individuals, the team next compared brain and non-brain
samples. Just as unexpectedly, they found a different number and distribution of mutations in the different tissues.
Theorising that the mutations may have a developmental
origin, the team profiled human stem cells and the neurons
they were transformed into in culture. The neurons indeed
had different recombination profiles to the stem cells.
The researchers also studied the mutations in disease
by examining samples from patients with Parkinson’s andAlzheimer’s disease-two common ailments that have been
linked to DNA damage. They found both disease- andtissue-specific mutation profiles.
The team’s findings open the door to a myriad of questions, such as what is controlling these ubiquitous DNA recombinations, what are the consequences for the fitness of the
genome, and are the mutations are a cause or consequenceof disease? Pascarella plans to start whittling down this listby going back to simple, controlled studies to understand themechanisms that drive the recombination of repeat elements.
In the meantime, the team have published a technicalprotocol to allow other scientists to detect and analyse Alu
and L1 recombination events. “We hope that with this tool,
many more people will be able to look at recombinationeven in their own data,” Pascarella concluded.

Lab Activities

A novel bioinformatics pipeline was used to detect recombination events in brain and non-brain (liver and kidney)tissues from healthy individuals and different regionsof the brain (parietal, frontal and temporal cortex) insamples from patients with Parkinson’s and Alzheimer’s
disease.

Delving deep and wide into SLE
136 SLE cases
89 healthy controls (HC)

Kazuyoshi Ishigaki
27 immune
cell types

×Replication
BiologyRNA-seq

Figure: Examining almost all immune cell types
in a large-scale transcriptome study of systemic
lupus erythematosus (SLE)In 27 immune cell types from 136 SLE cases and 89
healthy controls (HC), RNA transcript profiles werecompared between HC and patients with inactive SLE
and between patients with inactive and active SLE. The
respective cell-type-specific disease-state and diseaseactivity signatures were then subjected to extensive
downstream analyses using both unsupervised andsupervised approaches. Created with BioRender.com(https://www.biorender.com/)

Disease-statesignature

Disease-activity
signature

vs.

vs.

(disease establishment) (disease exacerbation)

HC

Inactive
SLE

Inactive
SLE

PC2

Treatment

Supervised
approach
Expression

Unsupervised
approach

ActiveSLE

Organ involvement

Genetics

PC1

A large-scale transcriptome study of almost all
types of immune cells in the body highlights theimportance of examining disease activity to understand and treat systemic lupus erythematosus.
Lupus is a disease that has been around since antiquity,when physicians named it after the Latin word for “wolf ”
in reference to the wolf-bite-like lesions inflicted on patients’ skin. Since then, lupus has been classified as an
autoimmune disease and found to take several forms, themost common of which is systemic lupus erythematosus(SLE). Due to its heterogeneous effects-which range frommild to widespread inflammation and organ damage-SLE
is notoriously difficult to treat.
Studies aiming to understand the cause and to develop treatments for SLE typically examine whole blood samples frompatients. However, this approach could be masking importantcell-specific effects, says Kazuyoshi Ishigaki, Team Leader of theLaboratory for Human Immunogenetics at IMS, since blood
contains a plethora of immune cells, some of which may be
more prevalent in certain individuals than others.
Now, in a first-of-its-kind study published in Cell, Ishigaki’s team and their collaborators from the University ofTokyo have attempted to dissect the cell-specific effects of
SLE by analysing the transcriptomes of almost all types of
immune cells in the body. To do this, the team recruited
136 patients with SLE and 89 healthy volunteers from the
Immune Cell Gene Expression Atlas from the University ofTokyo (ImmuNexUT) cohort and undertook the enormous
task of purifying 27 immune cell types from each individual’s blood and sequencing their transcriptomes.
Next, the researchers compared the cell-specific RNA
profiles of healthy volunteers and SLE patients to deterOriginal paper:
Nakano M, Ota M, Takeshima Y, Iwasaki Y, Hatano H, Nagafuchi Y,
Itamiya T, Maeda J, Yoshida R, Yamada S, Nishiwaki A, Takahashi
H, Takahashi H, Akutsu Y, Kusuda T, Suetsugu H, Liu L, Kim K, Yin
X, Bang SY, Cui Y, Lee HS, Shoda H, Zhang X, Bae SC, Terao C, Ya-

4mine the disease-state signatures. Unconventionally, theyalso compared the profiles of patients with stable SLE andactive SLE to extract the disease-activity signatures.
“Almost all disease-oriented studies ask how cases differ
from healthy people,” Ishigaki noted. “But most of the time,
only patients, not healthy people, visit the hospital. So we
think the more important comparison in medical practiceis case versus case.”
The researchers did a series of in-depth downstream
analyses of both signatures, linking the cell-specific datawith biological processes such as cytokine and transcription factor pathways, clinical observations such as whichorgans are affected, and treatment outcomes. These datasets, which are now publically available, could help otherscientists identify untapped features of SLE biology for
future research and even novel drug targets, Ishigaki said.
Importantly, the team found key discrepancies when
they integrated their transcriptome findings with previously published results from genome-wide association
studies (GWAS). Specifically, while genetic variants foundto be associated with SLE in GWAS mostly overlapped withdisease-state signatures, they were largely distinct from
disease-activity signatures.
Given that GWAS typically compares patients withhealthy individuals, Ishigaki notes that these findings are
not necessarily surprising. However, he believes that theyhighlight a crucial limitation of current GWAS.
“We believe that the disease activity signature is very valuable in clinical settings. That it did not show good consistency with GWAS findings indicates that focusing only on genetic results might lead researchers to miss critical aspects ofbiology,” Ishigaki said, adding that designing GWAS arounddisease activity could lead to more clinically relevant results.

mamoto K, Okamura T, Ishigaki K, Fujio K. Distinct transcriptome
architectures underlying lupus establishment and exacerbation.
Cell 185, 3375-3389.e21. (2022)

The final piece of the artificial embryo puzzle

Haruhiko Koseki
Research Highlights

Figure: Primitive endoderm stem cells (PrESCs)
have been successfully derived for the first time

The mammalian blastocyst is made up of three distinct
cell types: the epiblast, which gives rise to the embryo(red); the trophoblast, which forms the placenta (green);
and the primitive endoderm, which develops into the yolksac (blue). Until now, only stem cells representing theepiblast (ESC) and trophoblast (TSC) had been generated.
The newly cultured PrESCs fully recapitulate the functionof the primitive endoderm.

5

Data and Statistics

opmental potential of primitive endoderm. Science 375, 574-578(2022)

EventsOriginal paper:
Ohinata Y*, Endo TA, Sugishita H, Watanabe T, Iizuka Y, Kawamoto
Y, Saraya A, Kumon M, Koseki Y, Kondo T, Ohara O, Koseki H*.
Establishment of mouse stem cells that can recapitulate the devel-

Projects

In the early 1980s, a world of possibilities opened up
for biologists when British scientists Martin Evans andMatthew Kaufman successfully isolated and cultured embryonic stem cells (ESCs)-cells that can transform into
any tissue in the body. One possibility was the potential togenerate artificial embryos, which scientists believe could
be a powerful platform for understanding the biologicalprocesses needed to create life.
“Usually, the real proof of our understanding comesfrom the relationship between expectation and results,”
said Haruhiro Koseki, Team Leader of the Laboratory for
Developmental Genetics at IMS. “If we can make artificial
embryos, we should have the minimal components to construct and study this complex system.”
However, ESCs are only one component needed to create life. An early developmental structure found in mammals called the blastocyst contains three types of precursor
cells: those that give rise to the embryo, those that form theplacenta, and those that develop into the yolk sac.
In addition to successfully growing ESCs from the first
type, scientists have also already cultured trophoblast stem
cells (TSCs), which form the placenta, from the second
type. Meanwhile, attempts to produce precursors of theyolk sac in culture, known as the primitive endoderm, haveso far fallen short.
To achieve the final piece of the puzzle in mice, Koseki
and his team set about determining the optimal conditions
needed to grow primitive endoderm cells and maintaintheir developmental capability in culture. In their study

published in Science, the researchers, including first author
Yasuhide Ohinata, exposed blastocysts to various culture
cocktails-painstakingly tweaking countless components,
such as compounds that perturb key developmental signalling pathways and small molecules, until they had the conditions just right to produce primitive endoderm stem cells(PrESCs).
They tested the functionality of their PrESCs by injecting them into blastocysts that had been treated to remove
their primitive endoderm cells. When transplanted into theuterus of pseudopregnant mice, blastocysts that harboured
PrESCs not only implanted into the uterine lining, but also
developed into normal offspring. Meanwhile, blastocysts
lacking a primitive endoderm could not implant.
To test their long-range goal of creating embryos exclusively from cultured stem cells, the team next createdan artificial blastocyst from ESCs, TSCs and PrESCs andinjected it into pseudopregnant mice. The artificial blastocyst again successfully implanted, although this time nooffspring were produced.
“Implantation did not happen with only ESC and TSC
aggregates,” Koseki noted. “Our findings suggest the importance of PrESCs and the primitive endoderm for the
implantation of embryos into the uterine wall,” he said,
adding that further understanding of the developmental
mechanisms of these cells could one day improve implantation-related infertility problems in humans.
However, such a feat is still a long way away given thatblastocyst development in mice differs substantially fromthat in humans. To take a step closer towards this clinical objective, the team are now attempting to generate theprecursor cell types in pigs, which share more comparable
developmental mechanisms to humans.

Lab Activities

For the first time, IMS researchers have successfully
cultured stem cells that give rise to the yolk sac, revealing their critical role in implantation.

Beneficial bacterium breaks down trypsin

Kenya Honda

Paraprevotella clara
Figure: The little-known bacterium Paraprevotella clara degrades trypsin, resulting in a range ofbeneficial health effects(Left) High levels of trypsin lead to the degradation of
immunoglobulin A (IgA), which can no longer protect the
body against pathogens. Trypsin also helps viruses invade
healthy cells.
(Right) In the presence of P. clara, trypsin levels decline.
This leads to higher levels of IgA and corresponding
protection against pathogens, and the inhibition of viralentry.

Degradation of IgA
TrypsinPromotion ofviral entry

Protection from
pathogen infection

Intestinal epithelium

A novel beneficial bacterium that degrades the digestive enzyme trypsin could be an effective medicine for preventing everything from viral infections
to irritable bowel syndrome.
There has been a recent explosion in research on thetrillions of microorganisms that inhabit our bodiesknown collectively as the microbiome. In fact, studies conducted over the last decade have linked the gut microbiome
to conditions ranging from inflammatory bowel syndrome
to Alzheimer’s disease. These findings point to a multitudeof critical roles for gut microbes, some of which are justnow being unearthed.
Kenya Honda, Team Leader of the Laboratory for Gut
Homeostasis at IMS, and his team are some of the researchers studying the inner workings of the gut microbialcommunity. In a recent collaboration, they probed its function using a sensitive proteomics pipeline developed byformer IMS Team Leader, Osamu Ohara-allowing them tocomprehensively analyse the proteins present in the faecesof conventional mice compared to germ-free mice, whichlack all microorganisms.
To their surprise, they found that germ-free mice had elevated levels of trypsin, a digestive enzyme that degrades proteins in the small intestine. “Until now, no one had considered that the microbiota might contribute to the regulation of
the digestive enzyme levels in the intestine,” Honda said.
Given that high trypsin levels in the large intestine are implicated in complications such as Crohn’s disease, ulcerative
colitis, and irritable bowel syndrome, Honda conjectured that
identifying the bacterial species that degrades trypsin could
lead to treatments for patients with a range of afflictions.
In their paper published in Nature, Honda and colOriginal paper:
Li Y, Watanabe E, Kawashima Y, Plichta DR, Wang Z, Ujike M, Ang QY,
Wu R, Furuichi M, Takeshita K, Yoshida K, Nishiyama K, Kearney SM,
Suda W, Hattori M, Sasajima S, Matsunaga T, Zhang X, Watanabe K,
Fujishiro J, Norman JM, Olle B, Matsuyama S, Namkoong H, Uwamino

6

Trypsin degradation

leagues tested their theory using a classical top-down approach. First, they attempted to identify trypsin-degrading
bacteria by culturing faecal samples from germ-free micethat had received a human faecal transplant, which expectedly lowered the rodent’s trypsin levels. The faeces yielded
35 bacterial species, which co-first author Eiichiro Watanabe tirelessly narrowed down to just a single little-known
strain called Paraprevotella clara.
With the first-known trypsin-degrading bacterium in
hand, co-first author Youxian Li next sought to identify its
trypsin-degrading machinery. Through a series of painstaking
experiments, he demonstrated that P. clara uses a surface protein called PROKKA_00502 to bind and break down trypsin.
Finally, the team tested the clinical relevance of theirfindings in several ways. By disrupting PROKKA_0050-mediated trypsin degradation in mice, they unexpectedly foundthat it also reduced levels of the critical defence molecule
immunoglobulin A (IgA). “This means that P. clara could be
useful for maintaining overall health,” Honda said.
The team additionally tapped into knowledge thattrypsin-like enzymes help a variety of viruses invade
healthy cells. Experiments in mice infected with a lethal
dose of a mouse version of coronavirus showed that P. clara
improved survival. The bacterium’s trypsin-degrading machinery likewise proved beneficial for human patients with
COVID-19: those harbouring the human equivalent of
PROKKA_00502 presented with milder bouts of diarrhoea.
The team are already harnessing the clear therapeuticpotential of P. clara. Having patented their findings, they
are now working with a pharmaceutical company to develop a freeze-dried version of the bacterial strain, which they
hope to test on patients with inflammatory and irritablebowel disease in the future.

Y, Ishii M, Fukunaga K, Hasegawa N, Ohara O, Xavier RJ, Atarashi K,
Honda K. Identification of trypsin-degrading commensals in thelarge intestine. Nature 609, 582-589 (2022)

Predicting treatment response in esophageal cancer
Hidewaki Nakagawa

Biopsy specimens ofEsophageal Squamous Cell Carcinoma (ESCC)
Tumor Whole genome & RNAseq

Biopsy specimens were taken from 141 patients withesophageal squamous cell carcinoma (ESCC) prior totreatment with neoadjuvant chemotherapy and subjected
to whole-genome and RNA sequencing. Through analysisof the relationship between tumour gene expression
and response to chemotherapy, copy-number variations(CNVs) and neutrophils were among the main factors
found to be associated with chemotherapy response. Incorporating these factors into a machine learning model
enabled high accuracy prediction of patients who would
respond well (responder) and poorly (non-responder) to
chemotherapy.

CNVs
Immune signatures
Neutrophils
Smoking
Neoadjuvant
chemotherapy

Random forest

Machine learning
AUC=0.8

Non-responder

7

Data and Statistics

adjuvant chemotherapy response in esophageal squamous cell
carcinoma. Cell Rep Med 3, 100705 (2022)

Eventswhole-genome and RNA sequencing analyses of biopsy
specimens from 141 ESCC patients from Kindai University
Hospital before chemotherapy treatment. They then analysed the relationship between tumour gene expression andresponse to chemotherapy.
By classifying patients based the estimated abundanceof four immune cell types: CD8+ T, CD4+ T, B cells andneutrophils, the team found that NAC response was lower
in those with high levels of neutrophils. “This finding was
surprising as few studies have reported a relationship between neutrophils and chemotherapy response,” Nakagawa
said, adding that they plan to further investigate the role ofneutrophils in cancer in the future.
The researchers also examined copy number signatures, which their collaborators at the Cancer Research UK
Cambridge Institute have linked to chemotherapy responsein ovarian cancer. As Nakagawa explains it, the numberof copies of a gene is often altered in cancer, and the “signature” provides an overall profile of these copy-number
variations. Using an analysis method developed by the UKgroup, the team demonstrated that copy number signatures
were likewise related to NAC response in ESCC patients.
To use these factors to predict response, the team next
took the advice and lead of Sasagawa to incorporate thefactors into a machine learning model. By testing themodel on a small number of newly collected samples, theteam confirmed that they could predict patients’ chemotherapy response with high accuracy.
Sasagawa and Nakagawa believe that this model andothers like it will increasingly be used to stratify patientsas part of the precision medicine boom around the world.
The team is looking to develop prediction models for othertypes of cancers going forward.

Projects

In the 19th century, esophageal cancer was considered anaggressive and incurable disease, leaving clinicians to focus
mainly on relieving patients’ pain and swallowing difficulties.
Although it remains one of the most aggressive cancers eventoday, esophageal cancer is now mostly treatable thanks to thedevelopment of chemotherapy and surgical techniques.
The course of treatment typically involves chemotherapy first, then surgery. However, not all patients respond tochemotherapy. This holds true even for neoadjuvant chemotherapy (NAC), the gold standard for the dominant typeof esophageal cancer found in Japan and other parts of East
Asia called esophageal squamous cell carcinoma (ESCC).
“While some patients respond well to chemotherapy,
and some even have their tumours completely eliminated,others do not respond at all,” noted Hidewaki Nakagawa,
Team Leader of the Laboratory for Cancer Genomics at
IMS, who witnessed this reality first-hand as a gastrointestinal surgeon in the late 90s.
Nakagawa and his clinician colleagues wondered ifthey could somehow discriminate responders from nonresponders ahead of time. This would allow them to allocate those in the former group to receive chemotherapy
only, and those in the latter group to receive surgery firstsaving time and money.
To develop a way to predict response, young researcher
Shota Sasagawa in Nakagawa’s team first sought to identify the contributing genetic and immunological factors.
In their paper published in Cell Reports Medicine, which
is first-authored by Sasagawa, the researchers performed

Responder

Lab Activities

tumor
regression

A new machine learning model could help clinicians
determine whether esophageal cancer patients arelikely to respond to chemotherapy or if they would
benefit from receiving surgery first.

Original paper:
Sasagawa S, Kato H, Nagaoka K, Sun C, Imano M, Sato T, Johnson
TA, Fujita M, Maejima K, Okawa Y, Kakimi K, Yasuda T, Nakagawa
H. Immuno-genomic profiling of biopsy specimens predicts neo-

Research Highlights

Figure: Predicting chemotherapy response withmachine learningAward Winners 2022
Name of the awardee

Name of the award

Date of theannouncement

Hiroshi Ohno,
Team Leader, Laboratory for Intestinal Ecosystem

Uehara Award

Dec 2022

Azusa Inoue,
Team Leader, Laboratory for Epigenome Inheritance

The Commendation for Science and Technology by the Minister of Education,
Culture, Sports, Science and Technology, The Young Scientists’ PrizeApr 2022

Hiroshi Ohno,
Team Leader, Laboratory for Intestinal Ecosystem

Takamine Memorial Daiichi Sankyo Award

Jul 2022

Yukinori Okada,Team Leader, Laboratory for Systems Genetics

Osaka Science Prize

Nov 2022

Kaoru Ito,
Team Leader, Laboratory for Cardiovascular Genomics and Informatics

Circulation journal. Best reviewers award for 2021

Mar 2022

Yukinori Okada,Team Leader, Laboratory for Systems Genetics

Academic Awards, the Japanese Society of Human Genetics

Dec 2022

Momoko Horikoshi,
Team Leader, Laboratory for Genomics of Diabetes and Metabolism

Female Scientist Award, The 66th Annual Meeting of Japan Diabetes Society

May 2023

Shiro Ikegawa,
Team Leader, Laboratory for Bone and Joint Diseases

Russell A. Hibbs Basic / Translational Award, The 57th Annual Meeting of
Scoliosis Research Society

Sep 2022

Masahiro Nakano,
Postdoctoral Reseacher, Laboratory for Autoimmune Diseases

The European Alliance of Associations for Rheumatology (EULAR) 2022 Best
abstract award (Basic Science)

May 2022

Syunya Hatai,
Student Trainee Laboratory for Innate Immune Systems

The best poster award, The 2nd conference Food, microbiota and immunity

Jun 2022

Syunya Hatai,
Student Trainee Laboratory for Innate Immune Systems

Encouragement Award, The 50th Japanese Society for Mucosal Immunology

Jun 2022

Kiyokazu Kakugawa,Reseacher, Laboratory for Immune Crosstalk

Melvin Cohn Award of the La Jolla Immunology, Runner up

Oct 2022

Shota Sasagwa,
Researcher, Laboratory for Cancer Genomics

Best Young Researcher Poster Award, the 81st Annual meeting of the JapaneseCancer Association (JCA)

Sep 2022

Takashi Kanaya,
Deputy Team Leader, Laboratory for Intestinal Ecosystem

Tadamitsu Kishimoto Internationa Travel Award

Apr 2022

Tadashi Takeuchi,
Postdoctoral Researcher, Laboratory for Intestinal Ecosystem

ICMI2022 Travel Award, Japanese Society for Mucosal Immunology

Jul 2022

Tadashi Takeuchi,
Postdoctoral Researcher, Laboratory for Intestinal Ecosystem

Young Researchers Award, Japanese Society for Mucosal Immunology

Jul 2022

Yuuri Yasuoka,
Researcher, Laboratory for Comprehensive Genomic Analysis

The Young Scientist Award of the Zoological Society of JapanSep 2022

Kokoro Ozaki,
Deputy team leader, Laboratory for Comprehensive Genomic Analysis

The 14th CBIR Young scientist Inspire Symposium, The best presentation award,
2022

Feb 2022

Keiko Hikino,
Postdoctoral researcher, Laboratory for Pharmacogenomics

The American Society of Human Genetics 2022 Annual Meeting, Reviewers’
Choice Abstract Award

Oct 2022

Keiko Hikino,
Postdoctoral researcher, Laboratory for Pharmacogenomics

The 67th Annual Meeting of the Japan Society of Human Genetics, ASHG 2022
Annual Meeting Travel Award

Dec 2022

Kazuo Miyazawa,Researcher, Laboratory for Cardiovascular Genomics and Informatics

The 70th Annual Scientific Session of the Japanese College of Cardiology, The
Young Investigator Award

Sep 2022

Yoshihiko Tomofuji,
Visisting student, Laboratory for Systems Genetics

Japan Society of Promotion of Science Ikushi Priz

Jan 2023

Kyuto Sonehara,
Visisting researcger, Laboratory for Systems Genetics

Best presentation award, the 67th Annual Meeting of the Japanese Society of
Human Genetics

Dec 2022

Tatsuhiko Naito,
Visisting researcger, Laboratory for Systems Genetics

The University of Tokyo President’s Award for Students

Mar 2022

8

Part 2Lab Activities

Division of Genomic Medicine

Division of Genomic Medicine will develop new methods for genomebased drug discovery and produce supporting evidence for the realization of genomic medicine.

Laboratory for

Research Highlights

Transcriptome
Technology
Team Leader: Piero Carninci

Figure: Experimental approach for the annotation of somatic recombination of Alu and L1

Schematics of the experimental setup.

Carninci P, “Long non-coding RNAs and genomic regulation” The 10th Keio-Stanford Webinar: Functional
Genomics (USA/Online) September 2022
Carninci P. “Transcriptional regulation revealed by highthroughput genomics technologies: towards nucleic
acids medicine” Seminar at Tor Vergata University ofRome (Rome, Italy) June 2022
Carninci P, “Long non-coding RNAs from interactome
to function” SIBBM 2022 Frontiers in Molecular Biology(Rome, Italy) June 2022
Carninci P, “Biological regulation by non-coding RNAs
and non-coding genome” TRR 267 Webinar Series (Munich, Germany) June 2022

RNA Biology
We study the structure-function relationship of lncRNA using the SINEUPs,
antisense lncRNA that enhances translation of targeted proteins. We have madesubstantial progress by (1) producing the first full NMR structure of a functional SINE-derived RNA, (2) part of the protein interactome for the functionof SINEUPs (PTBP1 and HNRNPK) and (3) RNA modifications needed, suchas pseudouridine.
Aging
We showed that the genome is recombined in somatic human tissues in correspondence to SINE and LINE elements, with cell- and aging-specific patterns,
particularly in brains from old donors.
11

Data and Statistics

Invited presentations
Carninci P. “Conventional and unconventional capped
transcripts detected by long reads.” The Banbury Centermeetings (Cold Spring Harbor Laboratory), (New York,
USA) October 2022

FANTOM
The FANTOM6 Project has published a functional screening based on perturbation of the function of RNAs and imaging, identifying function for about~30% of analyzed lncRNAs. Moving into the FANTOM6 phase II, to broadly
decipher function based on the RNA interactome, we are broadly analyzing a
set of ~15 biological samples including iPS cells differentiated into neurons andactivated monocytes.
We produced and analyzed multiomics data to assign functions to regulatory RNAs, with a focus on identifying RNAs that regulate chromatin activity. We
give emphasis to RNA-chromatin interactomes using the RADICL-seq technology, identifying classes of chromatin interacting RNAs and inferring their functions.

EventsPascarella G, Hon CC, Hashimoto K, Busch A, Luginbühl
J, Parr C, Yip WH, Abe K, Kratz A, Bonetti A, Agostini F,
Severin J, Murayama S, Suzuki Y, Gustincich S, Frith M,
Carninci P*. Recombination of repeat elements generates somatic complexity in human genomes. Cell 185,3025-3040.e6 (2022)

Technologies for detection and analysis of regulatory
regions
We focus on the identification of genome regulatory elements that control
transcription, the transcribed functional RNAs and their biological functions.
- We optimized the CAGE technology reducing the amount of required RNA
for 96 well assays, all compatible with new sequencer models (Illumina Nextseq
and Novaseq). CAGE allows the detection of transcription of all capped RNAsand mapping promoters and enhancers that specifically regulate transcription.
We’re involved in a single-cell CAGE-like protocol, developing a reliable package of protocol plus computational tools.
- A comprehensive catalog of transcripts still lacks a model for a large number of lncRNAs and unconventional transcripts, including enhancer RNA, promoters and termination-associated RNAs, etc. We’ve adapted the cap-trapper
protocol for full-length RNA sequencing of polyA+ and – RNAs using Oxford
Nanopore technology.

Projects

de Hoon M, Bonetti A, Plessy C, Ando Y, Hon CC, Ishizu
Y, Itoh M, Kato S, Lin D, Maekawa S, Murata M, Nishiyori
H, Shin JW, Stolte J, Suzuki AM, Tagami M, Takahashi H,
Thongjuea S, Forrest ARR, Hayashizaki Y, Kere J, Carninci
P. Deep sequencing of short capped RNAs reveals novel
families of noncoding RNAs. Genome Res 32, 1727-35(2022)Lab Activities

Recent Major Publications
Robbe P, Ridout KE, Vavoulis DV, Dréau H, Kinnersley
B, Denny N, Chubb D, Appleby N, Cutts A, Cornish AJ,
Lopez-Pascua L, Clifford R, Burns A, Stamatopoulos
B, Cabes M, Alsolami R, Antoniou P, Oates M, Cavalieri
D; Genomics England Research Consortium; CLL pilot
consortium; Gibson J, Prabhu AV, Schwessinger R, Jennings D, James T, Maheswari U, Duran-Ferrer M, Carninci
P, Knight SJL, Månsson R, Hughes J, Davies J, Ross M,
Bentley D, Strefford JC, Devereux S, Pettitt AR, Hillmen
P, Caulfield MJ, Houlston RS, Martín-Subero JI, Schuh
A. Whole-genome sequencing of chronic lymphocytic
leukemia identifies subgroups with distinct biologicaland clinical features. Nat Genet 54, 1675-1689 (2022)

Laboratory for

Cellular Function
Conversion Technology
Team Leader: Harukazu Suzuki

Figure 6
Figure: Gene-expression analysis of the identified TFs with DNA-demethylation-promoting
activity

Gene-expression level of the 28 identified TFs in 23 cells
or tissues was subjected to cluster analysis and colorcoded.

Recent Major Publications
Suzuki T, Furuhata E, Maeda S, Kishima M, Miyajima Y,
Tanaka Y, Lim J, Nishimura H, Nakanishi Y, Shojima A,
Suzuki H. GATA6 is predicted to regulate DNA methylation in an in vitro model of human hepatocyte differentiation. Commun Biol 5, 414 (2022)

Miyajima Y, Noguchi S, Tanaka Y, Li JR, Nishimura H,
Kishima M, Lim J, Furuhata E, Suzuki T, Kasukawa T,
Suzuki H. Prediction of transcription factors associatedwith DNA demethylation during human cellular development. Chromosome Res 30, 109-121 (2022)
Yip CW, Hon CC, Yasuzawa K, Sivaraman DM, Ramilowski
JA, Shibayama Y, Agrawal S, Prabhu AV, Parr C, SeverinJ, Lan YJ, Dostie J, Petri A, Nishiyori-Sueki H, Tagami M,
Itoh M, López-Redondo F, Kouno T, Chang JC, Luginbühl
J, Kato M, Murata M, Yip WH, Shu X, Abugessaisa I,
Hasegawa A, Suzuki H, Kauppinen S, Yagi K, Okazaki Y,
Kasukawa T, de Hoon M, Carninci P, Shin JW. Antisenseoligonucleotide-mediated perturbation of long noncoding RNA reveals functional features in stem cells andacross cell types. Cell Rep 41, 111893 (2022)
Invited presentations
Qin XY. “Chemoprevention by vitamin A and its derivatives” 22nd IUNS-International Congress of Nutrition,
December 2022

12

DNA methylation at gene regulatory regions plays an important role indownstream gene expression. Interestingly, a subgroup of transcription
factors (TFs) can promote DNA demethylation at their own binding sites. We
have computationally predicted approximately 400 TFs that are likely associatedwith DNA demethylation. Validation of a subset of these candidate TFs revealed
that a large number of various TF families are associated with cell-type-specific
DNA demethylation during human cellular development. We also exploredthe precise mechanisms of TF-mediated DNA demethylation during the differentiation of iPS cells into hepatocytes. We found that GATA6 induces DNA
demethylation together with chromatin activation in a binding-site-specificmanner during endoderm differentiation, uncovering an epigenetic role fortranscription factors in early liver development. We are also focusing on application of knowledge about TF-mediated DNA demethylation in medical research.
We established model cells for familial platelet disorder with associated myeloid
malignancy (FPD). We found that ETS family TF binding motifs are enriched at
the hyper-methylated regions. The ETS family TF FLI1 was significantly downregulated in the FPD models and its knocked-down showed inefficient megakaryocyte differentiation. Mutations in Ten-Eleven Translocation-2 (TET2), an
enzyme involved in TF-mediated DNA demethylation, have been reported inhuman myeloid malignancies. Using single-cell RNA sequencing, we analyzed
progenitors isolated from hematopoietic cell-specific Tet2-deficient mice andidentified a novel group of progenitors that could be leukemic progenitors. In
addition, we have applied omics technologies to drug-mediated neuronal reprogramming from dedifferentiated fat cells, epithelial-to-mesenchymal transition(EMT) in cellular function modulation, ovarian follicles generated from pluripotent stem cells, in vitro cultured testis, and Mycobacterium tuberculosis infected
macrophages. We will also apply these technologies to studies of the tumor
microenvironment of hepatic tumorigenesis and the molecular mechanism ofintestinal regeneration.

Laboratory for

Research Highlights

Genome Information
Analyses
Team Leader: Chung-Chau Hon

Figure: Enrichment of disease heritability atmetacell resolution

Pascarella G, Hon CC, Hashimoto K, Busch A, Luginbühl
J, Parr C, Hin Yip W, Abe K, Kratz A, Bonetti A, Agostini F,
Severin J, Murayama S, Suzuki Y, Gustincich S, Frith M,
Carninci P. Recombination of repeat elements generates
somatic complexity in human genomes. Cell 185, 30253040 (2022)

Invited presentations
Hon CC. “An atlas of transcribed cis-regulatory elements
in human single cells” The 67th Annual Meeting of theJapan Society of Human Genetics (Yokohama, Japan)
December 2022

Hon CC. “An atlas of transcribed cis-regulatory elements
in human single cells” Graduate course “Introduction to
Advanced Medical Research”, Yokohama City University(Yokohama, Japan) October 2022
Hon CC. “An atlas of transcribed cis-regulatory elements
in human single cells” Department Seminar of HERMS,
Karolinska Institute (Stockholm, Sweden) October 2022
Hon CC. “An atlas of transcribed cis-regulatory elements
in human single cells” Department Seminar of IMBS,
The University of Hong Kong (Hong Kong, China) August
2022

13

Data and Statistics

Hon CC. “An atlas of transcribed cis-regulatory elements
in human single cells” Human Cell Atlas Asia Meeting(Bangkok, Thailand) November 2022

egulation of gene expression is tightly linked to pathogenesis and predisposition to complex diseases. Our team is dedicated to studying theroles of the non-coding genome in gene regulation within disease contexts. To
achieve this, we utilize three approaches: 1) performing functional perturbations of non-coding loci, 2) conducting large-scale profiling of regulatory element activities, and 3) using deep learning to decipher the sequence grammarof gene expression. Our work on functional perturbations of non-coding lociinvolves a collaboration with Takeda Pharma and focuses on Parkinson’s disease
as an example. Specifically, we performed a CRISPRi screening of non-coding
elements in neurons survival upon oxidative stress and identified the noncoding elements at Parkinson’s disease risk loci that potentially regulate genes
involved in autophagy, apoptosis, and stress responses. In addition, our teamdeveloped computational methods to detect authentic transcribed cis-regulatory elements (tCREs) at single-cell resolution and generated a single-cell atlasof tCREs across human tissues. We have devised a method that integrates thesetCRE data with genome-wide association data, enabling us to evaluate the relevance of cell types, transcription factors, and regulatory elements to complex
diseases (Figure). Currently, we are applying these methods to several population scale cohorts, including PBMCs from Asian populations, induced motor
neurons from ALS patients, and colon biopsies from Ulcerative Colitis patients.
Finally, we aim to integrate these transcriptomic data using deep learning models to derive predictive models of gene expression. These predictive models will
enable us to perform in silico mutagenesis and assess the effects of non-coding
elements on gene expression. With the use of these in silico mutagenesis data,
we have developed a reliable method to predict the target genes of non-coding
elements in a cell-type-specific manner. These methods will enable us to annotate the functional contexts of non-coding elements in a genome-wide andcell-type-specific manner for understanding their roles in gene regulation anddiseases.

EventsTanemoto S, Sujino T*, Miyamoto K, Moody J, Yoshimatsu Y, Ando Y, Koya I, Harada Y, Tojo A, Ono K, Hayashi
Y, Takabayashi K, Okabayashi K, Teratani T, Mikami Y,
Nakamoto N, Hosoe N, Ogata H, Hon CC*, Shin J, Kanai
T*. Single-cell transcriptomics of human gut T cells
identifies cytotoxic CD4+CD8A+ T cells related to mouse
CD4 cytotoxic T cells. Front Immunol 13, 977117 (2022)

R

Projects

Recent Major Publications
Moody J, Kouno T, Chang JC, Ando Y, Carninci P, Shin
JW, Hon CC*. SCAFE: a software suite for analysis oftranscribed cis-regulatory elements in single cells. Bioinformatics 38, 5126-5128 (2022)

Lab Activities

We have complied a tCRE atlas comprising >500,000
cells across human tissues. We collapsed this tCRE atlas
into 3,350 metacells and devised a novel method, basedon tCRE module activities, to estimate the enrichmentof disease heritability at each metacell and complieda cell-disease atlas for multiple complex diseases andtraits.

Laboratory for

Applied Computational
Genomics
Team Leader: Michiel de Hoon

Figure: Labeling of specific transcripts for visualization by electron microscopy

Noncoding RNA XIST was labeled with a transcriptspecific primary probe, a biotinylated secondary probecarrying a green fluorophore, a tertiary probe consistingof an anti-biotin antibody with a conjugated nanogold
bead for observation in EM, and a quaternary probe
consisting of an antibody against the tertiary probecarrying a red fluorophore. B. Overlapping signals of thesecondary and quaternary probe visible by light microscopy confirm successful labeling of XIST by the tertiaryprobe.

Recent Major Publications
Yip C, Hon C, Yasuzawa K, Sivaraman DM, Ramilowski
JA, Shibayama Y, Agrawal S, Prabhu AV, Parr C, Severin J,
Lan Y, Dostie J, Petri A, Nishiyori-Sueki H, Tagami M, Itoh
M, López-Redondo F, Kouno T, Chang J, Luginbühl J, Kato
M, Murata M, Yip W, Shu X, Abugessaisa I, Hasegawa A,
Suzuki H, Kauppinen S, Yagi K, Okazaki Y, Kasukawa T, De
Hoon M, Carninci P, Shin JW. Antisense oligonucleotidemediated perturbation of long non-coding RNA reveals
functional features in stem cells and across cell types.
Cell Rep 41, 111893 (2022)

De Hoon M, Bonetti A, Plessy C, Ando Y, Hon C, Ishizu Y,
Itoh M, Kato S, Lin D, Maekawa S, Murata M, Nishiyori
H, Shin JW, Stolte J, Suzuki A, Tagami M, Takahashi H,
Thongjuea S, Forrest AR, Hayashizaki Y, Kere J, Carninci
P. Deep sequencing of short capped RNAs reveals novel
families of noncoding RNAs. Genome Res 32, 17271735 (2022)
Hashimoto M, Saito Y, Nakagawa R, Ogahara I, Takagi
S, Takata S, Amitani H, Endo M, Yuki H, Ramilowski JA,
Severin J, Manabe R-I, Watanabe T, Ozaki K, Kaneko A,
Kajita H, Fujiki S, Sato K, Honma T, Uchida N, Fukami T,
Okazaki Y, Ohara O, Shultz LD, Yamada M, Taniguchi S,
Vyas P, De Hoon M, Momozawa Y, Ishikawa F. Combined
inhibition of XIAP and BCL2 drives maximal therapeutic
efficacy in genetically diverse aggressive acute myeloid
leukemia. Nat Cancer 2, 340-356 (2021)
Invited presentations
De Hoon M. “Genomics and transcriptomics at the RIKEN
Center for Integrative Medical Sciences” European Union,
European Commission, EURAXESS European Researcher
Days webinar (Online) December 2021

14

T

he Laboratory of Applied Computational Genomics uses bioinformatics methods to understand the molecular basis of cellular functioning inhuman health and disease. We are particularly interested in discovering andfunctionally classifying noncoding RNAs by transcriptome and chromatin conformation sequencing data analysis. In FANTOM6, we annotated the functionof >10,000 long noncoding RNAs based on the cellular response upon theirknockdown, as well as on their physical association with protein-coding genes
in chromatin conformation data. The interactive web portal ZENBU-Reports
for the visualization, analysis and dissemination of genome-scale bioinformatics analysis results was created by our lab for FANTOM6 and is also being usedby other research groups.
In close collaboration with the IMS Laboratory for Human Disease Models,
we apply our basic genomics expertise to personalized medicine to understandthe regulatory factors involve in acute myeloid leukemia (AML). We analyze theglobal properties of gene regulatory networks, noncoding RNAs, chromosomal
rearrangements, and chromatin conformation in AML patients. In collaboration with multiple IMS laboratories, we study the response of human airway
epithelial cells after infection by different strains of SARS-CoV-2 or influenza
virus, revealing differential gene expression and promoter usage, and promoter
switching.
Complementary to our bioinformatics research, our laboratory develops
protocols for electron microscope (EM) imaging of chromatin and specifictranscripts in the cell nucleus. Our aim is to open a new field of 3D genomics
by integrating EM imaging with sequencing data as an enabling technology todiscover the biophysical basis of gene regulation.

Laboratory for

Research Highlights

Large-Scale Biomedical
Data Technology
Team Leader: Takeya Kasukawa

Figure: refTSS web interface (renewed)(Left) Home page of the refTSS web interface. (Right)
Detail page of a TSS.

Lab Activities

Bono H, Sakamoto T, Kasukawa T, Tabunoki H. Systematic Functional Annotation Workflow for Insects. Insects
13, 586 (2022)
Abugessaisa I, Hasegawa A, Noguchi S, Cardon M,
Watanabe K, Takahashi M, Suzuki H, Katayama S, KereJ, Kasukawa T*. SkewC: Identifying cells with skewed
gene body coverage in single-cell RNA sequencing data.
iScience 25, 103777 (2022)

Kasukawa T. “Construction of an integrative data platform for transcriptional regulations” Togo Symposium(Online) October 2022
Kasukawa T. “Development of cis-regulatory element
database for data platform of transcriptional regulations” BioPackathon 2022 #9 (Online) September 2022
Morioka MS. “Development of the novel transcription
start site information database (refTSS4.0) and its
utilization tools for medical research applications" 9th
RIKEN-Genome Editing Joint Seminar (Hiroshima, Japan) June 2022

15

Data and Statistics

Abugessaisa I. “MycEXomics: Development of fieldfriendly POC diagnostic test for the four most common
causative agents of mycetoma” The Mycetoma Update
Seminar 2022 (Khartoum, Sudan) November 2022

ecause of rapid improvements in technologies to measure biomedical
phenomena, including sequencing technologies, many types of transcriptomic, genomic and epigenomic data have been generated and made publicly
available. Such data resources are potentially useful for the elucidation of biological systems and for the development of medical tools by performing largescale integrative analyses. Our mission is promoting such data-driven studies
in the biomedical field and developing component technologies to efficiently
reuse large-scale biomedical data by employing data engineering technologies.
Towards this goal, we now have several ongoing research projects. First, weare developing a database system to support the reuse of published single-cellomics data, especially single-cell RNA-seq data, by the curation and reprocessing of metadata, quality assessment and development of a web interface(SCPortalen, https://single-cell.riken.jp/). We have also developed a new QC
method (SkewC) to evaluate whether cells in the single-cell RNA-seq data canbe used for the downstream analysis and biological interpretation. Next, weare constructing a reference dataset of human and mouse transcription startsites that will enable investigators to integrate various information and datasets
related to transcriptional regulation (https://reftss.riken.jp/). From FY2022, westarted the development of a new database (fanta.bio) of cis-regulatory elements
in several mammalian genomes and the construction of a new integrated data
platform for transcriptional regulation, named INTRARED (https://www.intrared.
org/).
Along with the above core research projects, we are working on data coordination for several collaborative large-scale data production projects being donein RIKEN IMS. In addition to these research projects, we are also working toprovide and support the information infrastructure for several IMS laboratories. In practice, we have been managing high-performance computation servers and storage platforms for researchers in these laboratories, taking care of thecomputer environments for researchers and support staff and developing andmanaging web applications for support staff in IMS.

EventsInvited presentations
Kasukawa T, Kawaji H, Masuya H. “Construction of agenome-wide cis-regulatory element data resource forunderstanding the transcriptional regulation” The 45th
Annual Meeting of the Molecular Biology Society ofJapan (MBSJ2022) (Chiba, Japan) November 2022

B

Projects

Recent Major Publications
Yip CW, Hon CC, Yasuzawa K, Sivaraman DM, Ramilowski
JA, Shibayama Y, Agrawal S, Prabhu AV, Parr C, SeverinJ, Lan YJ, Dostie J, Petri A, Nishiyori-Sueki H, Tagami M,
Itoh M, López-Redondo F, Kouno T, Chang JC, Luginbühl
J, Kato M, Murata M, Yip WH, Shu X, Abugessaisa I,
Hasegawa A, Suzuki H, Kauppinen S, Yagi K, Okazaki Y,
Kasukawa T, de Hoon M, Carninci P, Shin JW. Antisenseoligonucleotide-mediated perturbation of long noncoding RNA reveals functional features in stem cells andacross cell types. Cell Rep 41, 111893 (2022)

Laboratory for

Advanced Genomics
Circuit
Team Leader: Jay W. Shin
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10

Single Cell Medical
Network JapanNS

23 projects

Figure:A) Single cell 5’ RNA-seq reveals promoter and enhancer regulatory elements in the human genome. Using this technology, Single Cell Medical Network (SCMN) consortium
was created in Japan to profile over 400,000 single cells across 23 projects – revealing
a comprehensive atlas of regulatory elements in the human genome. B) To functionally
Recent Major Publications
Yip CW, Hon CC, Yasuzawa K, Sivaraman DM, Ramilowski JA,
Shibayama Y, Agrawal S, Prabhu AV, Parr C, Severin J, Lan YJ,
Dostie J, Petri A, Nishiyori-Sueki H, Tagami M, Itoh M, LópezRedondo F, Kouno T, Chang JC, Luginbühl J, Kato M, Murata M,
Yip WH, Shu X, Abugessaisa I, Hasegawa A, Suzuki H, Kauppinen S, Yagi K, Okazaki Y, Kasukawa T, de Hoon M, Carninci P,
Shin JW*. Antisense-oligonucleotide-mediated perturbation oflong non-coding RNA reveals functional features in stem cells
and across cell types. Cell Reports 41, 111893 (2022)
Moody J, Kouno T, Chang JC, Ando Y, Carninci P, Shin JW*, Hon
CC. SCAFE: a software suite for analysis of transcribed cisregulatory elements in single cells. Bioinformatics 38, 51265128 (2022)
Ducoli L, Agrawal S, Sibler E, Kouno T, Tacconi C, Hon CC, Berger
SD, Müllhaupt D, He Y, Kim J, D'Addio M, Dieterich LC, Carninci
P, de Hoon MJL, Shin JW*, Detmar M. LETR1 is a lymphatic
endothelial-specific lncRNA that governs cell proliferation andmigration through KLF4 and SEMA3C. Nature Commun 12,925 (2021)

Invited presentations
Shin JW. “The past, present, and prospective of HCA Asia” Human
Cell Atlas Asia 2022 Meeting (Bangkok, Thailand) November 2022
Shin JW. “From Discovery to Functional Understanding of NonCoding Regulatory Elements” IHEC Annual Meeting and Canadian
Conference on Epigenetics (Montreal, Canada) October 2022
Shin JW. “Building the Cell Regulatory Network based on sc-5’
RNA-seq and Spatial Transcriptomics” Spatial Biology Congress(Hague, Netherlands) September 2022
Shin JW. “Human Cell Atlasing the Transcribed Cis-Regulatory
Elements” CZI Single-Cell Biology 2021 Annual Meeting (Paolo
Alto, USA/Online) October 2021

16

M

characterize regulatory elements, such as lncRNA, a systematic knockdown was performed to profile their molecular phenotypes – revealing their function, associations,location and regulation.

ost of the human genome is considered non-coding, yet we and others have found a plethora of regulatory elements – in forms of either
RNA or DNA – that regulate gene expression. How they control gene expression across a multitude of cell types and disease states is not well understood.
In my lab, we holistically interrogate gene regulation mediated by non-coding
regulatory elements through the implementation of single-cell 5’ RNA-seq. We
actively collaborate with medical institutions in Japan to map single cells using
spatial and single cell transcriptomics across human tissues. In collaboration
with Dr. Chung Chau Hon’s lab (IMS), we developed a computational algorithm to annotate cis-regulatory elements, including enhancer RNAs, at single
cell resolution. We are using these tools to interrogate cis-regulatory elements
in association with genetic disorders based on single-cell eQTL, as part of the
Human Cell Atlas (HCA) Asia project (CZI funded), and chromatin-chromatininteractions at single cell resolution using long-read DNA sequencers (AMED).
The lab also specializes in gene-targeting tools, including CRISPR-interference and antisense oligonucleotides, to elucidate the functional role of longnon-coding RNAs in human stem cells, brain development and cell reprogramming. We are combining gene perturbation methods with single-cell genomics
to elucidate non-coding regulatory elements in human brain organoid models
in a scalable and cost-effective manner. As part of the FANTOM6, we are analyzing non-coding regulatory elements by their associated molecular pathways
and interacting partners, including DNA-DNA, DNA-RNA and RNA-protein
interactions, to intervene and modulate gene regulation for potential therapeutic modalities.

Laboratory for

Research Highlights

Cellular Epigenomics
Team Leader: Aki Minoda

Figure: Construction of a Mouse Ageing Atlas
with single-cell genomics and UniverSC: a flexible cross-platform single-cell data processing
pipeline

Miyao T, Miyauchi M, Kelly ST, Terooatea TW, Ishikawa
T, Oh E, Hirai S, Horie K, Takakura Y, Ohki H, Hayama
M, Maruyama Y, Seki T, Ishii H, Yabukami H, Yoshida M,
Inoue A, Sakaue-Sawano A, Miyawaki A, Muratani M,
Minoda A, Akiyama N, Akiyama T. Integrative analysis of
scRNA-seq and scATAC-seq revealed transit-amplifying
thymic epithelial cells expressing autoimmune regulator. Elife 11, e73998 (2022)

Invited presentations
Minoda A. “Activation of type 2 innate immune responsewith ageing” Molecular Biology Society of Japan (Chiba,
Japan/Online) November 2022

Minoda A. “Activation of type 2 innate immune responsein old age” 17th International Conference on Innate
Immunity, (Ioannina, Greece) July 2022
Minoda A. “Mouse Ageing Atlas: effect of the microbiota
on ageing” Single Cell Genomics, Gordon Conference (LesDiablerets, Switzerland), May 2022
Minoda A. “Mouse Ageing Promoter Atlas: effect of the
microbiota on ageing” RIKEN Next Frontiers in Aging
Biology (Online) January 2022

Construction of a Mouse Ageing Atlas using single-cellgenomics
Inflammation is a major hallmark of ageing. To determine whether the presence of the microbiota is contributing to the increase in inflammation that isobserved with age (termed ‘inflammaging’), we are generating single-cell genomic (5’ scRNA-seq and scATAC-seq) datasets from various tissues in both
SPF and germ-free mice at various ages, as well as performing lipidomics (incollaboration with the Arita lab, IMS), metabolomics and microbiome (in collaboration with the Ohno lab, IMS) analyses. Such a rich collection of multiomics datasets will likely provide us with an unbiased insight at many different levels, including the effect of the microbiome, into the complex biologicalphenomena of ageing. Our preliminary analysis of the completed datasets fromeight different tissues captures increased inflammation signatures with old age
at the transcriptomic level, which are in fact reduced in the germ-free mice thatcompletely lack microbes. This indeed suggests that the microbiota contributes
to inflammaging.
Development of UniverSC: a flexible cross-platform singlecell data processing pipeline
Single-cell RNA-sequencing analysis to quantify RNA molecules in individual cells has become popular as it can generate a large amount of information from each experiment. We have developed UniverSC (https://github.com/
minoda-lab/universc), a universal single-cell RNA-seq data processing tool that
supports any UMI-based platform. Our command-line tool enables consistentand comprehensive integration, comparison and evaluation across data generated from a wide range of platforms. In an effort to democratize single-cell
analysis, UniverSC is also available through Docker as well as GUI (graphicaluser interface).

17

Data and Statistics

Minoda A. “Activation of type 2 innate immune responsewith ageing” Society for Leukocyte Biology (Kona, Hawaii, USA) October 2022

ur lab aims to determine epigenomic and transcriptomic changes in
a comprehensive manner in various models by applying the most advanced available technologies, such as single-cell genomics. This information
will be utilized to gain mechanistic insights into various biological questions at
the molecular level.

Events

Kelly ST, Battenberg K, Hetherington NA, Hayashi M,
Minoda A*. UniverSC: a flexible cross-platform singlecell data processing pipeline. Nature Communications
13, 6847 (2022)

O

Projects

Recent Major Publications
Hashimoto S, Nagoshi N, Shinozaki M, Nakanishi K,
Suematsu Y, Shibata T, Kawai M, Kitagawa T, Ago K,
Kamata Y, Yasutake K, Koya I, Ando Y, Minoda A, Shindo T,
Shibata S, Matsumoto M, Nakamura M, Okano H. Microenvironmental modulation in tandem with human stem
cell transplantation enhances functional recovery after
chronic complete spinal cord injury. Biomaterials 295,
122002 (2023)

Lab Activities

Left: 5’ scRNA-seq data from eight mouse tissues
obtained from young (2 months) and old (19 months)
SPF (specific pathogen-free) or GF (germ-free) mice are
combined and displayed.
Right: The pipeline and the GUI for UniverSC.

Laboratory forComprehensive Genomic
Analyses
Team Leader: Yasushi Okazaki

Figure: Missions and projects of Lab. for Comprehensive Genomic Analysis

We are investigating molecular basis of the diseases
including mitochondrial respiratory chain disorders(MRCDs), neurological diseases, and others. For mitochondrial diseases, we are analyzing on ~3,000 patientsin alliance with Juntendo Univ., Saitama Medical Univ.,
and Chiba Prefectural Children’s hospital. And we also
are studying molecular mechanisms underlying direct
reprogramming and taste sense. We address these issues by various technologies including short-/long-readsequencing of genome, transcriptome, epigenome, as
well as single-cell level transcriptomics and epigenomics. For these missions, we also are developing our
proprietary methodologies in wet and dry.

Recent Major Publications
Yasuoka Y. Tissue-specific expression of carbohydrate
sulfotransferases drives keratan sulfate biosynthesis in
the notochord and otic vesicles of Xenopus embryos.
Front Cell Dev Biol 11, 957805 (2023)

Imai-Okazaki A, Nitta KR, Yatsuka Y, Sugiura A, Arao M,
Shimura M, Ebihara T, Onuki T, Ichimoto K, Ohtake A,
Murayama K, Okazaki Y. Impact of measuring heteroplasmy of a pathogenic mitochondrial DNA variant at
the single-cell level in individuals with mitochondrial
disease. J Inherit Metab Dis 45, 1143-1150 (2022)
Yip CW, Hon CC, Yasuzawa K, Sivaraman DM, Ramilowski
JA, Shibayama Y, Agrawal S, Prabhu AV, Parr C, SeverinJ, Lan YJ, Dostie J, Petri A, Nishiyori-Sueki H, Tagami M,
Itoh M, López-Redondo F, Kouno T, Chang JC, Luginbühl
J, Kato M, Murata M, Yip WH, Shu X, Abugessaisa I,
Hasegawa A, Suzuki H, Kauppinen S, Yagi K, Okazaki Y,
Kasukawa T, de Hoon M, Carninci P, Shin JW. Antisenseoligonucleotide-mediated perturbation of long noncoding RNA reveals functional features in stem cells andacross cell types. Cell Rep 41, 111893 (2022)
Invited presentations
Yasuoka Y. “Exploring the evolutionary process ofvertebrates by developmental genomics” JT Biohistory
Research Hall Seminar (Takatsuki, Japan) January 2023

Ozaki K. “Analysis of mitochondrial diseases throughmultimodal genetic analyses” NGS EXPO 2022 (Osaka,
Japan) October 2022
Yasuoka Y. “Evolutionary studies on gene regulatory
networks in early animal embryogenesis” The 93rd annual meeting of the Zoological Society of Japan (Tokyo,
Japan) September 2022

18

F

rom FY2016 to FY2017, we provided technical support through nextgeneration sequencing to researchers in and outside of RIKEN as a facility named Genome Network Analysis Support (GeNAS). In FY 2018, we werereorganized into the Laboratory for Comprehensive Genomic Analysis (CGA)
to start our own research activities, while still contributing the support of otherresearchers, as a part of the “IMS genome platform” activities.
The objectives of our distinct research themes are to elucidate the molecularpathophysiology of human diseases, especially focusing on mitochondrial diseases, neurological diseases and other rare and intractable diseases, and to provide the technological basis for medical therapeutics. We employ a multi-omics
approach, with special emphasis on genome and transcriptome analyses. Specifically, we focus on the identification and characterization of novel causative
genes for these diseases. We have analyzed clinical cases in which it is difficult
to reach a molecular diagnosis, using state-of-the-art sequencing technologies
and sometimes developing our own proprietary methodologies. During the last
several years, we have identified at least 10 novel pathogenic variants and genes,
including two novel repeat expansion diseases.
We also have made major progress in our investigation of the pathogenesis of
two neurological diseases (Spinocerebellar ataxia type 34 and Cerebral autosomal
recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL)). A well-known antihypertensive drug candesartan reversed the molecularpathophysiology in CARASIL, emerging as a candidate for therapeutics.
We are committed to other medically relevant themes as well. We continue to
conduct single-cell analyses of mammalian taste receptor systems, as a platform
for lifestyle-related diseases. Epigenetic analyses (ChIP/ATAC/Methyl-seq) haveclarified molecular mechanisms underlying the direct reprogramming of fibroblasts into another distinctively differentiated cell type, as a prelude to regenerative medicine for intractable diseases. A high-throughput screening system andoptical visualization in hearts using zebrafish are under development to discover
new potential drug targets for the realization of personalized medicine.

Research Highlights

RIKEN-IFOM Joint
Laboratory for Cancer
Genomics
Team Leader: Yasuhiro Murakawa

Figure: Building an atlas of transcribed enhancers across human body for decoding humandiseases

Sato Y, Oguchi A, Fukushima Y, Masuda K, Toriu N, Taniguchi K, Yoshikawa T, Cui X, Kondo M, Hosoi T, Komidori
S, Shimizu Y, Fujita H, Jiang L, Kong Y, Yamanashi T,
Seita J, Yamamoto T, Toyokuni S, Hamazaki Y, Hattori M,
Yoshikai Y, Boor P, Floege J, Kawamoto H, Murakawa Y,
Minato N, Yanagita M. CD153/CD30 signaling promotes
age-dependent tertiary lymphoid tissue expansion andkidney injury. J Clin Invest 132, e146071 (2022)

Invited presentations
Murakawa Y. “Dynamics and evolution of human cisregulatory elements” 21st Takeda Science Symposium(Osaka, Japan) January 2023

Murakawa Y. “An atlas of transcribed enhancers acrosshelper T cell diversity for decoding human diseases”
BIMSB seminar (Berlin, Germany) October 2022
Murakawa Y. “Development of functional genomics
technologies towards understandings of human genome” 15th Diabetes Leading-edge Conference (Kyoto,
Japan) August 2022
Murakawa Y. “A compendium of human CD4+ T cellenhancers for decoding immune-mediated diseases”
CRICK-MSKCC-IFOM meeting (London, UK) May 2022

CAGE

Altering the gene
expression

PromoterT

he body-wide transcriptome is generated by the spatiotemporal orchestration of cis-regulatory DNA elements such as promoters and enhancers. In
particular, enhancers are distal cis-regulatory elements that are crucial for theestablishment of cell type-specific function and identity in health and disease.
We aim to decipher the cis-regulatory code that governs the transcriptionallandscapes of malignancies, thereby gaining fundamental insight into cancer
development and maintenance.
To investigate the cis-regulatory code, we developed a new method, native
elongating transcript-cap analysis of gene expression (NET-CAGE), to determine globally the 5’ ends (or transcription start sites) of nascent RNAs, which
permits sensitive detection of even unstable transcripts including enhancerderived RNAs. Thus, NET-CAGE enabled ultra-sensitive detection of a numberof enhancers at nucleotide resolution as well as the genes that are regulated bythem (Hirabayashi et al. Nature Genetics, 2019). More recently, we have developed a new 5’ single-cell RNA sequencing (5’ scRNA-seq) approach to investigate functional enhancers from heterogeneous cell types within a given tissue/
cell (Oguchi et al., revised manuscript in preparation). We believe in the importance of developing original disruptive technologies that can solve paradigms
that cannot otherwise be solved.
We are applying our new methods such as NET-CAGE and 5’ scRNA-seq
to describe the active cis-regulatory landscape across hundreds to thousands ofhuman samples including various types of tumors and immune cells, to comprehensively catalog cell-type specific enhancers, genes and long non-coding
RNAs. Furthermore, by integrating large-scale human disease genomics datawith clinical information, we study disease-relevant genetic elements that canbe exploited to develop novel molecular therapeutic targets and predictive biomarkers. Our ultimate long-term goal is to revolutionize drug discovery, medicine and healthcare.

19

Data and Statistics

Murakawa Y. “Development of genome analysis technology to elucidate the function of the human genome”
LSACJ Annual Meeting 2022 (Kobe, Japan) November
2022

Disease-SNPs

Events

Guerrini MM, Oguchi A, Suzuki A, Murakawa Y. Cap
analysis of gene expression (CAGE) and noncoding regulatory elements. Semin Immunopathol 44, 127-136(2022)

Enhancer RNA

Projects

Recent Major Publications
Koido M, Hon CC, Koyama S, Kawaji H, Murakawa Y,
Ishigaki K, Ito K, Sese J, Parrish NF, Kamatani Y, Carninci
P, Terao C. Predicting cell-type-specific non-coding RNA
transcription from genome sequence. Nature Biomed
Eng Online ahead of print (2022)

NET-CAGE

Cell-type specific
Enhancer

Lab Activities

Enhancers are small segments of DNA cis-regulatory
elements that significantly enhance the expression oftarget genes and play key roles in the establishmentof cell-type-specific function and identity. Single
nucleotide polymorphisms associated with humandiseases (GWAS-SNPs) are highly enriched in enhancer
regions and are thought to alter disease susceptibility
by changing the expression levels of target genes. We
have developed original methods such as NET-CAGE to
detect enhancer RNAs transcribed from active enhancers
with high sensitivity, and are studying the relationshipbetween enhancers and human diseases.

Laboratory for

Genotyping
Development

Team Leader: Yukihide Momozawa( A) Pathogenic-variant carrier(A)
Figure: Cumulative risk of gastric cancer according to Helicobacter pylori infection status in (A)pathogenic-variant carrier and (B) pathogenicvariant noncarrier((B)
B ) Pathogenic-variant noncarrier

Infection(+)

Individuals with both germline pathogenic variants inhomologous recombination genes (ATM, BRCA1, BRCA2,
PALB2) and Helicobacter pylori infection showed an excess risk of gastric cancer compared to individuals witheither factor alone. (N Engl J Med. 2023; 388:1181-1190)

Infection(+)
Infection(-)
Infection(-)

Recent Major Publications
Usui Y, Taniyama Y, Endo M, Koyanagi Y, Kasugai Y, Oze I,
Ito H, Imoto I, Tanaka T, Tajika M, Niwa Y, Iwasaki Y, Aoi T,
Hakozaki N, Takata S, Suzuki K, Terao C, Hatakeyama M,
Hirata M, Sugano K, Yoshida T, Kamatani Y, Nakagawa H,
Matsuda K, Murakami Y, Spurdle A, Matsuo K*, Momozawa Y*. Helicobacter pylori, homologous recombination genes and gastric cancer. N Engl J Med 388, 11811190 (2023)

Momozawa Y, Sasai R, Usui Y, Shiraishi K, Iwasaki Y,
Taniyama Y, Parsons MT, Mizukami K, Sekine Y, Hirata M,
Kamatani Y, Endo M, Inai C, Takata S, Ito H, Kohno T, Matsuda K, Nakamura S, Sugano K, Yoshida T, Nakagawa H,
Matsuo K, Murakami Y, Spurdle AB, Kubo M. Expansion
of Cancer Risk Profile for BRCA1 and BRCA2 Pathogenic
Variants. JAMA Oncol 8, 871-878 (2022)
Okawa Y, Iwasaki Y, Johnson TA, Ebata N, Inai C, Endo M,
Maejima K, Sasagawa S, Fujita M, Matsuda K, Murakami
Y, Nakamura T, Hirano S, Momozawa Y*, Nakagawa H*.
Hereditary cancer variants and homologous recombination deficiency in biliary tract cancer. J Hepatol 78, 333342 (2022)
Invited presentations
Momozawa Y. “Pan-cancer analysis of 14 cancer types
about BRCA1 and BRCA2” Annual Meeting of Japan
Society of Clinical Genetics in Obstetrics and Gynecology(Niigata, Japan) October 2022

Momozawa Y. “Application of AI-based genome platforms for cancer care” Annual Meeting of Japan Societyof Clinical Oncology (Kobe, Japan) October 2022
Momozawa Y. “A large case-control study of hereditarycancer-predisposing genes” Annual Meeting of the Japanese Cancer Association (Yokohama, Japan) September
2022
Momozawa Y. "Various heterogeneities about BRCA1and BRCA2" Sapporo International Cancer Symposium(Sapporo, Japan) June 2022
Momozawa Y. “Expectations for personalized medicine
based on pan-cancer analysis of 14 cancer types about
BRCA1 and BRCA2” Insight #2 (Tokyo, Japan) June 2022

20T

he aims of the Laboratory for Genotyping Development are to produce
large-scale genomic data for personalized medicine and to assist withresearch projects conducted in IMS, other universities and academic institutes,
and companies. Our laboratory published 96 papers in 2019-2022.
As our main project, we focused on rare germline pathogenic variants inhereditary cancer genes to broaden personalized medicine. We have analyzed
27 hereditary cancer genes using our previously developed targeted sequencing method in ~84,000 cancer patients with 23 cancer types and in ~38,000
controls from BioBank Japan. In a new study, we analyzed BRCA1 and BRCA2
across 14 cancer types in >100,000 samples to identify their pathogenic variants
that increase disease risk in new cancer types - biliary tract, esophageal, andgastric cancer. These results suggest that more surveillance of pathogenic variant carriers could be beneficial and the potential efficacy of a PARP inhibitor
specific for pathogenic variant carriers (JAMA Oncol 2022). We also performed
an integrated analysis of pathogenic variants and Helicobacter pylori infection in
gastric cancer in > 50,000 samples to show that both factors boost disease risk,
which suggests that pathogenic variant carriers should receive an evaluationof Helicobacter pylori infection status and its eradication if positive (New Engl
J Med 2023). We will expand this project to provide individual risk estimation
based on rare pathogenic variants, common variants, environmental factors,
and infections across 23 cancer types.
For supporting other research projects in IMS, we developed a Genome
Platform to support library preparation, next-generation sequencing and data
analysis. We have conducted 136 projects and performed sequencing runs with
MiSeq (N=517), HiSeq2500 (N=326), NextSeq2000 (N=72), NovaSeq6000(N=467), and Sequel II (N=11). Beginning in 2022, we also joined AMEDBINDS to support research projects in Japan.
We will continue to run our own projects and contribute to other research
projects for the implementation of personalized medicine.

Laboratory for

Research Highlights

Statistical andTranslational Genetics
Team Leader: Chikashi Terao

Static and dynamic information would enable precision medicine
Figure: Combining static and dynamic biologicalinformation would lead to precision medicine

StaticSomatic mutations

Somatic mutations
time

ce
ll
ty
pe
Cell type A
Cell type B

Terao C. “Genomics Unravels the Molecular Basis of Immune Diseases and Traits” The 114th Collagen Disease
Research Meeting (Niigata, Japan) November 2022
Terao C. “Aging and somatic mosaicism” The 22nd Scientific Meeting of the Japanese Society of Anti-Aging
Medicine (Niseko, Japan) September 2022
Terao C. “International Collaborative Genetic Studies
for Complex Traits” US-Japan Conference on Oncology(Washington, USA/Online) June 2022

Nat Biomed Engineer (2022)

Cell type C
Cell type D
Cell type EGenetic associations provide direct evidence for mechanisms of human
complex traits. We constructed a Japanese-specific genotype reference
panel containing 3,256 Japanese whole-genome sequence (WGS) data. We
combined ~260,000 Japanese subjects, the reference panel and statistical finemapping and identified 4,423 significant loci across 63 quantitative traits among
which 601 were novel and 9,406 putatively causal associations. Novel associations
included Japanese-specific coding, splicing and non-coding variants, exemplified
by a damaging missense variant with lower heart function and increased risk forheart failure (P=1.4×10-15 and OR=4.5 (95%CI:3.1-6.5)). We developed algorithms to detect structural variations (SVs) including copy number variations(CNVs). We developed HI-CNV which can sensitively detect CNVs based on
DNA microarray data. We also developed a computational algorithm (MOPline)that sensitively detects SVs using short-read WGS data. Using 3,672 high-coverage WGS datasets, MOPline stably detected ~16,000 SVs per individual, which isover 2-fold higher than previous large-scale projects, while exhibiting a comparable level of statistical quality metrics. We imputed SVs from 181,622 Japaneseindividuals and found novel associations for diseases and quantitative traits.
Regarding somatic information, we analyzed somatic chromosomal alterations and cell-specific gene regulation mechanisms. We describe populationspecific patterns of genomic mutations and clonal selection in hematopoietic
cells on the basis of 33,250 autosomal mosaic chromosomal alterations in
179,417 Japanese. In collaboration with the FANTOM consortium, we report
the development and utility of a machine-learning model (MENTR) that reliably links genome sequence and ncRNA expression at the cell type level.
Our overall long-term goal is to realize precision medicine/personalized genomic medicine by finding variants, especially population-specific ones, withstrong effect sizes, integrating germline information and somatic information
including gene expression, understanding the basis of complex traits based on
genetic findings, and constructing accurate evaluation models of the current
physiological status of the body and prediction models of diseases and outcomes.
21

Data and Statistics

Terao C. “Promising molecules in Large vessel vasculitis”
37th Annual Conference of Indian Rheumatology Association (IRACON) (Indore, India) November 2022

ce
ll
ty
pe

Machine learning
Koido et al,

EventsInvited presentations
Terao C. “G-PROB (Genetic Probability tool) - taking advantage of genetic risk scoring” 25th Asia-Pacific Leagueof Associations for Rheumatology Congress (APLAR)(HongKong, China) December 2022

Cell type B

Projects* as corresponding author, ** as equal first author

Cell type A

Cell type C

time

Hujoel MLA, Sherman MA, Barton AR, Mukamel RE,
Sankaran VG, Terao C, Loh PR.Influences of rare copynumber variation on human complex traits. Cell 185,4233-4248. e27 (2022)

Genomic Translational Medicine

Terao et al, Nature 2020

Gene expression profile

Ishigaki K, Sakaue S, Terao C**, Luo Y, Sonehara K, Yamaguchi K, Amariuta T, Too CL, Laufer VA, Scott IC, Viatte
S, Takahashi M, Ohmura K, Murasawa A, Hashimoto M,
Ito H, Hammoudeh M, Emadi SA, Masri BK, Halabi H,…, Huizinga T, Dieudé P, Schneider M, Kerick M, Denny
JC; BioBank Japan Project, Matsuda K, Matsuo K, Mimori
T, Matsuda F, Fujio K, Tanaka Y, Kumanogoh A, Traylor
M, Lewis CM, Eyre S, Xu H, Saxena R, Arayssi T, Kochi Y,
Ikari K, Harigai M, Gregersen PK, Yamamoto K, Louis
Bridges S Jr, Padyukov L, Martin J, Klareskog L, Okada
Y, Raychaudhuri S. Multi-ancestry genome-wide association analyses identify novel genetic mechanisms inrheumatoid arthritis. Nat Genet 54, 1640-1651 (2022)

Prediction of diseases

Dynamic (consecutive、tissue/cell type-specific)

Ota et al, Cell 2021

Recent Major Publications
Koido M, Hon CC, Koyama S, Kawaji H, Murakawa Y,
Ishigaki K, Ito K, Sese J, Parrish NF, Kamatani Y, Carninci
P, Terao C*. Prediction of the cell-type-specific transcription of non-coding RNAs from genome sequences via
machine learning. Nat Biomed Eng Online ahead ofprint (2022)

Current status

Gene expression profile

Lab Activities

It is important to utilize not only static biological information (germline variants) but also dynamic biologicalinformation (gene expression profiles and somatic
mutations) in order to predict an individual's prognosis
and risk of developing diseases. Dynamic biologicalinformation should be different for each tissue. Machinelearning-based methods can efficiently integrate staticand dynamic biological information.

Germline variants

Laboratory for

Pharmacogenomics

Figure: Functional characterization of variants
in genes important for clinical drug therapy
using a mammalian suspension cell expression
system capable of producing large amounts ofrecombinant protein

CYP2D6

pcDNA 3.4 TOPO vector

Transfection ofhuman Expi293F cells

The in vitro experimental system was applied to theevaluation of the effects of novel CYP2D6 variants on
metabolic activities for a typical CYP2D6 substrate dextromethorphan.

CYP2D6-expressing cells
Determination of
metabolite
formation activity

37℃
incubation

Recent Major Publications
Hikino K, Tanaka N, Koido M, Tomizuka K, Koike Y, Ito
S, Suzuki A, Momozawa Y, Kamatani Y; BioBank Japan
Project Consortium; Mushiroda T, Terao C. Genetic Architectures Underlie Onset Age of Atopic Dermatitis. J
Invest Dermatol 142, 3337-3341 (2022)

Diekstra MHM, Swen JJ, van der Zanden LFM, Vermeulen
SH, Boven E, Mathijssen RHJ, Fukunaga K, Mushiroda T,
Hongo F, Oosterwijk E, Cambon-Thomsen A, Castellano
D, Fritsch A, Donas JG, Rodriguez-Antona C, Ruijtenbeek
R, Radu MT, Eisen T, Junker K, Roessler M, Jaehde U, Miki
T, Böhringer S, Kubo M, Kiemeney LALM, Guchelaar
HJ. Genome-Wide Meta-Analysis Identifies Variants
in DSCAM and PDLIM3 That Correlate with Efficacy
Outcomes in Metastatic Renal Cell Carcinoma Patients
Treated with Sunitinib. Cancers (Basel) 14, 2838 (2022)
Siamoglou S, Koromina M, Hishinuma E, Yamazaki S,
Tsermpini EE, Kordou Z, Fukunaga K, Chantratita W,
Zhou Y, Lauschke VM, Mushiroda T, Hiratsuka M, Patrinos
GP. Identification and functional validation of novel
pharmacogenomic variants using a next-generation
sequencing-based approach for clinical pharmacogenomics. Pharmacol Res 176, 106087 (2022)
Invited presentations
Mushiroda T. “Pharmacogenetic testing for preventionof severe cutaneous adverse drug reactions” The 67th
Annual Meeting of the Japan Society of Human Genetics(Yokohama, Japan) December 2022

Mushiroda T. “Clinical implementation of pharmacogenetic biomarkers” The 96th Annual Meeting of theJapanese Pharmacological Society (Yokohama, Japan)
December 2022
Hikino K. “Pharmacogenomics in Pediatric Patients” The43rd Annual Scientific Meeting of the Japanese Societyof Clinical Pharmacology and Therapeutics (Yokohama,Japan) December 2022
Hikino K. “Pharmacogenomics” The 49th Annual Meeting of the Japan Society of Developmental Pharmacology and Therapeutics (Tokyo, Japan) November 2022
Hikino K. “Personalized medical care for pediatric drug
therapy and pharmacogenomics” The 49th Annual
Meeting of the Japanese Society of Toxicology (Sapporo,
Japan) June 2022

22

Dextromethorphan

I

Metabolite

LC-MS/MS

500

Normalactivity

400
300

Reducedactivity

200
100
0

Non-functional*1 (wild type)*10 (P34S)*134 (R344Q)*137 (R497H)*135 (R414C)*136 (P430L)*133 (G340R)*131 (L231P)*132 (N285S)
N.D.
*128 (V68G)*129 (W128X) N.D.
*130 (C191F) N.D.

CMV promoter

Dextromethorphan O-demethylase activity(μL/min/g protein)

Team Leader: Taisei Mushiroda

ndividual responses to drugs can vary widely. Lack of drug efficacy can leadto inadequate disease control and is a waste of resources; conversely, adverse
drug reactions (ADRs) are frequent and often unpredictable. Many polymorphisms have been identified in genes that affect the efficacy or risk of ADRs forvarious drugs. In the USA, information on 310 germline genomic biomarkers
is available on US FDA-approved drug labels. However, in Japan, the National
Health Insurance system currently covers only three genetic tests, UGT1A1,
NUDT15 and CYP2C9, to predict drug responses prior to the drug administration. Therefore, we are aiming for clinical implementation of as many germline
pharmacogenomic (PGx) biomarkers as possible to realize more appropriate
and patient-friendly genotype-based drug therapy.
In collaboration with domestic hospitals, we are conducting genomic
analyses for the identification of PGx biomarkers useful for prediction of drug
responses. Since it is difficult for individual countries acting alone to collectenough samples for PGx research, we conduct international PGx collaborations, such as the Southeast Asian Pharmacogenomics Research Network(SEAPharm). To achieve our mission, the application of PGx biomarkers toclinical practice, we advance our research according to three primary steps: i)establishment of infrastructure for identification of PGx biomarkers, ii) identification by genomic analyses of PGx biomarkers associated with drug efficacy/
ADRs, and iii) construction of an integrative database for clinical implementation of PGx testing. To construct the database, we already have PGx variant
data for approximately 3,500 individuals in 10 populations, including Japanese,and have constructed a mammalian suspension cell expression system capableof mass-producing recombinant proteins based on the variant information.
Using this system, we evaluate functional changes caused by variants in genes
important for clinical drug therapy (PGx variant annotation data) and predict
drug levels in the blood of carriers of the variants (simulated pharmacokineticdata).

Laboratory for

Research Highlights

Bone and Joint Diseases
Team Leader: Shiro Ikegawa

Figure: Clinical features of osteopetrosis, Ikegawa type caused by bi-allelic loss of function
mutations in SLC4A2

E
Recent Major Publications
Xue JY, Ikegawa S, Guo L. SLC4A2, another gene involvedin acid-base balancing machinery of osteoclasts, causes
osteopetrosis. Bone 167, 116603 (2023)

Xue JY, Grigelioniene G, Wang Z, Nishimura G, Iida A,
Matsumoto N, Tham E, Miyake N, Ikegawa S, Guo L.
SLC4A2 deficiency causes a new type of osteopetrosis. J
Bone Miner Res 37, 226-235 (2022)

Ikegawa S. “Skeletal Dysplasia from the Basics” The 95th
Annual Meeting of the Japanese Orthopedic Society(Kobe, Japan) May 2021

23

Data and Statistics

Ikegawa S. “Genomic Study of Bone and Joint Diseases”
Foreign Expert Seminar, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (Beijing,
China/Online) July 2022

2) Genomic Study of Skeletal Dysplasia
Skeletal dysplasia is a group of heritable (monogenic) disorders affecting
the skeleton, More than 450 diseases belong to this category. Skeletal dysplasia
is an intractable disease, thus many patients are waiting for an effective treatment. We are engaging in clinical and basic studies of skeletal dysplasia. Bylarge-scale mutation screening, including exome sequencing, we have identified
disease-causative genes. As of now, we have identified 32 novel genes including
TMEM53 for craniotubular dysplasia, Ikegawa type and SLC4A2 for osteopetrosis, Ikegawa type.
Through the analyses of phenotypes and diseases genes, we consider themolecular mechanisms of bone and joint formation and the pathogenesis ofcommon bone and joint diseases, as well as the diagnosis and treatment of rare
intractable diseases. Using the disease genes for skeletal dysplasia as candidate
genes, we perform association studies for common bone and joint diseases corresponding to skeletal dysplasia, the so-called “rare to common” approach.

EventsInvited presentations
Ikegawa S. “Genetic Testing in Japan for Skeletal Dysplasia and MPS” APAC MPS Summit 2022 (Taipei/Tokyo/
Sydney/Seattle/Online) August 2022

Projects

Suetsugu H, Kim K , Yamamoto T, Bang SY, Sakamoto Y,
Shin JM, Sugano N, Kim JS, Mukai M, Lee YK , Ohmura
K, Park DJ , Takahashi D, Ahn GY, Karino K, Kwon YC,
Miyamura T, Kim J, Nakamura J, Motomura G, Kuroda T,
Niiro H, Miyamoto T, Takeuchi T, Ikari K, ... Seki T, Tanaka
Y, Kubo T, Hisada R, Yoshioka T, Yamazaki M, Kabata T,
Kajino T, Ohta Y, Okawa T, Naito Y, Kaneuji A, Yasunaga
Y, Ohzono K, Tomizuka K, Koido M, Matsuda K, Okada
Y, Suzuki A, Kim BJ, Kochi Y, Lee HS, Ikegawa S, Bae SC ,Terao C. Novel susceptibility loci for steroid-associatedosteonecrosis of the femoral head in systemic lupus
erythematosus. Hum Mol Genet 31, 1082-1095 (2022)

1) Genomic Study of Common Diseases
Common bone and joint diseases are serious worldwide problems for healthand the economy, as exemplified by the WHO initiative “Bone and Joint DeBcade” (2000-2010) and the “Locomotive syndrome campaign” in Japan. We
are searching for susceptibility genes for common (polygenic) bone and joint
diseases, including osteoarthritis (OA), lumbar disc disease (LDD)/herniation(LDH), osteoporosis, avascular necrosis of the femoral head (ANF), scoliosis,
and ossification of the posterior longitudinal ligament of the spine (OPLL).
Through genome-wide association studies (GWASs) and next-generation
sequencing approaches, we identify and characterize susceptibility genes andclarify their pathogenic mechanisms at the molecular level. Using the genome
information obtained from these studies, we will realize our final goal of “personalized medicine”. GWASs for OA, LDD/LDH, adolescent idiopathic scoliosis, OPLL, and ANF are in progress and we have succeeded in the identificationof many susceptibility genes. Functional studies of the genes in vitro and using
animal models are underway.

Lab Activities

Note generalized increase of bone density including
skull. Arrow heads: pseudo-fracture of the femur.

Laboratory for

Genomics of Diabetes
and Metabolism
Team Leader: Momoko Horikoshi

Figure: Two distinct T2D-association signals at the
ANK1-NKX6-3 locus are associated with the expression levels of two transcripts in two tissues

Top, Regional association plot for East Asian sexcombined BMI-unadjusted meta-analysis at the ANK1NKX6-3 locus highlighting three distinct T2D-association
signals (P<1x10-5): signal 1, rs33981001; signal 2,
rs62508166; signal 3, rs144239281. Variants are colored
red and blue according to the strength of East Asianlinkage disequilibrium (LD) with the lead variants offirst and second signals, respectively. Middle, Variant
rs12549902, which is in high LD (EAS LD r2=0.80) withsignal 1 rs33981001, shows the strongest association
with the expression level of NKX6-3 in pancreatic islets(n=118). Bottom, Variant rs516946, which is in high LD(EAS LD r2=0.96) with signal 2 rs62508166, shows thestrongest association with the expression level of ANK1
in subcutaneous adipose tissue (n=770).

Recent Major Publications
Mahajan A, Spracklen CN, Zhang W, Ng MCY, Petty LE, Kitajima
H, Yu GZ, Rüeger S, Speidel L, Kim YJ, Horikoshi M, Mercader
JM, Taliun D, Moon S, Kwak SH, Robertson NR, Rayner NW, Loh
M, Kim BJ, Chiou J, Miguel-Escalada I, Della Briotta Parolo P,
Lin K, Bragg F, Preuss MH, Takeuchi F, Nano J, Guo X, Lamri A,
Nakatochi M, Scott RA, Lee JJ, Huerta-Chagoya A, Graff M, Chai
JF, Parra EJ, Yao J, Bielak LF, Tabara Y, Hai Y, Steinthorsdottir V,
Cook JP, Kals M, Grarup N, Schmidt EM, Pan I, Sofer T, Wuttke M,
Sarnowski C et al. Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery
and translation. Nat Genet 54, 560-572 (2022)
Ruth KS, Day FR, Hussain J, Martínez-Marchal A, Aiken CE,
Azad A, Thompson DJ, Knoblochova L, Abe H, Tarry-Adkins JL,
Gonzalez JM, Fontanillas P, Claringbould A, Bakker OB, Sulem P,
Walters RG, Terao C, Turon S, Horikoshi M, Lin K, Onland-Moret
NC, Sankar A, Hertz EPT, Timshel PN, Shukla V, Borup R, Olsen
KW, Aguilera P, Ferrer-Roda M, Huang Y, Stankovic S, Timmers
PRHJ, Ahearn TU, Alizadeh BZ, Naderi E, Andrulis IL, Arnold AM,
Aronson KJ, Augustinsson A, Bandinelli S, Barbieri CM, Beaumont RN, Becher H, Beckmann MW, Benonisdottir S, Bergmann
S, Bochud M, Boerwinkle E, Bojesen SE, Bolla MK et al. Genetic
insights into biological mechanisms governing human ovarian
ageing. Nature 596, 393-397 (2021)
Chen J, Spracklen CN, Marenne G, Varshney A, Corbin LJ, Luan
J, Willems SM, Wu Y, Zhang X, Horikoshi M, Boutin TS, Mägi R,
Waage J, Li-Gao R, Chan KHK, Yao J, Anasanti MD, Chu AY, Claringbould A, Heikkinen J, Hong J, Hottenga JJ, Huo S, Kaakinen
MA, Louie T, März W, Moreno-Macias H, Ndungu A, Nelson SC,
Nolte IM, North KE, Raulerson CK, Ray D, Rohde R, Rybin D,
Schurmann C, Sim X, Southam L, Stewart ID, Wang CA, Wang
Y, Wu P, Zhang W, Ahluwalia TS, Appel EVR, Bielak LF, Brody JA,
Burtt NP, Cabrera CP, Cade BE et al. The trans-ancestral genomicarchitecture of glycemic traits. Nat Genet 53, 840-860 (2021)

Invited presentations
Horikoshi M. “Large-scale genome-wide association studyof type 2 diabetes” The 9th Cutting‐edge Forum for Diabetes
Complication (Chiba, Japan) October 2022

24

O

ur lab is interested in investigating the genetic background of diabetes
and related metabolic traits that may help us better understand the underlying disease mechanisms. We have been focusing on the genetic contribution to type 2 diabetes (T2D) susceptibility in the Japanese population by using
the rich genetic resources generated by Biobank Japan (BBJ). By using the full
BBJ collection, we conducted a single population Genome-wide association
study (GWAS) of T2D in 191,764 Japanese. In addition to the then established>150 T2D loci, we identified 28 novel loci. We then joined this effort with ourinternational collaborators in the Asian Genetic Epidemiology Network forT2D (AGEN-T2D) to include 433,540 East Asian individuals in a GWAS metaanalysis. We identified 301 distinct association signals at 183 loci. Previously
undescribed associations included signals in or near genes and a microRNA
cluster that affects the differentiation of skeletal muscle and adipose tissues,
which are essential in the development of T2D. Interestingly, expression quantitative trait loci at two overlapping T2D signals affect two genes in different
tissues (Figure). Association studies in diverse populations demonstrated thebenefit of identifying additional loci and elucidating disease-associated genes,
biology and pathways. These East Asian T2D association data were combinedwith those from other major ethnicities to conduct a multi-ancestry GWAS
meta-analysis of 1,339,889 individuals. The increased sample size and expanded
population diversity enhanced the number of associated loci to 237 and improved the fine-mapping ability to localize 54.4% of T2D associations to a single variant with >50% posterior probability. Multi-ancestry genetic risk scoresenhanced the transferability of T2D prediction across diverse populations.

Laboratory forTeam Leader: Kaoru ItoEuropean GWAS

Japanese GWAS

BioBank Japan (1st cohort)

AFGen consortium HUNTdeCODEUK Biobank
MGI
DiscovEHR

9,826 cases
140,446 controls

Figure: Comprehensive analysis of Atrial fibrillation

60,620 cases
970,216 controls

P < 5.0 × 10-8 for MAF ≥ 1%
P < 5.7 × 10-9 for MAF < 1%

Trans-ancestry meta-GWAS

Replication

77,690 cases
1,167,040 controls

BioBank Japan (2nd cohort)
4,602 cases
44,075 controls

150 genome-wide significant loci (33 novel loci)

Association analysis of 5 novel loci

Gene expression analysis•

Enrichment analysis (ChIP-Atlas)•

TWAS (MetaXcan)•

Functional assay (iPCMs)•

GTEx v8

Invited presentations

Ito K. “Frontiers in Genomic Analysis and its Clinical Application
for Complex Cardiovascular Diseases” The 4th National Cerebral
and Cardiovascular Center Seminar Series (Osaka, Japan/Online) September 2022
Ito K. “Frontiers of Cardiovascular Genomic Analysis Leveraging
Large Biobanks” 2022 Annual Meeting of Japan Bioinformatics
Society (Osaka, Japan) September 2022
Ito K. “The Development of Cardiovascular Genetic Risk Score
and Prospects for the Clinical Implementation” The 54th Annual
Scientific Meeting of Japan Atherosclerosis Society (Kurume,
Japan), July 2022
Ito K. “Elucidating the genetic background of atrial fibrillation
and realizing the precision medicine” The 7th Annual Scientific
Meeting of Japan Cardiovascular Association (Online) May 2022

Causality analysis by MR•

Trans-ancestry PRS•

Two-sample MR•

Prediction of relevant phenotypes•

Cross-trait causality of AF

C

ardiovascular diseases remain the leading cause of death worldwide.
Therefore, understanding their pathogenesis from a basic research perspective and changing clinical practice based on this knowledge, as well as identifying new therapeutic targets, are critical for global health. To this end, we areusing state-of-the-art technologies such as whole genome sequencing and artificial intelligence, in addition to conventional statistics, to elucidate the precise
mechanisms and to promote better use of medical and genomic information.
Among the cardiovascular diseases, our team mainly targets not only common diseases such as atherosclerotic diseases, arrhythmias and heart failure,but also rare diseases such as Kawasaki disease, chronic thromboembolic pulmonary hypertension and cancer treatment-related cardiac dysfunction. At
present, we are: 1) Conducting large-scale studies to understand the genetic
underpinnings of ischemic heart disease, the most common atherosclerotic disease, and atrial fibrillation, the most common arrhythmia, as well as identifying
the genetic differences between Japanese and Europeans, in collaboration withinternational consortia. 2) Developing and validating a new genetic analysis
method based on a machine learning algorithm that solves the “P greater thanN” scenario, where the sample size is small but the number of variants to beanalyzed is large. 3) Elucidating of the mechanism of rare cardiovascular diseases using human omics data from multi-center patients in Japan. 4) Performing prospective cohort studies to examine the possibility of clinical applicationof genomic information. 5) Developing a functional analysis system using
massively parallel in vitro assays with artificial intelligence. 6) Developing andvalidating deep learning-based cardiovascular age for clinical applications. We
also play an important role in genomic analyses of AMED GRIFIN and AMED
intractable disease projects for cardiovascular diseases.
Our goal is to provide useful genomic/omics information and novel medical/biological indicators than can change and improve preventive/diagnostic/
management/treatment strategies for cardiovascular diseases.
25

Data and Statistics

Ito K. “Genetic Underpinnings of Atrial Fibrillation and Prospects for the Clinical Application” The 87th Annual Scientific
Meeting of the Japanese Circulation Society (Fukuoka, Japan)
March 2023

Polygenic risk prediction

EventsAragam KG, Jiang T, Goel A, Kanoni S, Wolford BN, Atri DS,
Weeks EM, ..., Ito K, Jang DK, Kamatani Y, Khera AV, Komuro I,
Kullo IJ, Lotta LA, Nelson CP, Roberts R, Thorgeirsson G, Thorsteinsdottir U, Webb TR, Baras A, Bjorkegren JLM, Boerwinkle E,
Dedoussis G, Holm H, Hveem K, Melander O, Morrison AC, OrhoMelander M, Rallidis LS, Ruusalepp A, Sabatine MS, Stefansson
K, Zalloua P, Ellinor PT, Farrall M, Danesh J, Ruff CT, Finucane
HK, Hopewell JC, Clarke R, Gupta RM, Erdmann J, Samani NJ,
Schunkert H, Watkins H, Willer CJ, Deloukas P, Kathiresan S,
Butterworth AS; CARDIoGRAMplusC4D Consortium. Discovery
and systematic characterization of risk variants and genes
for coronary artery disease in over a million participants. Nat
Genet 54, 1803-1815 (2022)

Downstream
analysis

Projects

Ieki H, Ito K, Saji M, Kawakami R, Nagatomo Y, Takada K, Kariyasu T, Machida H, Koyama S, Yoshida H, Kurosawa R, Matsunaga
H, Miyazawa K, Ozaki K, Onouchi Y, Katsushika S, Matsuoka
R, Shinohara H, Yamaguchi T, Kodera S, Higashikuni Y, Fujiu K,
Akazawa H, Iguchi N, Isobe M, Yoshikawa T, Komuro I. Deeplearning- based age estimation from chest X-rays indicatescardiovascular prognosis. Commun Med (Lond) 2, 159 (2022)

log10 BF > 6 (MANTRA)

Transcription factor analysis

Recent Major Publications
Miyazawa K, Ito K, Ito M, Zou Z, Kubota M, Nomura S, Matsunaga H, Koyama S,Ieki H, Akiyama M, Koike Y, Kurosawa R,
Yoshida H, Ozaki K, Onouchi Y; BioBank Japan Project; Takahashi
A, Matsuda K, Murakami Y, Aburatani H, Kubo M, Momozawa Y,
Terao C, Oki S, Akazawa H, Kamatani Y, Komuro I. Cross-ancestry
genome-wide analysis of atrial fibrillation unveils disease
biology and enables cardioembolic risk prediction. Nat Genet
55, 187-197 (2023)

Lab Activities

We not only identified new disease susceptibility loci forthe disease, but also suggested new key molecules forthe pathophysiology and provided evidence for clinicalapplication of the genomic information.

FinnGen7,244 cases
56,378 controls

Meta-analysis

31 genome-wide significant loci (5 novel loci)Research Highlights

Cardiovascular Genomics
and Informatics

Laboratory for

Systems Genetics
Team Leader: Yukinori Okada

Figure: Construction of gut microbiome catalogof the Japanese population

We constructed a Japanese population-specific microbial genome (MAG) of both metagenome (JMAG) andvirome (JVD) by integrating in house 787 gut metagenome shotgun sequence data (Tomofuji Y et al. Cell
Genom 2022).
Recent Major Publications
Tomofuji Y, Kishikawa T, Maeda Y, Ogawa K, Otake-Kasamoto
Y, Kawabata S, Nii T, Okuno T, Oguro-Igashira E, Kinoshita M,
Takagaki M, Oyama N, Todo K, Yamamoto K, Sonehara K, Yagita M,
Hosokawa A, Motooka D, Matsumoto Y, Matsuoka H, Yoshimura M,
Ohshima S, Shinzaki S, Nakamura S, Iijima H, Inohara H, Kishima
H, Takehara T, Mochizuki H, Takeda K, Kumanogoh A, Okada Y*.
Prokaryotic and viral genomes recovered from 787 Japanese gut
metagenomes revealed microbial features linked to diets, populations, and diseases. Cell Genom 2, 100219 (2022)
Namkoong H, Edahiro R, Takano T, Nishihara H, Shirai Y, Sonehara K, Tanaka H, Azekawa S, Mikami Y, Lee H, Hasegawa T,
Okudela K, Okuzaki D, Motooka D, Kanai M, Naito T, Yamamoto
K, Wang QS, Saiki R, Ishihara R, Matsubara Y, Hamamoto J,
Hayashi H, Yoshimura Y, Tachikawa N, Yanagita E, Hyugaji T,
Shimizu E, Katayama K, ... Biobank Japan Project; Yosuke Omae
Y, Nannya Y, Ueno T, Katayama K, Ai M, Fukui Y, Kumanogoh A,
Sato T, Hasegawa N, Tokunaga K, Ishii M, Koike R, Kitagawa Y,
Kimura A, Imoto S, Miyano S, Ogawa S, Kanai T, Fukunaga K,
Okada Y*. DOCK2 is involved in genetics and biology of severe
COVID-19. Nature 609, 754-760 (2022)
Ishigaki K, Sakaue S, Terao C, Luo Y, Sonehara K, Yamaguchi K,
Amariuta T, Too CL, Laufer VA, Scott IC, Viatte S, Takahashi M,
Ohmura K, Murasawa A, Hashimoto M, Ito H, Hammoudeh M,
Emadi SA, Masri BK, Halabi H, Badsha H, Uthman IW, Wu X, Lin
L, Li T, ... BioBank Japan Project, Matsuda K, Matsuo K, Mimori
T, Matsuda F, Fujio K, Tanaka Y, Kumanogoh A, Traylor M, Lewis
CM, Eyre S, Xu H, Saxena R, Arayssi T, Kochi Y, Ikari K, Harigai
M, Gregersen PK, Yamamoto K, Louis Bridges S Jr, Padyukov
L, Martin J, Klareskog L, Okada Y*, Raychaudhuri S*. Multiancestry genome-wide association analyses identify novel
genetic mechanisms in rheumatoid arthritis. Nat Genet 54,
1640-1651 (2022)

Invited presentations
Okada Y. “Methodologies in whole-genome sequence-based
association studies” International Common Disease Alliance
Meeting (Copenhagen, Denmark) December 2022
Okada Y. “Multi-trait and cross-population genome-wide association studies across autoimmune and allergic diseases identify shared and distinct genetic component” American Collegeof Rheumatology Covergence (Philadelphia, USA) November
2022
Okada Y. “Statistical genetics, disease biology, and drug discovery” Pan-cohort studies, Tohoku Medical Megabank (Sendai,
Japan/Online) October 2022
Okada Y. “Statistical genetics, disease biology, and drug discovery” International Conference of Precision Medicine, Taiwan
University (Taiwan/Online) October 2022
Okada Y. “Big data analysis of autoimmune diseases” 41st Annual Scientific Meeting of Korean College of Rheumatology
2021 (Seoul, Republic of Korea/Online) October 2021

26

T

he genome is the human blueprint. The goal of our team is to decipher
the blueprint and elucidate its hidden biology. An individual’s genetic
background has substantial impact on their risk of a wide range of complex
human diseases. Systems Genetics is a research field that evaluates the causality of human genetic variations on human phenotypes, using statistical andbioinformatics approaches. Recent developments in genome sequencing technologies have provided ample resources for genomics research. However, little
is known regarding how to develop the methodology to integrate large-scale
human genomics data with diverse biological and clinical information. In ourteam, we focus on large-scale human genome, omics and phenome data, andthe underlying high-dimensional network. By developing novel methodologies in statistical genetics and machine learning, we redefine human biology assystems genetics. Our team aims to elucidate disease biology and contribute tonovel drug discovery and implementation of genomic personalized medicine.
We successfully conducted large-scale, cross-population and biobank-driven
genome-wide association studies (GWAS) of hundreds of both common andrare human phenotypes, which identified >10,000 genetically associated loci.
Public release of the GWAS results contributed to construction of a global genotype-phenotype catalog. Population genetics analysis of the GWAS resource
revealed the evolutionary landscape of the Japanese population. In parallel, wedeveloped novel human omics layers, such as the gut microbiome, by metagenome shotgun sequencing, microRNA expression profiles by short non-coding
RNA sequencing and cell type-specific expression profiles by single-cell RNA
sequencing. Integrative analysis of trans-layer omics resources with human
genetics, represented as a polygenic risk score (PRS), demonstrated its value in
implementation of personalized medicine. To accelerate genomics-driven drug
development, our team released bioinformatics tools to translate human disease
genetics into candidate compounds for drug repositioning. A series of achievements by our team encompasses diverse scientific fields towards a true understanding of the blueprint.

Intra-TAD density change (

2

2

0

0

-2

-2

-4

-4

Laboratory for

10

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Functional
Non-coding
Genomics
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Egg - Control inter TAD interactions

ρ = 0.07 (n.s.)

non-piRNAtarget

4

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-6
ρ = 0.32 (p < 10 )piRNA target
10

10

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Team Leader: Yuka
W.-2 Iwasaki-2

Figure: Stepwise Piwi – piRNA-mediated regulation of nuclear architecture and chromatin state

F

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in

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Piwi

Panx
Nxf2 p15

Egg
HP1a

0.2

Lab Activities

Piwi – piRNA-mediated transcriptional silencing oftransposable elements is required to maintain genomic
integrity. We found that stepwise heterochromatinstructure formation is found to also involve Piwi –piRNA-mediated nuclear architecture changes at target
regions.

-4

-4

4

0.2

HP1a - Control inter TAD interactions

ρ = 0.22 (p < 0.01)
non-piRNAtarget0.1

Research Highlights

Inter-TAD density change (Z-score)

H1 - Control inter TAD interactions

ρ = 0.19 (p < 0.01)
piRNA target

0.0

0.2

Piwi-piRNA target TEs
Active histone markRepressive histone markIwasaki et al. EMBO J (2021)

Fig 6. Downstream factors, H1, Egg, and HP1a, cooperatively regulate chromatin con
in the Piwi-piRNA pathway.

Hasuwa H, Iwasaki YW, Yeung WKA, Ishino K, Masuda
H, Sasaki H, Siomi H. Production of functional oocytes
requires maternally expressed PIWI genes and piRNAs in
golden hamsters. Nature Cell Biology 23, 1002-1012(2021)

Invited presentations
Iwasaki YW. “Co-transcriptional silencing and heterochromatin formation by nuclear PIWI – piRNA complex”
Cold Spring Harbor Asia “RNA biology meeting” (Awaji,
Japan) December 2022

Iwasaki YW. “Understanding and reconstructing small
RNA-mediated heterochromatin formation” The 60th
Annual Meeting of the Biophysical Society of Japan(Hakodate, Japan) September 2022
Iwasaki YW. “Understanding and reconstructing small
RNA-mediated heterochromatin formation” RIKEN IMSMcGill Symposium (Online) September 2022
Iwasaki YW. “Understanding and reconstructing small
RNA-mediated heterochromatin formation” Japan-UK
Regulation through Chromatin Conference (Leicester,UK) August 2022

27

Data and Statistics

Iwasaki YW. “Understanding and reconstructing small
RNA-mediated heterochromatin formation” The 46th
Annual Meeting of the Molecular Biology Society ofJapan (Chiba, Japan) December 2022

ne of the significant achievements of recent transcriptome research is
elucidating the importance of "non-coding genomic regions" that do not
encode proteins. In diverse eukaryotes, non-coding genomic regions occupy
enormous portions of the genome. They include non-coding RNAs, which do
not code for proteins but perform various functions as RNAs, and transposable
elements that have the property of transposing or jumping around the genome.
Non-coding RNAs (ncRNAs) have been proposed to play critical roles inregulating the flow of genetic information, resulting in their critical impact
on cellular processes, organismal development and disease. However, the vast
majority of ncRNAs have not yet been functionally characterized and theirprecise functional mechanisms remain to be elucidated. We have been investigating small non-coding RNA functions using bioinformatics and biochemical
approaches. Our recent interest is to elucidate the transcriptional regulatory
mechanism of a class of small RNAs called PIWI-interacting RNAs (piRNAs),
which are capable of regulating transposable element expression via heterochromatin formation. We aim to further characterize this process and to develop asystem to reconstruct and utilize this small RNA-guided heterochromatin formation. In addition, we will perform a functional screening of ncRNAs, which
are capable of regulating nuclear events such as heterochromatin formation andchromatin compaction. We are also interested in transposable elements, which
may function as long ncRNAs or have potential functions as regulatory DNA
elements or domain structures within the genome. We are planning to uncover
the uninvestigated molecular functions of transposable elements.
Our overall long-term goal is to understand diseases, including developmental disorders, from new perspectives by clarifying and regulating the functional
mechanisms of non-coding genomic regions.

EventsIwasaki YW, Sriswasdi S, Kinugasa Y, Adachi J, Horikoshi
Y, Shibuya A, Iwasaki W, Tashiro S, Tomonaga T, Siomi
H. Piwi – piRNA complexes induce stepwise changes innuclear architecture at target loci. The EMBO Journal
40, e108345 (2021)

O

Projects

Recent Major Publications
Takeuchi C, Yokoshi M, Kondo S, Shibuya A, Saito K,
Fukaya T, Siomi H, Iwasaki YW. Mod (mdg4) variants
repress telomeric retrotransposon HeT-A by blocking
subtelomeric enhancers. Nucleic Acids Research 50,
11580-11599 (2022)

Laboratory for

Retrotransposon
Dynamics
Team Leader: Tomoichiro Miyoshi

Figure: Current model for L1 retrotransposition
facilitated by DNA repair factors

L1 ORF2p EN activity creates a nick in genomic DNA togenerate a 5’ phosphate and 3’ hydroxyl group to initiate
genomic insertion. The 5’ phosphate group is recognized
by PARP2, thereby leading to a local accumulation of
PAR (poly[ADP]-ribosylation). PAR can further recruit
RPA to the L1 integration site. RPA may then bind totransiently exposed ssDNA regions in retrotransposition
to protect ssDNAs from being attacked by the APOBEC3
cytidine deaminase, a potent inhibitor of L1.

Recent Major Publications
Luqman-Fatah A, Watanabe Y, Uno K, Ishikawa F, Moran
JV, Miyoshi T. The interferon stimulated gene-encoded
protein HELZ2 1 inhibits human LINE-1 retrotransposition and LINE-1 RNA-mediated type I interferon induction. Nat Commun 14, 203 (2023)

Luqman-Fatah A, Miyoshi T. Human LINE-1 Retrotransposons: Impacts on the Genome and Regulation by Host
Factors. Genes Genet Syst Online ahead of print (2022)
Invited presentations
Miyoshi T. “Mechanisms of retrotransposition of LINE1, a mobile genetic element” The 192nd Bio Seminarat Nagahama Institute of Bio-Science and Technology(Nagahama, Japan) October 2022

Miyoshi T. “Host defense mechanisms against inhibitionof human LINE-1 retrotransposition” The 23rd Symposium of the Graduate School of Biostudies (Kyoto, Japan)
July 2022
Miyoshi T. “Mechanisms of human LINE-1 retrotransposition” Kyoto University Leading Scientist Seminar (Kyoto,
Japan) March 2022

28

RPA recruitment

RPA accumulation

A3A

PAR

5’

5’

PARP2
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3’

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AAATT
TT

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OR

3’
Nick

PARP2 activation

PARP2
P

A
AAATT
TT

F2
OR
Reverse transcription

5’
3’

PARP2
P

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TTT

ssDNA protection by RPA
during L1 retrotransposition

Figure 1: Current model for L1 retrotransposition facilitated by DNA repair factors
L1 ORF2p EN activity creates a nick in genomic DNA to generate a 5' phosphate and 3' hydroxyl
group to initiate genomic insertion. The 5' phosphate group is recognized by PARP2, thereby
maintenanceofofgenetic
information is criticallivingorganleadingtable
to a local
accumulation
PAR (poly[ADP]-ribosylation).
PARforcanallfurther
recruitRPA
to the L1
integrationsite. RPA
may then bind
to transiently
ssDNA
regions inrepetiretroisms.
However,transposable
elements(TEs),exposed
the most
abundanttransposition to protect ssDNAs from being attacked by APOBEC3 cytidine deaminase, ative sequences in mammals, can cause structural variants and disease-causing
potent inhibitor of L1.

S

mutations. TEs mobilize into new genomic locations via a DNA (i.e., DNAtransposon) or RNA intermediate (i.e., retrotransposon). Human retrotransposons, Long INterspersed Element-1 (LINE-1s or L1s) and Short INterspersed
Elements (SINEs) including Alu, respectively comprise ~17% and ~11% of the
genome and still frequently “jump” in the genome. De novo L1 and Alu insertion termed retrotransposition have led to sporadic genetic diseases including
various types of cancer; however, much remains to be clarified about the mechanisms of action. We posit that a mechanistic understanding of retrotransposition is critical for unraveling the processes that lead to human disease, genetic
variation and genome evolution.
We currently focus on i) exploring the mechanisms of L1/Alu retrotransposition and ii) investigating the impact of L1/Alu expression on diseaseassociated phenotypes such as chronic inflammation. Since L1/Alu have been
co-evolving within the host genomes through millions of years, host cellular
proteins likely have a dynamic and functional interplay with the L1/Alu retrotransposon-derived RNAs and proteins. However, previous studies of mammalian retrotransposons have lacked a biochemical perspective. Therefore, wehave tackled proteomic analyses of the L1 encoded proteins to identify hostfactors that control L1 retrotransposition. This allowed the identification of anumber of L1 regulators, including conserved DNA repair proteins and innate
immune response factors. Furthermore, our extensive genetic and biochemical
analyses demonstrated that L1s exploit the host DNA repair system to expand
their copy number in the genome; however, in response, the host antiviral system may counteract the L1 activities to maintain genome integrity.
Our long-term goal is to elucidate the mechanisms underlying “jumping” ofretrotransposons and to develop new methods to suppress L1/Alu activities.

Division of Human Immunology

Division of Human Immunology will elucidate the principles of theimmune system and develop a research platform for human immunology.

Laboratory for

Autoimmune Diseases
Team Leader: Kazuhiko Yamamoto

Healthy individuals
Figure: Advanced multi-omics data sets for theevaluation of human immune function
In collaboration with the Laboratories for Human Immunogenetics, Systems Genetics, Cancer Genomics,
Metabolomics,Integrative Genomics, Intestinal Ecosystem,
Immunotherapy, Statistical and Translational Genetics, LargeScale Biomedical Data Technology and YCI unit for proteomics.

Environmental factors
Age, sex, microbiome

Cell type‐specific eQTLs
Epigenome(open chromatin, histone marks)
Cis/trans

Gene expression
regulators
enhancer

Immune‐related promoter
genetic variants lncRNA(several thousands) transcription factor

Recent Major Publications
Nakano M, Ota M, Takeshima Y, Iwasaki Y, Hatano H, Nagafuchi
Y, Itamiya T, Maeda J, Yoshida R, Yamada S, Nishiwaki A, Takahashi H, Takahashi H, Akutsu Y, Kusuda T, Suetsugu H, Liu L,
Kim K, Yin X, Bang SY, Cui Y, Lee HS, Shoda H, Zhang X, Bae SC,
Terao C, Yamamoto K, Okamura T, Ishigaki K, Fujio K. Distinct
transcriptome architectures underlying lupus establishment
and exacerbation. Cell 185, 3375-3389.e21 (2022)
Ishigaki K, Sakaue S, Terao C, Luo Y, Sonehara K, Yamaguchi K,
Amariuta T, Too CL, Laufer VA, Scott IC, Viatte S, Takahashi M,
Ohmura K, Murasawa A, Hashimoto M, Ito H, Hammoudeh M,
Emadi SA, Masri BK, Halabi H, Badsha H, Uthman IW, Wu X, Lin
L, Li T, Plant D, Barton A, Orozco G, Verstappen SMM, Bowes
J, MacGregor AJ, Honda S, Koido M, Tomizuka K, Kamatani Y,
Tanaka H, Tanaka E, Suzuki A, ... Kochi Y, Ikari K, Harigai M, Gregersen PK, Yamamoto K, Louis Bridges S Jr, Padyukov L, Martin J,
Klareskog L, Okada Y, Raychaudhuri S. Multi-ancestry genomewide association analyses identify novel genetic mechanisms inrheumatoid arthritis. Nat Genet 54, 1640-1651 (2022)
Takeshima Y, Iwasaki Y, Nakano M, Narushima Y, Ota M, Nagafuchi Y, Sumitomo S, Okamura T, Elkon K, Ishigaki K, Suzuki A,
Kochi Y, Yamamoto K, Fujio K. Immune cell multiomics analysis
reveals contribution of oxidative phosphorylation to B-cellfunctions and organ damage of lupus. Ann Rheum Dis 81,
845-853 (2022)

Invited presentations
Yamamoto K. “Immunogenetics of rheumatoid arthritis& way forward” 24th Asia-Pacific League of Associations
for Rheumatology (Hong Kong, China) December 2022

Yamamoto K. “Data-driven functional analysis of human
lymphocytes” Tsinghua RIKEN Joint workshop (Online)
November 2022
Yamamoto K. “Human immune diversity for infection
and vaccine development” RIKEN-KI-SciLifeLab Symposium (Stockholm, Sweden) October 2022
Yamamoto K.“Evaluation of human immune function for
vaccine development” McGill-RIKEN Symposium (Montreal, Canada) September 2022
Yamamoto K. Ishigaki K. “Trans-ancestry genome-wide
association study identifies novel genetic mechanisms
in rheumatoid arthritis” International Forum of Rheumatoid Arthritis 2022 (Beijing, China/Online) September
2022

30

T

Target geneIntermediate
phenotypes

Immune cells

proteome
lipidomemetabolome
TCR/BCR
immunologicalmemoryNatural immunity

macrophages
dendritic cells
NK cells/NKT cells
innate lymphoid cells

Acquired immunity
T cells
B cells

he majority of the disease-susceptibility genetic variants revealed by ge1
nome-wide association study (GWAS) function as expression quantitative
trait loci (eQTLs) that are involved in gene expression. The effects of eQTL arefrequently found in a cell type-specific manner. Such cell specificity is largely
due to epigenomic alterations, such as cell type-specific histone modifications
and DNA methylation in specific regions of chromosomes. It has been further
reported that disease susceptibility variants significantly overlap with the location of histone modifications in promoters and active enhancers of specific immune cell subsets. Therefore, it is possible to obtain causal information about
the intermediate phenotypes between genetic information and disease state byqualitatively and quantitatively measuring the functional molecules of immunocompetent cells in various immunological diseases by focusing on diseasesusceptibility genetic variants, gene expression (mRNA), epigenome, and proteins.
We are performing functional genomic strategies for integrating GWAS
results with the current understanding of specific diseases, mainly focusing
on promoters, enhancers, and long non-coding RNAs. We are isolating nearly
30 different lymphocyte subsets from human peripheral blood mononuclear
cells of healthy individuals and analyzing genotypes, gene expression and open
chromatin regions. Cells from healthy individuals are expected to exhibit theleast biased gene expression. Since chromosomes are transmitted to offspring incertain blocks and many neighboring genetic variants behave similarly, it is noteasy to determine which among them is the true causal variant. Using several
methods including CAGE analysis, we are tracking down the targets.
We are also performing various analyses using recently developed single-cell
technologies. By integrating these pieces of information, we can understand thephysiological and pathological changes of the whole immune system of an individual and the ways for intervening under unfavorable conditions.

Laboratory for

Research Highlights

Cell Signaling
Team Leader: Takashi Saito

Inducer ?
RIPK1
RIPK3

Figure: RIPK1 regulatory mechanism of T cellsenescence and consequent inflammation andage-related diseases

Invited presentations
Saito T. “T cell senescence regulated by RIPK1/RIPK3 /caspase-8 induces age-related inflammation diseases”
Hokkaido Univ. Seminar (Sapporo, Japan/Online) December 2022

Saito T. “Mechanism of inducing T cell senescence followed by inflammation diseases” OIST conference (Okinawa, Japan) March 2022
Saito T. “Regulation of adhesion and activation of T
cells at Immune synapse” The 44th Annual Meeting ofMolecular Biology Society of Japan 2021 (Yokohama,Japan/Online) December 2021

Senescent T cells

Inflammaging
diseases
Cytokines
Chemokines
SASPT

he objective of our team is to determine the molecular mechanisms of T
cell activation, differentiation and function. Ultimately, we wish to elucidate the onset of T cell function/activation and be able to modulate the process
to prevent immune diseases such as autoimmunity and allergic inflammation.
For this purpose, we have analyzed the regulation of T cell activation/function
from a signaling perspective.
During the analyses on the modulation of T cell function by innate-likesignals, we found that Receptor-interacting serine/threonine-protein kinase 1(RIPK1) plays a critical role in T cell function and particularly cellular senescence. RIPK-1 is known to function both in cell death and survival. We generated and analyzed T cell-specific RIPK1-deficient (tKO) mice to analyze its
function in metabolism and aging of T cells. RIPK1-tKO mice develop various
inflammatory diseases with aging (inflammaging) and early death. T cells in the
KO mice show a senescence phenotype from early life through constitutive activation of Caspase-8, RIPK3 and mTORC1. Inhibition of mTORC1 or caspase-8/
RIPK3 eliminated the T cell senescence and age-related disease phenotypes.
Therefore, RIPK3/caspase-8 induced basal activation of mTORC1 and a senescence program, leading to inflammaging. It has been suggested that senescentcells influence neighboring cells to induce senescence. When senescent T cells
were transferred into normal mice, they returned to a normal state, whereas
normal T cells become senescent when transferred into RIPK1-KO mice, suggesting critical roles of environmental signals for regulating senescence.
Our finding that TCR-microclusters (MC) initiate T cell activation led us toanalyze the dynamics of signaling molecules at the immune synapse. Similar toour previous studies of CTLA4 and PD-1, we have analyzed the dynamic regulation of another inhibitory co-stimulator, LAG3. LAG3 was also colocalizedwith the TCR-MC upon TCR stimulation to mediate inhibition of T cell activation. Since this association is critical for the inhibitory function, anti-LAG3 Ab
induced separation of the LAG3 cluster from the TCR-MC and, consequently,
enhancement of T cell activation. Our analyses provide a dynamic view ofsignal regulation to define the inhibitory mechanism. Furthermore, we havealso analyzed negative regulation of T cell activation by autoimmune-related
PTPN22. Its deficiency resulted in enhanced activation and an increase in effector/memory T cells. Analysis of the associated proteins revealed that PTPN22
was recruited to the TCR-MC to comprise an “inhibitory complex” with otherinhibitory molecules to inhibit activation. A PTPN22 mutant causing susceptibility to autoimmune diseases was defective in recruitment to the TCR-MC.
These studies help define the mechanism of autoimmune susceptibility causedby the mutation.
31

Data and Statistics

Kumagai A, Nara T, Uematsu M, Kakinuma Y, Saito T,
and Masuda K. Development and characterization ofa unique anti-IgE monoclonal antibody cross-reactive
between human and canine IgE. Immun. Inflamm. Dis9, 1740-1748 (2021)

Senescencerelated genes

EventsTakemori T, Sugimoto-Ishige A, Nishitsuji H, Futamura
Y, Harada M, Kimura-Someya T, Matsumoto T, Honma T,
Tanaka M, Yaguchi M, Isono K, Koseki H, Osada H, Miki
D, Saito T, Tanaka T, Fukami T, Goto T, Shirouzu M, Shimotohno K, Chayama K. Establishment of a monoclonal
antibody against human NTCP that blocks HBV infection.
J. Virol 96, e0168621 (2022)

Senescent Tissue
Environmental signals

Projects

Recent Major Publications
Imanishi T, Unno M, Yoneda N, Motomura Y, Mochizuki M,
Sasaki T, Moro K, Pasparakis M, and Saito T. RIPK1 blocks
T cell senescent regulated by RIPK3 and caspase-8. Science Advances 9, eadd6097 (2023)

Over-activation Akt mTORC1 ERKNormal Tissue
Environmental. signals

Lab Activities

RIPK1 inhibits excess activation of mTORC1 by inhibiting
RIPK3 and Caspase-8. Overactivation of mTORC1 induces
expression of senescence-related genes, promotes T
cell senescence, which leads to the production of various cytokines and chemokines, and also promotes thesenescence-associated secretory phenotype (SASP),
which promotes tissue senescence and induces agerelated diseases. Senescent tissue environmental signals
enhance mTORC1 activation and exacerbate aging andage-related diseases. On the other hand, normal tissue
environmental signals inhibit mTORC1 activation and T
cell senescence and inflammaging.

Caapase-8

Laboratory for

Lymphocyte
Differentiation
Team Leader: Tomohiro Kurosaki

Figure: Antibody feedback takes place with
SARS-CoV-2 mRNA vaccination

After initial vaccination, B cells harboring BCRs specificfor dominant epitopes (green) are initially activatedand differentiate into plasma cells producing antibodies(green antibodies). Then, for example, after a second
vaccine dose, the produced antibodies mask their own
epitopes, preventing activation of the B cells recognizing
the cognate dominant epitope. Instead, B cells targetinga subdominant epitope (red) are activated, thereby producing antibodies (red antibodies). In the case of SARSCoV-2 vaccination, these red antibodies can also crossreact with and neutralize the Omicron variant viruses.

Recent Major Publications
Inoue T, Shinnakasu R, Kawai C, Yamamoto H, Sakakibara S, Ono C, Itoh Y, Terooatea T, Yamashita K, Okamoto
T, Hashii N, Ishii-Watabe A, Butler NS, Matsuura Y,
Matsumoto H, Otsuka S, Hiraoka K, Teshima T, Murakami
M, Kurosaki T. Antibody feedback contributes to facilitating the development of Omicron-reactive memory B
cells in SARS-CoV-2 mRNA vaccinees. J Exp Med 220,e20221786 (2023)

Koike T, Fujii K, Kometani K, Butler NS, Funakoshi K, Yari S,
Kikuta J, Ishii M, Kurosaki T, Ise W. Progressive differentiation toward the long-lived plasma cell compartmentin the bone marrow. J Exp Med 220, e20221717 (2023)
Tanaka S, Ise W, Baba Y, Kurosaki T. Silencing and activating anergic B cells. Immunol Rev 307, 43-52 (2022)
Invited presentations
Fukuyama H. “Transdermal adjuvant for next-generation
vaccines” RIKEN-KI-SciLifeLab Symposium: Preparing forthe next pandemic (Solna, Sweden) October 2022

Kurosaki T. “Involvement of BCR signal strength in Germinal center selection” The EMBO workshop on Germinal
centers and immune niches (Rehovot, Israel) September
2022
Kurosaki T. “Differentiation to plasma cells and theirfates” Dynamics of Immune Repertoires: Exploration andTranslation working group “The primary B-cell immune
response” (Dresden, Germany) July 2022
Kurosaki T. “Memory B cells; their generation and activation mechanisms” EMBO Workshop Lymphocyte antigen
receptor signaling (Siena, Italy) May 2022
Kurosaki T. “B cell fate decisions during germinal center(GC) reactions” UCL Symposium (London, U.K) May 2022

32

G

iven that most BCRs of memory B cells and long-lived plasma cells(LLPCs) are extensively somatically hypermutated (SHM), it is importantto understand how the germinal center (GC) reaction is taking place, thereby
generating memory B cells and LLPCs. From 2019 to 2022, our laboratory
has particularly focused on clarifying two fundamental questions. First, dothey (memory B cells and LLPCs) act redundantly or does each play a uniquerole? Second, if such unique roles exist, does each generation mechanism explain these unique roles? From a translational view, we have been establishingplatforms for generating single cell BCR (scBCR) repertoire data and analysisof their function by producing recombinant mAb. Then, by employing thistechnology, we have addressed the question of why a third dose of the original
Wuhan SRAS-CoV-2 mRNA vaccine elicits potent neutralizing antibody activity against the Omicron variant (as shown in the Figure).
As mentioned above, we have been studying basic mechanisms to generate memory B cells and LLPCs, but, how these two cellular compartments aremaintained has not been well addressed. Particularly, identification of key factors to make differentiation of short-lived plasma cells (SLPCs) into LLPCs is
one of the unresolved important questions. Previous studies considered theplasma cells residing in the bone marrow simply as LLPCs. However, given thatthe bone marrow also contains SLPCs, caution for interpretation of the previous data is required. Thus, to overcome this weak point, we have employed atime-stamping method for plasma cells, thereby allowing us to directly measure
the decay time and to distinguish SLPCs and LLPCs.

Laboratory for

Research Highlights

Transcriptional
Regulation
Team Leader: Ichiro Taniuchi

Figure: Runx3/Cbfβ2 dependent developmentof Thetis antigen-presenting cells imparts Tregdependent tolerance to gut microbiota

Okuyama K, Taniuchi I. Three residues in the BTB domain
promote a good partnership between NuRD and Thpok.
Sci Immunol 7, eabq1408 (2022)

Invited presentations
Taniuchi I. “Applying BioID in Mice” 95th Annual Meetingof the Japanese Biochemical Society (Nagoya, Japan)
November 2022

Taniuchi I. “The Roles of Runx family proteins in cancer
immunity” 13th annual scientific meeting of SGCC (Singapore, Singapore) July 2022
Taniuchi I. “Phosphorylation of Runx proteins controls
thymocyte fate” SEMMinars at IFOM-IEO (Milan, Italy)
June 2022

T

he primary developmental program of T lymphocytes that occurs in thethymus has been shaped to select useful and non-self-reactive immune
soldiers to generate pools of lymphocytes with a broad variety of antigen specificities. This selection process requires a sophisticated nuclear program that integrates environmental cues sensed by T cell antigen receptors (TCR). My laboratory has been addressing how TCR signals are sensed and are coupled withcell fate determination programs in the nucleus by using helper versus cytotoxic
lineage choice as a model, in which repression of Zbtb7b and Cd4 genes by
Runx-dependent silencers at these loci serves as a key regulatory mechanism.
Our previous studies showed that the WRPY peptide motif at the C-terminalend of the Runx protein is essential for repression of Zbtb7b and Cd4 genes byrecruiting TLE/Groucho corepressor family proteins. Our current genetic study
confirmed that the terminal tyrosine (Y) residue is absolutely required for appropriate coupling of MHC restriction with appropriate cell fate. We have confirmed that the terminal Y residue is phosphorylated and that this phosphorylation is essential for the interaction of Runx proteins with TLE proteins. We areinvestigating how this phosphorylation is regulated.
Our second objective is to understand the functions of Runx/Cbfβ transcription factor complexes during immune system development. In mice lacking
Cbfβ2, one of two RNA splice variants of the Cbfb gene, peripherally-induced
Rorγt+Foxp3+ pTreg cells are specifically lost and colitis spontaneously develops within 3 months (Fig1. A). Development of pTregs is restored by inducible
transgenic expression of Cbfβ2 in antigen-presenting cells. We then examinedcandidate cells for this APC and found that Thetis cell subsets (TC2 and TC3)
were lost in Cbfβ2-deficient mice (Fig. 1B). Thus, our results have resolved acontroversial issue of what is the actual APC for pTreg differentiation.

33

Data and Statistics

Taniuchi I. “Phosphorylation on the terminal tyrosine
residue in Runx proteins links environmental cues withcell fate determination” The 23rd international RUNX
conference (San Antonio, USA) October 2022

12 weeks

EventsDouchi D, Yamamura A, Matsuo J, Lee JW, Nuttonmanit
N, Melissa Lim YH, Suda K, Shimura M, Chen S, Pang
S, Kohu K, Kaneko M, Kiyonari H, Kaneda A, Yoshida H,
Taniuchi I, Osato M, Yang H, Unno M, Bok-Yan So J, Yeoh
KG, Huey Chuang LS, Bae SC, Ito Y. A Point Mutation
R122C in RUNX3 Promotes the Expansion of Isthmus
Stem Cells and Inhibits Their Differentiation in the Stomach. Cell Mol Gastroenterol Hepatol. 13, 1317-1345(2022)

Cbfb2m/2m

Projects

Recent Major Publications
Yamashita M, Taniuchi I. Fine-tuning Notch1 by thestage-specific enhancer. Nat Immunol. 23, 1509-1511(2022)

Cbfb+/+Lab Activities(A) Spontaneous colitis development and specific loss of
Rorγt+ FoxP3+ pTreg cells in the gut of Cbfβ2-deficient(Cbfb 2m/2m) mice. (B) Flow cytometry analysis of Thetis
cell (TC) subsets in mesenteric lymph nodes. Cbfβ2deficient mice lack TC2 and TC3 subsets and their development is restored by inducible transgenic expressionof Cbfβ2 from the Rosa26 locus by a Rorc-cre transgene,which is accompanied by restoration of Rorγt+ FoxP3+
pTreg development.

B
B

A
A

Laboratory for

Immune Cell Systems
Team Leader: Shigeo Koyasu*Ref; Immugen data base*Ref; Immugen data base
NK/ILC1

Figure:(Top panels) Expression levels of VIPR2 (left) and HTR1b(right) on splenic NK/ILC1, SI-ILC2, and SI-ILC3. (Bottom
panels) Weight gain of wild type or Vipr2-/- mice (left)
and wild type or Htr1b-/- mice (right) fed a high-fat diet.

ILC2
ILC3

Misawa T, Wagner M, Koyasu S. ILC2s and adipose tissue homeostasis: Progress to date and the road ahead.
Front Immunol 13, 876029 (2022)
Wagner M, Koyasu S. Cancer immunosurveillance by
ILC2s. Trends Cancer 8, 792-794 (2022)
Invited presentations
Koyasu S. “Role of innate lymphoid cells in diet-induced
obesity” Japanese-German Immunology Workshop 2022
(Gosler, Germany) September 2022

Koyasu S. “Group 2 innate lymphoid cells and allergic
inflammation” The 50th Annual Meeting of the JapaneseSociety for Clinical Immunology (Tokyo, Japan) October
2022

34

30
25
20
15
10
5
0

VIPR2+/+
VIPR2-/-

0 7 14 21 28 35 42 49 56

HFD feeding daysO

Weight gain (g)Recent Major Publications*Nomura H, *Wada N, Takahashi H, Kase Y, Yamagami
J, Egami S, Iriki H, Mukai M, Kamata A, Itoh H, Fujii H,
Ishikura T, Koseki H, Watanabe T, Yamada T, Ohara O,#Koyasu S, #Amagai M. IgM to IgG class-switching is anecessary step for pemphigus phenotype induction indesmoglein 3-specific B cell receptor knock-in mouse.
J Immunol 208, 582-593 (2022)

Weight gain (g)

0

20
15

10
20
30
40
HTR1b Expression Value
Normalized by DESeq2

HTR1b+/+
HTR1b-/-

10
50

0 7 14 21 28 35 42 49 56

HFD feeding days

ur long-term goal is to elucidate the immune cell network to understandhow immune cells induce complex immune reactions in our bodies.
Among a variety of immune cells, we have focused on innate lymphoid cells(ILCs) and their role in adipose tissue homeostasis and tumor immunity. We
have previously shown that ILC2 and ILC3 in the small intestine but not in the
adipose tissue are involved in diet-induced obesity. We also showed that theIL-2/ILC2/3 axis plays an important role in the induction of obesity. Transcriptomic analysis revealed that a serotonin receptor, HTR1b, and a receptor forvasoactive intestinal peptide, VIPR2, were highly expressed on ILC2. Htr1b-/and Vipr2-/- mice were generated and both were shown to be resistant to dietinduced obesity, suggesting that intestinal hormones acting on ILCs play a rolein the induction of obesity. In addition to obesity, starvation is also known to
induce liver steatosis. We have noticed that Rag2-/- mice with a larger num-berof ILCs compared to wild-type mice had more severe steatosis but Il2rg-/-Rag2-/mice lacking all lymphocytes had less severe steatosis compared to wild typemice upon starvation. Both ILC2 and ILC3 are involved in this process by regulating lipid uptake in the small intestine. Using the B16 mela-noma model, we
have previously shown that the IL-33/ILC2/eosinophil axis suppressed tumor
growth. In humans, expression of IL33 (activation of ILC2) and SIGLEC8 (recruitment of eosinophils) are associated with better overall survival in melanoma patients, whereas no correlation was observed between the expression levelsof IL33 and SIGLEC8 and overall survival for some other tumors, such as lungsquamous cell carcinoma and pancreatic adenocarcinoma. We have further
noticed that ILC2 in the skin plays a role in melanoma-associ-ated lymphangiogenesis and are currently studying its mechanisms.

Laboratory for

Research Highlights

Innate Immune Systems
Team Leader: Kazuyo Moro

Figure: Schematic representation of ILC1-mediated epithelial barrier response

Kobayashi T, Moro K. A hairy situation for ILC2s. Immunity 55, 1756-1758 (2022)
Kabata H, Motomura Y, Kiniwa T, Kobayashi T, Moro K.
ILCs and Allergy. Adv Exp Med Biol 1365, 75-95 (2022)

Moro K. “4th International Conference on Innate Lymphoid Cells” (Hawaii, USA) September 2022

Moro K. “The Role of Type 2 innate lymphoid cells inmucosal tissues” Food, Microbiota and Immunity 2022
(Prague, Czech) June 2022
Moro K. “The discovery of group 2 innate lymphoid cells”
Global Immunetalks (Online) March 2021

35

Data and Statistics

Moro K. “The role of group 2 innate lymphoid cells in
pulmonary diseases” 2022 Advanced Immunology
Course (FIMSA) (Taiwan/Online) August 2022

EventsInvited presentations
Moro K. “The Scientific Organizing Committee of the2022 Annual Meeting of the Society for Leukocyte Biology” (Hawaii, USA) October 2022O

ur team has been investigating group 2 innate lymphoid cells (ILC2s),
the innate lymphoid lineage cells identified in 2010. ILC2s are present invarious tissues such as fat, lung, intestine, liver, and skin and mediate immune
responses to parasite infections via strong type 2 cytokine production, including IL-5, IL-13, IL-9 and GM-CSF. Unlike T and B lymphocytes, ILC2s lackantigen-specific receptors and are activated by stroma cell-derived cytokines
such as IL-33. Type 2 cytokines produced by ILC2s play an important rolein the pathogenesis of allergic diseases such as asthma and atopic dermatitis;
however, most previous studies on allergy have focused on the role of adaptive
immune cells (T and B cells) in antigen-dependent allergic responses and thecontribution of the innate immune system has been underestimated. Therefore, one of our goals was to investigate the mechanisms by which ILC2 activation is triggered and persistently regulated to establish new therapeutic strategies for allergic diseases. Moreover, we also aim to uncover pleiotropic effector
functions of ILC2s. We clarify the roles of ILC2s in homeostatic maintenanceof barrier integrity, metabolic regulation and the aging process. Furthermore,
as ILC2s are involved not only in allergic diseases but also in a variety of otherimmune-related diseases, we are also investigating how ILC2s are associatedwith the pathogenesis of non-allergic diseases such as fibrosis and endometriosis. Our long-term goal is a comprehensive understanding of innate immune
systems, particularly ILC2 biology, which plays a key role in human health anddiseases.

Projects

Recent Major Publications
Kobayashi T, Moro K. Tissue-Specific Diversity of Group 2
Innate Lymphoid Cells in the Skin. Front Immunol 13,885642 (2022)

Lab Activities

Mechanical damage induces release of extracellular ATP(eATP) from epithelial cells, which initiates keratinocyte
proliferation. eATP simultaneously increases amphiregulin (AREG) production in skin-resident ILC1, whichfurther promotes barrier restoration. The ILC1-meditaed
barrier response plays a key role in the protection
against mechanical damage-induced oxidative stressand DNA damage.

Laboratory for

Immune Homeostasis
Team Leader: Taishin Akiyama

Figure:Single cell RNA-seq of isolated TA-TEC candidates andtheir progeny after the reaggregation thymic organ
culture.
Well-based scRNA-seq analysis of TA-TEC and theirprogeny was performed and the data were integrated
with droplet-based scRNA-seq data of TECs for the assignment of cell type.

Recent Major Publications
Miyao T, Miyauchi M, Kelly ST, Terooatea TW, Ishikawa
T, Oh E, Hirai S, Horie K, Takakura Y, Ohki H, Hayama
M, Maruyama Y, Seki T, Ishii H, Yabukami H, Yoshida M,
Inoue A, Sakaue-Sawano A, Miyawaki A, Muratani M,
Minoda A, Akiyam N, Akiyama T*. Integrative analysis of
scRNA-seq and scATAC-seq revealed transit-amplifying
thymic epithelial cells expressing autoimmune regulator. Elife 11, e73998 (2022)

Katayama Y, Yokota R, Akiyama T, Kobayashi TJ. Machine
Learning Approaches to TCR Repertoire Analysis. Front
Immunol 13, 858057 (2022)
Nishijima H, Matsumoto M, Morimoto J, Hosomichi K,
Akiyama N, Akiyama T, Oya T, Tsuneyama K, Yoshida H,
Matsumoto M. Aire Controls Heterogeneity of Medullary Thymic Epithelial Cells for the Expression of SelfAntigens. J Immunol 208, 303-320 (2022)
Invited presentations
Akiyama T. “Regulatory mechanisms underlying gene
expression in thymic epithelium” The 5th TsinghuaRIKEN Joint Workshop on Recent Progress in Immunology (Online) November 2022

36

T

he thymus plays critical roles in the development of self-tolerant T cells
and regulatory T cells, and therefore, thymic dysfunction causes immunodeficiency and autoimmune diseases. The aims of our study are 1) to
identify molecular and cellular mechanisms regulating T cell selection and differentiation in the thymus, 2) to elucidate mechanisms underlying the onset of
immure-related diseases caused by dysregulation of the thymus and 3) to define
the impacts of environmental changes, including aging, on thymic functions
and their underlying mechanisms.
Medullary thymic epithelial cells (mTECs) play essential roles in preventing
the onset of autoimmune diseases. mTECs ectopically express and present several thousands of tissue-specific antigens (TSAs) and induce apoptosis of TSAreactive T cells and otherwise converts them into regulatory T cells. The ectopic
TSA expression by mTECs is regulated by the transcriptional regulator AIRE
and other regulators. AIRE-expressing (AIRE+) mTECs turnover with around a2-week lifetime, however, mechanisms involved in maintaining mTECs remain
elusive. We recently found evidence for the presence of AIRE+ transit amplifying TEC progenitors that differentiate into mature mTECs expressing TSAs
(Figure).
Thymoma, a tumor of TECs, is closely associated with the onset of various
autoimmune diseases, including myasthenia gravis, which are called thymomaassociated autoimmune diseases. Elucidation of altered gene expression andits regulatory mechanism in thymoma TEC may identify new mechanisms
involved in the onset and progression of autoimmune diseases. We performed
single-cell RNA-seq analysis of tumor and normal TECs from human thymoma
patients and thereby identified specific transcriptional regulators down-regulated in tumor mTECs compared to normal mTECs. Validating the functionsof these candidate regulators would be important to find new mechanisms forsuppressing the onset of autoimmune diseases.

Laboratory for

Research Highlights

Immune Crosstalk
Team Leader: Hilde Cheroutre

a aThemis/Ty1(Runx1)

Figure: Proximity between RUNX1 and THEMIS
visualized by the PLA assaybba. ERT2-Themis;Runx1Ty1 knock-in mice were treated
with/without Tamoxifen and thymocytes were examined. Magenta dot indicates proximity between Runx1
and Themis. Nuclei were stained with DAPI.
b. Numbers of dots in the nucleus and cytoplasm werecounted. The X axis shows the total number of dots in asingle cell and the Y axis shows log2 value of the ratio
between nucleus and cytoplasm.

2

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Tamo
Oil

-3

Seo GY, Takahashi D, Wang Q, Mikulski Z, Chen A, Chou
TF, Marcovecchio P, McArdle S, Sethi A, Shui JW, Takahashi M, Surh CD, Cheroutre H, Kronenberg M. Epithelial
HVEM maintains intraepithelial T cell survival and contributes to host protection. Sci Immunol 7, eabm6931(2022)

Invited presentations
Kakugawa K. “Dynamic THEMIS subcellular localization
is essential for its function” La Jolla Immunology Conference (La Jolla, USA) October 2022

Cheroutre H. “Gastrointestinal Tract XX: Making andBreaking a Gut” FASEB meeting (Steamboat Springs,
USA) August 2022
Cheroutre H. “RARa controls FOXP3 T cell fate but not as
a nuclear receptor” (North Carolina, USA) April 2022
Cheroutre H. Oklahoma seminar "Protective tolerance: a
new concept in immunology" (Oklahoma, USA) February 2022

e discovered THEMIS as an essential gene for T cell development.
Many GWAS studies revealed that the Themis locus associates withT cell-driven autoimmune diseases such as Celiac Disease, Multiple Sclerosis,
Rheumatoid Arthritis and Atopic Dermatitis. THEMIS is involved in T cell receptor (TCR) signaling as an adapter molecule able to modulate signal strength.
THEMIS-deficiency results in impaired development and selection of conventional mature T cells. However, the mechanisms used by THEMIS to control
TCR signaling remain unclear and controversial. Moreover, THEMIS is alsopresent in the nucleus, but its nuclear function has not been addressed.
We aimed to identify THEMIS interacting proteins in the cytoplasm andnucleus with/without TCR stimulation by biotinylating enzyme and Mass spectrometry. We introduced a TurboID-Themis fusion construct into the mouse T
cell hybridoma, 2B4 and compared the array of biotinylated proteins after TCR
stimulation with those of unstimulated 2B4 and found that, besides cytoplasmic components, several important nuclear proteins were biotinylated. These
included histone modification enzymes, transcription factors such as Runx1,
components of the nuclear pore complex, and chromatin-remodeling proteins.
We further identified dynamic interactions between RUNX1 and THEMIS
using the Proximal Ligation Assay (PLA). When the 2B4 cell line overexpressing ERT2-THEMIS was treated with 4-OH tamoxifen, colocation and directinteraction of these molecules was detected as ERT2-THEMIS entered thenucleus.
Taken together, these findings demonstrate that THEMIS has a dual function in T cells, participating in proximal TCR signaling at the cell surface andtranslating those signals into the nucleus where, through interaction with nuclear components, THEMIS directs gene expression leading to cell proliferationand differentiation.

37

Data and Statistics

Cheroutre H. Praespero Summit on Autoimmunity andautoimmune diseases (Vancouver, Canada) September
2022

W

EventsLiu W, Chou TF, Garrett-Thomson SC, Seo GY, Fedorov E,
Ramagopal UA, Bonanno JB, Wang Q, Kim K, Garforth
SJ, Kakugawa K, Cheroutre H, Kronenberg M, Almo SC.
HVEM structures and mutants reveal distinct functionsof binding to LIGHT and BTLA/CD160. J Exp Med 218,
e20211112 (2021)

Total dot number

Projects

Recent Major Publications
Dicker M, Li Y, Giles DA, Verstichel G, Castelan VC, AscuiGac G, Chou TF, Perez-Jeldres T, Cheroutre H, Kronenberg
M. CD4+-mediated colitis in mice is independent of
the GPR183 and GPR18 pathways. Front Immunol 28,1034648 (2022)

Tamo

60

-1

-2

Oil

50

Lab Activities

Log2 (nucleus/cytoplasm)

3

Laboratory for

Inflammatory Regulation
Team Leader: Takashi Tanaka

PDLIM1 deficiency
PDLIM1 PDZ

LIM

Human

Figure: Loss-of-function mutations in PDLIM1
cause immunodeficiency due to T cell exhaustion in both human and mice

Mice
Young mice

Impaired PDLIM1 protein expression
in PDLIM1-deficient patientIFN(ng/ml)(Upper left) No PDLIM1 protein expression was detectedin peripheral blood mononuclear cells from PDLIM1
deficient patient examined by western blot analysis.
(Lower left) Clinical course of immunological presentation in PDLIM1 deficient patient. (Right) Age-relatedchange of IFNγ and IL-17 production from Th1 and Th17
cells from PDLIM1 deficient mice examined by ELISA.

60

40

IB: -actin30Late childhood : immunodeficiency

Recent Major Publications
Takemori T, Sugimoto-Ishige A, Nishitsuji H, Futamura
Y, Harada M, Kimura-Someya T, Matsumoto T, Honma T,
Takana M, Yaguchi M, Isono K, Koseki H, Osada H, Miki
D, Saito T, Tanaka T, Fukami T, Goto T, Shirouzu M, Shimotohno K, Chayama K. Establishment of a monoclonal
antibody against human NTCP that blocks HBV infection.
J Virol 96, e01686-21 (2022)

Saiga H, Ueno M, Tanaka T, Kaisho T, Hoshino K. Transcription factor MafB-mediated inhibition of type I
interferon in plasmacytoid dendritic cells. Int Immunol
34, 159-172 (2021)
Invited presentations
Tanaka T. “Biological function of Nahlsgen to control
inflammatory responses in the skin” Special lecture inpress conference for the new product “NAHLSNURSE”(Kyoto, Japan) October 2022

38

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0

300

60

200

80

IL-17

(ng/ml)

2.0
1.5

40

1.0

30
100

10

Infancy~: immune dysregulation
early childhood(ng/ml)

400

50

20

Clinical course of
PDLIM1-deficient patientIFN(pg/ml)60

50

IB: PDLIM1

IL-17

old mice

20

0.5

10

Th1

0

Th17

0

Th1

0

Th17

WT
PDLIM1 KO

he inflammatory response, initiated by dendritic cells, is an important
host defense mechanism to eliminate invading microbial pathogens.
However, these responses must be terminated at the appropriate time point,
otherwise excessive responses may cause massive damage to the host and leadto inflammatory diseases, indicating that negative regulatory systems for inflammation are critical to prevent immunopathology. Our research goal is to
identify a series of key negative regulators of inflammation and clarify the molecular mechanisms by which these negative regulators control the homeostasisof the human immune system and prevent the onset of inflammatory diseases.
PDLIM1 (PDZ and LIM domain protein-1) is a negative regulator of NF-κBmediated inflammatory responses. We previously reported that mice lacking
PDLIM1 showed enhanced inflammation, expecting that the lack of PDLIM1
in human may cause inflammatory diseases. Contrary to this prediction, ahuman patient with a homozygous loss-of-function mutation in PDLIM1 wasrecently identified and found to develop immunodeficiency. Notably, the patient initially presented with immune dysregulation and enhanced proinflammatory cytokine production in early childhood. However, later in childhood,the patient developed immunodeficiency, suffering from recurrent bacterial
infections in the skin and respiratory tract, due to a loss of Th17 cells. Interestingly, PDLIM1-deficient mice showed an immunological phenotype similar tothat seen in human PDLIM1 deficiency. The young PDLIM1-deficient mice
showed enhanced NF-κB-dependent Th1 and Th17 cell differentiation and thisphenotype was completely reversed in elderly PDLIM1-deficient mice with
suppressed Th1 and Th17 cell differentiation. FACS analysis of CD4+T cells
from both the PDLIM1-deficient patient and the mice showed exaggerated expression of markers associated with T cell activation and exhaustion, suggestingthat excessive activation of CD4+T cells in PDLIM1 deficiency may cause T cell
exhaustion leading to immunodeficiency.
These data identify PDLIM1 as a novel regulator of Th1 and Th17 differentiation, whose deficiency in human causes a novel type of primary immunodeficiency.

Laboratory for

Research Highlights

Cytokine Regulation
Team Leader: Masato Kubo

Figure: IL-4 and IL-13 signals independently control IgE-mediated allergic responses

IL-4

Common γ

IL-4RαJak1

Jak3

IL-4RαIL-13Rα1

Cutaneous allergensensitization

Jak2

Jak1

Lab Activities

The IL-4 signal directly induces class-switch recombination in B cells. IL-13 controls the development of MHCIIhi
migratory cDC2s. Cutaneous allergen sensitization
promotes IgE-mediated allergic responses by the emergence of IL-13Rα1-expressing cDC2s, which promote TH2
and GATA3 expressing TFH (TFH2).

IL-13

Tyk2

TSLP
IL13R+ cDC2
GC-B
IgE
IgE

Naive
T cells

GATA3+

Recent Major Publications
Harada Y, Sasaki T, Wibisana J-N, Okada-Hatakeyama
M, Ueno H, Burrows PD, Kubo M. Type 2 helper T cells
convert to Interleukin-1 13 expressing follicular helper T
cells after antigen repriming. Translational and Regulatory Sciences 5, 1, (2023)

Tomiaki C, Miyauchi K, Ki S, Suzuki Y, Suzuki N, Morimoto
H, Mukoyama Y, Kubo, M. Role of FK506-sensitive signal
in asthmatic lung inflammation. Front Immunol 13,
1014462 (2022)

Kubo M. “Immune Regulation against viral infection andtype 2 immunity” JSICR/MMCB joint symposium (Tokyo,
Japan) June 2022
Sasaki T. & Kubo M. “A pathogenic role of IL-13 in anaphylaxis” The 50th Annual Meeting of the JapaneseSociety for Immunology, Nara Kasugano, International
Forum I-RA-KA (Nara, Japan) December 2021
Kubo M. “Different immunodominance of influenza virus
between infection and vaccination” The 5th International Immunological Memory and Vaccine Forum (5thIIMVF) (Online) April 2021

IgE responsesT

he adaptive immune system has evolved to mount different types of responses that are matched to the type of invading pathogen. There are two
broad divisions of effector CD4+ T cells: T follicular helper (TFH) cells and nonTFH effector cells. T cell-derived cytokines and cytokine signals play a criticalrole in the effector and regulatory functions of immune responses. We havedevoted our efforts to establishing a series of mouse models for allergic diseases(asthma, atopic dermatitis (AD), food allergy, and anaphylaxis).
We established a cutaneous allergen sensitization (CAS) system using a vitamin D3 analog Calcipotriol (MC903), which is known to cause skin inflammation and barrier dysfunction. The CAS model promotes IgE-mediated allergic
responses, but the precise mechanisms remain unclear. Single-cell RNA-seq
revealed the emergence of IL-13 receptor alpha 1 chain (IL-13Rα1)-expressing
type 2 conventional dendritic cells (cDC2s) in CAS. Similar DC populations
were identified in allergic rhinitis individuals with IgE antibodies specificto cedar pollen. Lineage-specific disruption of IL-13 signaling resulted in amarked reduction of MHC class IIhi (MHCIIhi) cDC2s, which control the germinal center entry of TFH cells required for IgE responses. These data reveal aunique role for IL-13 in enhancing the expansion of MHCIIhi cDC2s and associated TFH cell responses in the allergy setting. Therefore, IL-13Rα1-expressing
cDC2s are the critical cells connecting local and systemic lymphoid organs tofacilitate efficient induction of type 2 TFH response in the independent way of
IL-4 mediate signaling.
39

Data and Statistics

Invited presentations
Kubo M. “Immune Regulation against viral infection andtype 2 immunity” Allergy Research Conference Series,
Feinberg School of Medicine, Northwestern University(USA/Online) September 2022

GC-B

Events

Liu T-T, Kim S, Desai P, Kim D-H, Huang X, Ferris ST, Wu
R, Ou F, Egawa T, Van Dyken SJ, Diamond MS, Johnson
PF, Kubo M, Murphy TL, Murphy KM. Ablation of cDC2
development by triple mutations within the Zeb2 enhancer. Nature 607, 142-148 (2022)

TFH2

TH2

Projects

IgM
IgG1

Dermal DC

Laboratory for

Human Immunogenetics
Team Leader: Kazuyoshi Ishigaki

A

B

Figure: Overview of our multi-ancestry GWAS(A) The left panel shows geographical regions andancestries in this study. The right panel shows the Manhattan plot of our multi-ancestry GWAS. (B) A representative example of the fine-mapped variant at the LEF1
locus. The bottom figure indicates the gene regulatory
activity in CD4+ T cells (T-bet IMACT annotation track;
Amariuta and Ishigaki et al. Nat Genet 2020).

Recent Major Publications
Ishigaki K, Sakaue S, Terao C, Luo Y, Sonehara K, Yamaguchi K, Amariuta T, Too CL, Laufer VA, Scott IC, Viatte S,
Takahashi M, Ohmura K, Murasawa A, Hashimoto M, Ito
H, Hammoudeh M, Emadi SA, Masri BK, Halabi H, Badsha H, Uthman IW, Wu X, Lin L, Li T, Plant D, ... BioBank
Japan Project; Matsuda K, Matsuo K, Mimori T, Matsuda
F, Fujio K, Tanaka Y, Kumanogoh A, Traylor M, Lewis CM,
Eyre S, Xu H, Saxena R, Arayssi T, Kochi Y, Ikari K, Harigai
M, Gregersen PK, Yamamoto K, Louis Bridges S Jr, Padyukov L, Martin J, Klareskog L, Okada Y, Raychaudhuri S.
Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis.
Nat Genet 54, 1640-1651 (2022)

Nakano M, Ota M, Takeshima Y, Iwasaki Y, Hatano H,
Nagafuchi Y, Itamiya T, Maeda J, Yoshida R, Yamada S,
Nishiwaki A, Takahashi H, Takahashi H, Akutsu Y, Kusuda
T, Suetsugu H, Liu L, Kim K, Yin X, Bang SY, Cui Y, Lee
HS, Shoda H, Zhang X, Bae SC, Terao C, Yamamoto K,
Okamura T, Ishigaki K, Fujio K. Distinct transcriptome
architectures underlying lupus establishment and exacerbation. Cell 185, 3375-3389.e21 (2022)
Ishigaki K, Lagattuta KA, Luo Y, James EA, Buckner JH,
Raychaudhuri S. HLA autoimmune risk alleles restrict
the hypervariable region of T cell receptors. Nat Genet
54, 393-402 (2022)
Invited presentations
Ishigaki K. “T cell receptor and immune regulation” The
71st Annual Meeting of The Japanese Society of Allergology (Tokyo, Japan) October 2022

Ishigaki K. “Autoimmunity pathology elucidated byfunctional genetics and AI” Symposium of the Japan
College of Rheumatology, AI and Rheumatology (Tokyo,
Japan) June 2022
Ishigaki K. “Trans-ancestry genome-wide association
study identifies novel genetic mechanisms in rheumatoid arthritis” The 66th Annual General Assembly and
Scientific Meeting of the Japan College of Rheumatology(Yokohama, Japan) April 2022

40O

ur laboratory aims to elucidate the genetic basis of autoimmunity and wehave committed to five major research topics. The first is computationaland experimental fine-mapping. We conducted the largest-scale multi-ancestry
genome-wide association study (GWAS) for rheumatoid arthritis and successfully fine-mapped multiple risk variants (Ishigaki et al. Nature Genetics 2022a).
In addition, our laboratory has established a genome-editing platform using
primary human T cells and experimentally validated the molecular functionsof the fine-mapped variants. The second topic is the high-throughput screening of causal cellular states. We have established an experimental system that
accurately and efficiently quantifies the chromatin accessibility of the target
genomic region. By applying this system to cells with various conditions, we aresearching for the causal cellular states where the risk variant exerts their regulatory functions. The third topic is functional genetics using single-cell analysis.
We established a novel analytical method to search expression quantitative traitloci (eQTL) from single-cell gene expression data (Nathan et al. Nature 2022).
We are expanding this method to infer continuous cellular states affecting theeQTL effect magnitude and to evaluate how the polygenic risk score impacts
cellular states. The fourth topic is the T cell receptor (TCR). We developed anovel analytical TCR pipeline and have reported that human leukocyte antigen(HLA) risk alleles affect thymic selection to increase the frequency of autoreactive TCRs (Ishigaki et al. Nature Genetics 2022b). We applied the same analytical pipeline to another study and identified TCR features of regulatory T cells(Lagattuta et al. Nature Immunology 2022). The last topic is the clinical transcriptome. We analyzed a large-scale transcriptome dataset of systemic lupus
erythematosus (SLE) patients and identified two distinct transcriptome signatures: disease state and activity signatures (Nakano et al. Cell 2022). All of theseresearch activities contribute to a better understanding of human autoimmunity
pathology.

Laboratory for

Research Highlights

Immunological Memory
Team Leader: Shiki Takamura

Figure: Schematic model of the maintenance ofCD8+ TRM and TEM in the lung

Invited presentations
Takamura S. “Generation and maintenance of epithelialtropic CD8+ T cells in the peripheral tissues and tumor”
The 51st Annual Meeting of the Japanese Society for
Immunology (Kumamoto, Japan) December 2022

41

Data and Statistics

Takamura S, Kato S, Motozono C, Shimaoka T, Ueha S,
Matsuo K, Miyauchi K, Masumoto T, Katsushima A, Nakayama T, Tomura M, Matsushima K, Kubo M, Miyazawa
M. Interstitial-resident memory CD8+ T cells sustain
frontline epithelial memory in the lungs. J Exp Med
216, 2736-2747 (2019)

he global pandemic of SARS-CoV-2, with its high mutation rate, has emphasized the urgent need to develop vaccines capable of eliciting longlasting protective immunity to the original virus as well as its variant strains.
Although neutralizing antibody responses are easily evaded by mutation of
their cognate epitopes on envelope proteins, antigen-specific CD8+ T cells cancross-react with novel variants by targeting highly-conserved internal viralproteins. It is now appreciated that tissue-resident memory CD8+ T cells (CD8+
TRM) comprise a unique T cell subset that permanently resides in peripheral tissues and plays a predominant role in protective immunity at barrier surfaces.
Because of the anatomical and microenvironmental differences in each peripheral tissue, the mechanisms by which CD8+ TRM are generated and maintainedin each tissue differ significantly. Hence, our laboratory aims to understand factors regulating the formation of CD8+ TRM in each tissue with a view to developing novel vaccination and therapeutic strategies.
Using a mouse model of influenza virus infection and experimental approaches, such as intravenous antibody staining and parabiosis, to precisely
discriminate memory T cell subsets, we have discovered that CD8+ TRM in thelung are generated and maintained in transient niches created at the site of tissue damage and regeneration and that CD8+ TRM in these sites are maintained
independently of tissue-circulating effector memory T cells (TEM) in the lung.
We have termed these sites Repair-Associated Memory Depots (RAMD). At
the early stages of infection, we also demonstrated that pulmonary monocytes
provide local antigen signaling that drives the subsequent formation of CD8+
TRM in the RMAD. Furthermore, CD8+ TRM in the RAMD are found to undergo
homeostatic proliferation and express the chemokine receptor CXCR6, which
promotes the continual migration of TRM from the RAMD to the lung airways,
independently of memory in the circulation, thereby sustaining local protective
immunity.
TRM also contribute to cancer immunity as high frequencies of TRM in thetumor are associated with an improved response to tumor immunotherapy andfavorable clinical outcomes in patients with cancer. In particular cases, however,TRM exacerbate autoimmunity, allergy, and inflammatory disease. Thus, our ultimate research goal is to precisely manipulate the formation of TRM according
to the individual situation.

EventsHayward SL, Scharer CD, Cartwright EK, Takamura S,
Tiger li ZR, Boss JM, Kohlmeier JK. Environmental cues
regulate epigenetic reprogramming of airway-resident
memory CD8 T cells. Nat Immunol 21, 309-320 (2020)

T

Projects

Recent Major Publications
Takamura S. Divergence of tissue-memory T cells: Distribution and function-based classification. Cold Spring
Harb Perspect Biol 12, a037762 (2021)

Lab Activities

In the lung interstitium, CD8+ TRM cells (a major population) are predominantly localized in the RAMD while
CD8+ TEM cells (a minor population) distribute sparsely
in unaffected areas. Reactivation of CD8+ TRM cells leads
to upregulation of CXCR6, which drive continual migration to the airway in response to CXCL16 expressed
constitutively in the lung airways. Some CD8+ TRM cells
in the RAMD undergo homeostatic proliferation to compensate for the continuous loss of cells by intraepithelial
migration. Lung interstitium CD8+ TRM cells are primarily
maintained independently of CD8+ TEM cells, althougha low level of TEM to TRM conversion may occur. Whiletissue-circulating CD8+ TEM cells in the lung interstitium
leave tissues via lymphatics, some cells migrate to the
airways in response to CXCR3 ligands. Airway memory
CD8+ T cells are continuously replenished by new cells
recruited from the lung interstitium.

Infectious Diseases
Research Unit
Unit Leader: Haruhiko Koseki

Figure: A schematic view of our researchstrength and direction

The newly established BSL-3 provided a unique opportunity to perform infectious disease research, leading toinventions.

Recent Major Publications
Takeshita M, Fukuyama H, Kamada K, Matsumoto T,
Makino-Okamura C, Uchikubo-Kamo T, Tomabechi Y, Hanada K, Moriyama S, Takahashi Y, Ishigaki H, Nakayama
M, Nguyen CT, Kitagawa Y, Itoh Y, Imai M, Maemura T,
Furusawa Y, Ueki H, Iwatsuki-Horimoto K, Ito M, Yamayoshi S, Kawaoka Y, Shirouzu M, Ishii M, Saya H, Kondo Y,
Kaneko Y, Suzuki K, Fukunaga K, Takeuchi T. SARS-CoV-2
neutralizing antibodies with therapeutic effects in two
animal models. iScience 25, 105596 (2022)

Miyauchi K, Adachi Y, Tonouchi K, Yajima T, Harada Y,
Fukuyama H, Deno S, Iwakura Y, Yoshimura A, Hasegawa
H, Yugi K, Fujii SI, Ohara O, Takahashi Y, Kubo M. Influenza virus infection expands the breadth of antibody
responses through IL-4 signalling in B cells. Nat Commun 12, 3789 (2021)
Takeuchi T, Miyauchi E, Kanaya T, Kato T, Nakanishi Y,
Watanabe T, Kitami T, Taida T, Sasaki T, Negishi H, Shimamoto S, Matsuyama A, Kimura I, Williams IR, Ohara O,
Ohno H*. Acetate differentially regulates IgA reactivity
to commensal bacteria. Nature 595, 560-564 (2021)
Invited presentations
Koseki H. “SKP1A links Polycomb-repressed genes withproteasome” Okinawa Institute of Science and Technology (OIST) (Okinawa, Japan) November 2022

Koseki H. “The role for variant PRC1 during transcriptional phase transition” University of Oxford (Oxford, UK)
September 2022
Koseki H. “The role for variant PRC1 during transcriptional phase transition” Friedrich Miescher Institute for
Biomedical Research (FMI) (Basel, Switzerland) September 2022
Koseki H. “The role for variant PRC1 during transcriptional phase transition” University of Copenhagen (Copenhagen, Denmark) September 2022

42

T

he Infectious Diseases Research Unit was newly established in August2021 during the COVID-19 pandemic in response to a demand fromsociety and the scientific communities. The unit has built and runs BSL-3 and
ABSL-3 laboratories, the only such facilities in the entire RIKEN. Our unit has
a two-sided mission: performing our own research and providing a core facility
service open to both internal and external research communities.
We aim to provide the basis of therapeutic intervention for infectious diseases and to prepare for the next pandemics. Our own research covers thegeneration of animal models of infectious diseases, the development of nextgeneration vaccines, and the understanding of the pathogenesis of various
infectious diseases. The following achievements are highlighted: (1) generationof an infectious diseases model animal for COVID-19; (2) discovery of a newtransdermal adjuvant for a next-generation vaccine; (3) isolation of therapeuticbroadly neutralizing human monoclonal antibodies; (4) delineating the mechanisms of the humoral response following administration of the COVID-19
mRNA vaccine; (5) genome-wide CAGE analysis of CoV-2 infected cells.
Our unit attracts several research groups from RIKEN and elsewhere andone of the fruitful collaborations with them led to success in obtaining a seriesof human broadly neutralizing antibodies against SARS Coronavirus 2 (CoV-2),
leading us to apply for international patents.
We learn from COVID-19 how to prepare for the next pandemic. Our invention of a next-generation vaccine and our understanding of the pathogenesisof infectious diseases will help control the coming pandemics.

Division of Disease
Systems Biology

Division of Disease Systems Biology will elucidate the regulation of
homeostasis and disease onset as a dynamic living system.

Laboratory for

Developmental Genetics
Team Leader: Haruhiko Koseki

Figure: Image of a trophoblast giant cell (TGC)
derived from extra-embryonic tissues of a Prc1
mutant mouse embryo

Green signals show Xist RNA which coats the inactive X
chromosome (Xi). Red signals show primary transcripts
of an X-linked gene Rnf12. Blue signals show DAPI staining that represents nuclear genomic DNA. Arrow; Rnf12
RNA transcribed from the Xist-coated Xi. Arrowhead;
Rnf12 RNA transcribed from the active X chromosome(Xa). Rnf12 is normally silenced on the Xi in PRC1intact TGCs. Upon PRC1 deletion, however, Rnf12 isderepressed and transcribed on the Xi in the ∆PRC1 TGC
shown here. Scale bar = 5 micrometers.

Recent Major Publications
Masui O, Corbel C, Nagao K, Endo T, Kezuka F, Diabangouaya P, Nakayama M, Kumon M, Koseki Y, Obuse C,
Koseki H*, Heard E*. Polycomb complexes PRC1 and
PRC2 are each essential for maintenance of X inactivation in extraembryonic lineages. Nature Cell Biol 25,
134-144 (2023)

Takano J, Ito S, Dong Y, Sharif J, Nakajima-Takagi Y,
Umeyama T, Han Y, Isono K, Kondo T, Iizuka Y, Miyai T,
Koseki Y, Ikegaya M, Sakihara M, Bardwell V, Nakayama
M, Ohara O, Hasegawa Y, Hashimoto K, Arner E, Klose1 R,
Iwama A, Koseki H*, Ikawa T.* PCGF1-PRC1 links chromatin repression with DNA 1 replication during hematopoietic cell lineage commitment. Nature Commun 13,7159 (2022)
Ohinata Y*, Endo TA, Sugishita H, Watanabe T, Iizuka
Y, Kawamoto Y, Saraya A, Kumon M, Koseki Y, Kondo T,
Ohara O, Koseki H*. Establishment of mouse stem cells
that can recapitulate the developmental potential ofprimitive endoderm. Science 375, 574-578 (2022)
Invited presentations
Koseki H. “SKP1A links Polycomb-repressed genes withproteasome” Okinawa Institute of Science and Technology (OIST) (Okinawa, Japan) November 2022

Koseki H. “The role for variant PRC1 during transcriptional phase transition” University of Oxford (Oxford, UK)
September 2022
Koseki H. “The role for variant PRC1 during transcriptional phase transition” Friedrich Miescher Institute for
Biomedical Research (FMI) (Basel, Switzerland) September 2022
Koseki H. “The role for variant PRC1 during transcriptional phase transition” University of Copenhagen (Kopenhagen, Danmark) September 2022

44

T

he Developmental Genetics Laboratory not only pursues its own research
program towards understanding epigenetic regulation of organ development but also plays pivotal roles in maintaining core facilities for experimental
animals and human induced pluripotent stem cells (iPSCs) and in leading acharged mission to understand the pathogenesis of human atopic dermatitis(AD).
In the epigenetics project, we are focusing on understanding how CpG
island (CGI) promoters are linked with enhancers and how epigenetic inheritance is maintained after DNA replication. Particular emphasis has been placedon how Polycomb group (PcG) factors function in combination with the ubiquitin-proteasome pathway, DNA replication mechanisms, and DNA damage
responses.
A large part of the group is devoted to the maintenance of a high-standard
mouse facility in IMS. Through the Animal Core Facility, the group is also
responsible for the generation of knock-out and transgenic animals for thevarious research laboratories at the center, and for the generation of germ-free,gnotobiotic, and humanized mice.
We have started a study to apply iPSC technology for human immunology
research and therapeutic development. The core facility for iPSC research is engaged in developing efficient protocols to reprogram various lymphocytes andinduce differentiation of iPSCs into lymphoid lineage cells. We are particularly
engaged in the generation of iPSC-derived NKT cells for their clinical use incancer therapy and have initiated a Phase I clinical study to approve their safety.
This research is partly supported by AMED.
No matter what the human disease, it is becoming important to find a way
to stratify patients in order to provide the best option for therapeutic intervention. We found that Atopic Dermatitis (AD) is a good model to tackle this issue,
because of its clinical diversity in both symptoms and therapeutic responses.
Our approach is to establish mathematical models for AD based on mouse AD
models induced by various genetic perturbations and then to extrapolate themodel into humans, mainly by using marker genes and protein expression inpatients.

Laboratory for

Research Highlights

Intestinal Ecosystem
Team Leader: Hiroshi Ohno

MicrobeFusimonas intestini

Figure: Schematic representation of the combination of a high fat diet and Fusimonas intestinileading to obesity and metabolic disorders

Metabolize
Metabolite
Trans-unsaturated fatty acids

OH
O

Intestinal barrier dysfunction

Recent Major Publications
Takeuchi T, Kameyama K, Miyauchi E, Nakanishi Y,
Kanaya T, Fujii T, Kato T, Sasaki T, Tachibana N, Negishi
H, Matsui M, Ohno H. Fatty acid overproduction by gut
commensal microbiota exacerbates obesity. Cell Metab35, 361-375.e9 (2023)

Ohno H. “Gut microbial carbohydrate metabolism impacts host insulin resistance” 74th Annual Meeting of
the German Society of Hygiene and Microbiology (Berlin,
Germany) September 2022
Ohno H. “Gut microbial carbohydrate metabolism
impacts host insulin resistance” ImmunoZoom Seminar(Online) July 2022
Ohno H. “Host insulin resistance is attributable to gut
microbial monosaccharide productivity” Symposium 5“Frontiers in the regulation of metabolism by the gut”
The 65th Annual Meeting of the Japan Diabetes Society(Kobe, Japan) May 2022

45

Data and Statistics

Ohno H. “Impacts of smoking on the gut ecosystem andpathogenesis in inflammatory bowel disease” Strategic
International Session ST1 “New frontiers of omics approach in gastroenterology” Japan Digestive Disease
Wek 2022 (Fukuoka, Japan) October 2022G

ut microbiota is the consortium of numerous commensal bacteria residing in our intestines. Our lab has been studying the molecular mechanisms of host-gut microbiota interactions, which deeply impact the host physiology and pathology. We have been applying an integrated omics approach,where exhaustive analyses at different layers of organismal activities are combined, including (meta)genomics, epigenomics, (meta)transcriptomics, andmetabolomics.
The host does not freely allow the residence of those microorganisms. The
intestinal immune system has developed the ability to sense the bacteria in the
gut lumen and tries to contain them. In charge of this process is the M cell,a unique subset of intestinal epithelial cells evolved to recognize and take up
luminal bacteria and transfer them to the underlying dendritic cells for initiation of intestinal immune responses. Our lab has been studying the molecularmechanisms of M-cell differentiation and functions. A main end product ofintestinal immune responses is immunoglobulin (Ig) A. IgA is a major class of
immunoglobulins produced and secreted in the mucosal tissues including theintestine. We have recently shown that the amount and specificity of IgA towardcommensal bacteria is regulated by the combination of gut microbial metabolites, microbial components and the intestinal immune system.
Regarding the impact of host-gut microbiota interactions on disease pathogenesis, we have made some progress in the past years. The bacterial composition of the gut lumen and mucosa are distinct and the mucosa-associatedbacteria are thought to correlate more closely with host pathophysiology. We
have shown that colonic lavage samples from humans can be used to make agood noninvasive estimation of the mucosal microbiota composition. We havealso investigated the impact of gut microbiota on autoimmune diseases, namely
type 1 diabetes and multiple sclerosis, as well as metabolic disorders including
obesity and glucose intolerance.

EventsInvited presentations
Ohno H. “Impact of gut microbial metabolites shortchain fatty acids on the host immunity and physiology”
Symposium S16 US-Japan Immunology Program Coorganized Session “Microbiota and the host immune
system” The 51st Annual Meeting of the JapaneseSociety for Immunology (Kumamoto, Japan) December
2022

Metabolic endotoxemia
Obesity and related disorders

Projects

Nagata N, Takeuchi T, Masuoka H, Aoki R, Ishikane M,
Iwamoto N, Sugiyama M, Suda W, Nakanishi Y, TeradaHirashima J, Kimura M, Nishijima T, Inooka H, MiyoshiAkiyama T, Kojima Y, Shimokawa C, Hisaeda H, Zhang F,
Yeoh YK, Ng SC, Uemura N, Itoi T, Mizokami M, Kawai T,
Sugiyama H, Ohmagari N, Ohno H. Human gut microbiota and its metabolites impact immune responses in
COVID-19 and its complications. Gastroenterology 164:272-288 (2022)

Lab Activities

The gut commensal Fusimonas intestini metabolizes
fatty acids on a high fat diet to produce trans-unsaturated fatty acids such as elaidate, which causes downregulation of tight junction genes and barrier dysfunction,
resulting in metabolic endotoxemia and ultimately
obesity and related metabolic disorders. (Reproduced
from Takeuchi T et al. Cell Metab 35: 361, 2023).

Shi Z, Takeuchi T, Nakanishi Y, Kato T, Beck K, Nagata R,
Kageyama T, Ito A, Ohno H. A Japanese Herbal Formula,
Daikenchuto, Alleviates Experimental Colitis by Reshaping Microbial Profiles and Enhancing Group 3 Innate
Lymphoid Cells. Front Immunol 13, 903459 (2022)

Diet
High-fat dietLaboratory for

Integrative Genomics
Team Leader: Jun Seita

Figure:Figure 1a
The massively parallel single-cell culture system consistsof a fully automated microscope, a cell culture robot, aliquid handling robot, and a computer system to control
them. This allows reinforcement learning to learn theeffects of interventions by observing the state of individual cells, intervening in the environment surrounding
the cells and then observing the results of the intervention again over time.
Figure 1b
In the newly built room for mass spectrometers and lab
automation, four cutting-edge mass spectrometers, Q
Exactive, Orbitrap Exploris 480, Orbitrap Eclipse (notseen), and Sciex TF5600 (right to left) are providing awide range of proteomics analyses in IMS.
Figure 1a

Recent Major Publications
Masui O, Corbel C, Nagao K, Endo TA, Kezuka F, Diabangouaya P, Nakayama M, Kumon M, Koseki Y, Obuse C,
Koseki H, Heard E. Polycomb repressive complexes 1 and
2 are each essential for maintenance of X inactivationin extra-embryonic lineages. Nat Cell Biol 25,134-144(2023)

Tanaka J, Senpuku H, Ogawa M, Yasuhara R, Ohnuma
S, Takamatsu K, Watanabe T, Mabuchi Y, Nakamura S,
Ishida S, Sadaoka T, Takaki T, Shirota T, Shimane T, Inoue
T, Sakai T, Mori M, Tsuji T, Saito I, Mishima K. Human
induced pluripotent stem cell-derived salivary glandorganoids model SARS-CoV-2 infection and replication.
Nat Cell Biol 24, 1595-1605 (2022)
Ohinata Y, Endo TA, Sugishita H, Watanabe T, Iizuka Y,
Kawamoto Y, Saraya A, Kumon M, Koseki Y, Kondo T,
Ohara O, Koseki H. Establishment of mouse stem cells
that can recapitulate the developmental potential ofprimitive endoderm. Science 375, 574-578 (2022)
Invited presentations
Seita J. “The Grand Unification Happening “Now” in Deep
Learning and its Impact on Single-cell Analysis” Tokyo
Medical & Dental University and SONY Clinical Summit(Online) December 2022

Seita J. “State-of-the-art single cell analysis and Human
Cell Atlas project” The 102nd Hokkaido Medical CongressSpecial Lecture (Sapporo, Japan) October 2022
Seita J. “Big Data to Create Personalized Health Care Utilization of Cohort-Biobank” Tohoku Medical Megabank Organization (Sendai, Japan) August 2022
Seita J. “Potential of Deep Learning for Medical DX” The37th Annual Meeting of The Academy of Pharmaceutical
Science and Technology, Japan (APSTJ) (Online) May
2022
Seita J. “Reality of Deep Learning in Medicine” The
Biometric Society for Japan Annual Meeting, Special
Session (Tokyo, Japan) May 2022

46

Figure 1b

W

e are continuing to evolve the laboratory for integrative genomics toward multi-omics and the AI era. As a part of IMS “Genome Platform”,
we are implementing methods for single-cell epigenomics and transcriptomics.
We also launched the next generation proteomics facility by combining thelatest mass spectrometers and deep learning computation to estimate protein
structure and protein-protein interactions. In 2022, we launched the “Scientificdiscovery by AI” project where multi-omics and AI-driven biology are fully
merged. We built a system to investigate where reinforcement learning will autonomously discover biological phenomena.

Laboratory for

Research Highlights

Mucosal Immunity
Team Leader: Sidonia Fagarasan

Figure: Spermidine (SPD) boosts mitochondria
FAO by directly binding to MTP

Zhang B, Vogelzang A, Fagarasan S. Secreted immune
metabolites that mediate immune cell communicationand function. Trends Immunol 43, 990-1005 (2022)

Fagarasan S. “A novel B cell-derived metabolite inhibiting anti-tumor immunity” The 81st Annual Meeting of
the Japanese Cancer Association (Yokohama, Japan/
Online) September 2022

47

Data and Statistics

Fagarasan S. “The biochemical dialog between major
physiological systems of the body mediated by immune
cells” Clinical Immunology: Kyoto and Osaka University
Joint meeting (Osaka, Japan/Online) July 2022

Immune system function declines with age, with many yet-to-be-discoveredfactors contributing to such a decline. Cancer incidence increases with age andone of the most powerful cancer treatments, namely checkpoint blockade therapy, is reported to be less effective in aged patients. We found that supplementation with spermidine, a natural polyamine that decreases in abundance withage, improves the effectiveness of anti-PD1 therapy in aged mice. Surprisingly,
spermidine supplementation also synergized with anti-PD1 treatment in young
mice, significantly reduced tumor growth and prolonged animal survival. Theseobservations raised the question of whether spermidine directly influences immune system function.
We found that addition of spermidine to anti-PD1 therapy increased thenumber of effector and memory CD8+ T cells in the tumor environment as wellas in the draining lymph nodes. The expansion of effector CD8+ T cells was
associated with enhanced mitochondrial activity, as evidenced by increasedoxidative phosphorylation and spare respiratory capacity of CD8 + T cells.
Such mitochondrial activity was unexpectedly observed even at one hour after
stimulation and was due to increased mitochondrial fatty acid oxidation (FAO)(summarized in the Figure).
At the molecular level, we found that spermidine directly binds and allosterically activates the hydroxyl coenzyme A dehydrogenase subunits α andβ (HADHA and HADHB), which comprise the mitochondrial trifunctional
protein (MTP). MTP is the critical enzyme to FAO, and T cell–specific deletion of Hadha abolished the antitumor effect of spermidine supplementation in
combination with anti-PD-L1. In summary, these findings not only highlight amechanism by which spermidine deficiency may contribute to poor T cell function in the context of aging but also reveal the therapeutic potential of combining immune checkpoint blockade with spermidine supplementation to enhance
antitumor immunity.

EventsInvited presentations
Fagarasan S. “A novel B cell-derived metabolite inhibiting anti-tumor immunity” 2022 Cell Research Symposium Cancer and Immunity: Mechanism and Therapeutics (Tiantai, China/Online) September 2022

Immunometabolism and aging: identifying secreted metabolites with immune regulatory function

Projects

Recent Major Publications
Al-Habsi M, Chamoto K, Matsumoto K, Nomura N, Zhang
B, Sugiura Y, Sonomura K, Maharani A, Nakajima Y, Wu Y,
Nomura Y, Menzies R, Tajima M, Kitaoka K, Haku Y, Delghandi S, Yurimoto K, Matsuda F, Iwata S, Ogura T, Fagarasan S*, Honjo T*. Spermidine activates mitochondrial
trifunctional protein and improves antitumor immunity
in mice. Science 378, eabj3510 (2022)*corresponding authors

Lab Activities

A schematic representation of spermidine effect on
cytotoxic T cells (adapted from Science report). Decreased SPD levels in aged CD8+ T cells, leads to low FAO
activity, less ATP production and less effector functions.
SPD supplementation rejuvenates aged CD8+ T cells by
activating FAO upon direct binding to mitochondrial trifunctional protein (MTP). Spermidine supplementation
enhances the efficacy of PD-1 blockade cancer immunotherapy in aged animals otherwise non-responsive totreatment. Adapted from Al-Habsi M et al. Science 378,
eabj3510 (2022).

Laboratory for

Gut Homeostasis
Team Leader: Kenya Honda

Figure:Discovery and effects of the biosynthetic pathway that
produces isoallo-lithocholic acid (isoalloLCA), a secondary bile acid unique to centenarians.
Recent Major Publications
Li Y, Watanabe E, Kawashima Y, Plichta DR, Wang Z, Ujike
M, Ang QY, Wu R, Furuichi M, Takeshita K, Yoshida K,
Nishiyama K, Kearney SM, Suda W, Hattori M, Sasajima
S, Matsunaga T, Zhang X, Watanabe K, Fujishiro J, Norman JM, Olle B, Matsuyama S, Namkoong H, Uwamino
Y, Ishii M, Fukunaga K, Hasegawa N, Ohara O, Xavier RJ,
Atarashi K, Honda K. Identification of trypsin-degrading
commensals in the large intestine. Nature 609, 582589 (2022)

Tuganbaev T, Yoshida K, Honda K. The effects of oral
microbiota on health. Science 376, 934-936 (2022)
Sato Y, Atarashi K, Plichta DR, Arai Y, Sasajima S, Kearney
SM, Suda W, Takeshita K, Sasaki T, Okamoto S, Skelly AN,
Okamura Y, Vlamakis H, Li Y, Tanoue T, Takei H, Nittono
H, Narushima S, Irie J, Itoh H, Moriya K, Sugiura Y, Suematsu M, Moritoki N, Shibata S, Littman DR, Fischbach
MA, Uwamino Y, Inoue T, Honda A, Hattori M, Murai T,
Xavier RJ, Hirose N, Honda K. Novel bile acid biosynthetic
pathways are enriched in the microbiome of centenarians. Nature 599, 458-464 (2021)
Invited presentations
Honda K. “Mining the gut microbiota to develop rationally designed microbial therapeutics” at NIH, Immunology Online Seminar Series (USA/Online) March 2022

Honda K. “Mining the gut microbiota and identifying effector microbes to combat pathogen infection” The 2022
Gut Microbiota for health summit (USA/Online) March2022
Honda K. “Identifying effector microbes that causallyaffect the host physiology to develop defined microbial
therapeutics” The 10th Microbiome Interactions in
Health and Disease meeting (EU/Online) October 2021
Honda K. “Microbiota and regulation of intestinal immunity” The 2021 Principles of Mucosal Immunology
course, Society for mucosal Immunology (USA/Online)
July 2021
Honda K. “Mining the microbiota and identifying effector microbes that causally affect the host physiology”
KEYSTONE SYMPOSIA Impact of Microbiota Composition,
Metabolism and Phage on the Host – Harnessing theMicrobiome for Disease Prevention and Therapy (USA/
Online) January 2021

48

Trillions of microorganisms reside in the intestine and maintain gut homeostasis. Our laboratory has been focusing on identifying commensal
bacteria that induce specific branches of immune cells in the intestine. We havesucceeded in isolating bacterial consortia that stimulate targeted immune responses, including induction of CD4+Foxp3+ regulatory T (Treg) cells, TH17
cells, TH1, and CD8 T cells. The 17 Treg cell-inducing consortium is now
under evaluation in a Phase 2 study for therapy in patients with ulcerative colitis. The 11 CD8 cell-inducing consortium is now under evaluation in Phase 1/2
studies in the US in combination with anti-PD1 mAb for therapy in patientswith checkpoint inhibitor refractory melanoma, gastric cancer and colorectal
cancer.
In addition to immune modulatory bacteria, we identified and isolated bile
acid-metabolizing bacteria from the feces of centenarians. Centenarians display
decreased susceptibility to ageing-associated illness, chronic inflammation andinfectious disease. We found that centenarians have a distinct gut microbiome
enriched in microbes capable of generating unique secondary bile acids (BAs),
including isoallo-lithocholic acid (isoalloLCA). By screening bacterial isolates
from a centenarian’s fecal microbiota, we identified Odoribacteraceae strains
as effective producers of isoalloLCA. Furthermore, we found that isoalloLCA
has potent antimicrobial effects against gram-positive (but not gram-negative)
multidrug-resistant pathogens, including Clostridioides difficile and Enterococcus faecium. These findings suggest that specific bile acid metabolism may be
involved in reducing the risk of pathobiont infection, thereby potentially contributing to the maintenance of intestinal homeostasis. We have also succeededin identifying trypsin-degrading gut bacteria and dermatitis-suppressing skincommensal bacteria. We anticipate our findings will assist in designing bacterial consortia that will be able to durably modify the microbiota and the host,resulting in the development of state-of-the-art therapeutics for numerous diseases.

Laboratory for

Research Highlights

Skin Homeostasis
Team Leader: Masayuki Amagai

Data-driven integrative research
MedicalrecordFigure: Comprehensive analysis of skin barrier
homeostasis and development of corneotherapy

Ito Y, Amagai M. Controlling skin microbiome as a newbacteriotherapy for inflammatory skin diseases. Inflamm Regen 42, 26 (2022)

Amagai M. “Homeostatic mechanisms of skin barrier
and their disruption in skin inflammation” 12th Asian
Dermatological Congress (Tokyo, Japan) August 2022
Amagai M. “Corneoptosis, new functional cell death andlive imaging” The 121st Annual Meeting of the Japanese
Dermatological Association (Kyoto, Japan/Online) June
2022

Intravital SC pH imaging

Candidates of anti-inflammatory
microbial consortiums

Skin barrier
analysis
Nanomeshdevice data

Intravital
microbiome
imaging

upper SC
middle SC
lower SC

Skin barrier
Stratum Corneum

Air-liquid interface Barrier

Tight Junction

Corneoptosis

SC
SG

Liquid-liquid interface Barrier

SG1

High [Ca2+]i -acidic pH
Phase II
Phase I
High [Ca2+]i –neutral pH

SS

Corneoptosis(SG1 cell death)The epidermis, the outer layer of the skin, has two sets of protective barriers, the stratum corneum (SC) and tight junctions (TJs). These two barriers prevent the easy penetration of external antigens into the body. The SC
is unique, as it can maintain its homeostasis, even though it consists of deadkeratinocytes (corneocytes). In addition, the SC is known as a habitat for skinmicrobiota and alterations in skin microbiota composition, termed dysbiosis,
have been associated with chronic inflammatory conditions, such as atopic
dermatitis (AD). Our group is trying to clarify (1) how SC homeostasis is maintained under normal conditions and how it is impaired and affects microenvironments of the skin during inflammation, and (2) how skin microbiota interacts with host epidermis to worsen or ameliorate the inflammatory state. Our
experimental approaches are comprehensive, combining molecular biology, live
imaging, microbiology, and data-driven clinical research.
We recently demonstrated via intravital imaging of mouse skin that a uniquetype of cell death, termed corneoptosis, of the uppermost stratum granulosum
keratinocytes (SG1 cells) requires controlled intercellular acidification to convert SG1 cells into corneocytes and that the SC has three stepwise pH zones.
In addition, we identified Staphylococcus cohnii, whose colonization is accompanied by activation of host glucocorticoid-related pathways and induction ofanti-inflammatory genes in the skin and is therefore effective at suppressing
inflammation in multiple dermatitis mouse models. Furthermore, we have succeeded in long-term continuous measurement (30h) of skin electrical resistanceusing nanomesh electrodes with excellent elasticity, durability, and air permeability. This enables us to measure dynamic change patterns of SC barrier functions of human skin. Combining these tools and techniques, and going backand forth between our basic science findings in mice and those in clinical science in humans, we aim to develop more targeted therapeutic approaches withfewer side effects for patients suffering from inflammatory skin diseases.

49

Data and Statistics

Invited presentations
Amagai M. “Homeostatic mechanisms of stratum corneum as niche for skin microbiota” The 51st of Annual
Meeting of the Japanese Society for Immunology (Kumamoto, Japan) December 2022

Microbiome
data

EventsMiyamoto A, Kawasaki H, Lee S, Yokota T, Amagai
M, Someya T. Highly Precise, Continuous, Long-TermMonitoring of Skin Electrical Resistance by NanomeshElectrodes. Adv Healthc Mater 11, e2102425 (2022)

Skinsamples

Projects

Recent Major Publications
Morimoto A, Fukuda K, Ito Y, Tahara U, Sasaki T, Shiohama A, Kawasaki H, Kawakami E, Naganuma T, Arita
M, Sasaki H, Koseki H, Matsui T, Amagai M. MicrobiotaIndependent Spontaneous Dermatitis Associated with
Increased Sebaceous Lipid Production in Tmem79Deficient Mice. J Invest Dermatol 142, 2864-2872.
e2866 (2022)

Blood
samples

Lab Activities

Our team is trying to clarify the mechanisms of skin barrier homeostasis by focusing on the stratum corneum(SC), tight junction (TJ), and SG1 cells. We establisheda live imaging system, focusing on a unique SG1 cell
death termed ‘corneoptosis’ and SC-pH distribution. By
using an optimized plasmid injection method to study
the cornification process in mice, we found that thecorneoptosis consists of two phases (I and II). We also
study the SC-pH profile and host-microbe interactions
on skin. Furthermore, we are conducting data-driven
clinical research in order to stratify the diversity of AD
pathophysiology and identify beneficial skin microbiota
that have the potential to suppress inflammation. For
this purpose, we are conducting association analysis
with clinical and microbial data as well as integrating
data from whole genome analysis and transcriptomic
analysis using skin specimens from patients with AD.

Skin images

Laboratory for

Tissue Dynamics
Team Leader: Takaharu Okada

Figure: IL-31 receptor-expressing skin sensory
nervesWhole-mount confocal immunofluorescence images ofthe ear skin from control (Nav1.8-Cre R26CAG-floxStoptdTomato) and sensory nerve-specific IL-31RA-deficient(Nav1.8-Cre l31rafl/fl R26CAG-floxStop-tdTomato) mice.
The images show horizontal views.

Recent Major Publications
Yeh CH, Finney J, Okada T, Kurosaki T, Kelsoe G. Primary
germinal center-resident T follicular helper cells are aphysiologically distinct subset of CXCR5hiPD-1hi T follicular helper cells. Immunity 55, 272-289.e7 (2022)

Gomi M, Sakurai Y, Okada T, Miura N, Tanaka H, Akita H.
Development of Sentinel LN Imaging with a Combination of HAase Based on a Comprehensive Analysis of theIntra-lymphatic Kinetics of LPs. Mol Ther 29, 225-235(2021)
Takahashi S, Ishida A, Kubo A, Kawasaki H, Ochiai S,
Nakayama M, Koseki H, Amagai M, Okada T. Homeostatic pruning and activity of epidermal nerves are
dysregulated in barrier-impaired skin during chronic itchdevelopment. Sci Rep 9,8625. (2019)
Invited presentations
Okada T. “The role for sensory neuronal IL-31 receptor
and STAT3 in inflammatory itch” The 51st Annual Meeting of the Japanese Society for Immunology, Symposium 14 (Kumamoto, Japan) December 2022

Okada T. “Activation mechanisms of primary sensory
neurons transmitting itch” The 30th International Symposium of Itch (Online) November 2021
Okada T. “Imaging analysis of epidermal sensory nerves
and keratinocyte tight junctions” The 58th Annual Meeting of the Biophysical Society of Japan, Symposium 2S-7
(Online) September 2020
Okada T. “Dynamic homeostasis of epidermal sensory
nerves and its breakdown caused by barrier dysfunction”
World Allergy Congress 2019, JSA symposium (Lyon,
France) December 201950

T

he goal of the laboratory is to understand the mechanisms that underlie
tissue homeostasis and its breakdown during disease development. As amost recent focus, we have been studying the mechanisms by which sensory
nerves are activated to induce pathogenic pruritus in inflammatory skin conditions such as atopic dermatitis. The therapeutic strategies for pruritus are
currently undergoing a profound transformation and the IL-31 receptor is oneof the major new targets. Our work provides direct evidence that the IL-31
receptor on sensory neurons (Figure), but not on keratinocytes, is essential for
IL-31-induced itch. Moreover, our study demonstrates that sensory neuronal
STAT3 is essential for IL-31-induced itch and further contributes to IL-31-independent itch associated with dermatitis. These are unexpected findings because
previous reports suggested that the STAT molecules including STAT3 mightplay only modulatory roles in itch induced by type 2 cytokines including IL-31.
We have been also continuing our studies to understand the mechanismsof adaptive immune responses. Since 2018 before COVID-19 started, we havebeen collaborating with expert researchers in the field of drug delivery to investigate the mechanism by which an mRNA vaccine equipped with a novel lipid
material elicits efficient CD8+ T cell responses. Our work elucidates the in vivo
cellular mechanism by which mRNA vaccine antigens are presented for activation of CD8+ T cells.

Laboratory forTeam Leader: Makoto Arita

Figure: Innovative lipidomics for creation of the
Lipidome Atlas

Non-targeted lipidomics

Lipidome Atlas

Biology & Disease

Lab Activities

The Lipidome Atlas will facilitate the discovery of new
biological systems shaped by lipid diversity, leading toan integrated understanding of lipid-centric biology.
Spatial transcriptomics/proteomics

Recent Major Publications
Iino Y, Naganuma T, Arita M. Dysregulated ceramide
metabolism in mouse progressive dermatitis resulting
from constitutive activation of Jak1. J Lipid Res 64,
100329 (2023)

Uchino H, Tsugawa H, Takahashi H, Arita M. Computational mass spectrometry accelerates C=C position-resolved untargeted lipidomics using oxygen attachment
dissociation. Commun Chem 5, 162 (2022) selected in
2022 Editor’s Highlights

Invited presentations
Arita M. “Advanced lipidomics technology reveals the
biology of lipid diversity and disease control” 11th
International Singapore Lipid Symposium (iSLS11) (Singapore, Singapore) March 2023

Arita M. “Cutting-edge lipidomics technology reveals
the biology of lipid diversity and disease control” 17th
International Conference on Bioactive Lipids in Cancer,
Inflammation and Related Diseases (New Orleans, USA)
November 2022

L

ipids constitute biological membranes and play a variety of other roles asenergy sources, signaling molecules, and their precursors. Some lipids arebiologically active as single molecules, while others are involved in the formation of membrane domains as molecular assemblies. Since lipids are extremely
diverse molecules, the precise determination of different molecular species oflipid – a process we have termed “LipoQuality”, is important for understanding
their functions in physiology and disease, and for discovering novel bioactive lipids that may have therapeutic benefits. In general, dysregulated lipid
metabolism is associated with diseases such as obesity, atherosclerosis, stroke,
hypertension, and diabetes, and hence there is great interest in furthering ourunderstanding of how they behave within complex biological systems. We aim
to elucidate the mechanisms that create, regulate, and recognize lipid diversity
as a spatiotemporal system by constructing a “Lipidome Atlas”, as well as toelucidate diseases caused by its disturbance. The discovery of the significance oflipid molecules involved in various life phenomena and their diversity throughnon-targeted, highly accurate, and in-depth original technologies is expected tohave a ripple effect on a wide range of life science fields and contribute to medical science and a healthy and long-lived society based on scientific evidence.

Data and Statistics

Arita M. “From LipoQuality to the Lipidome Atlas: Advanced lipidomics to elucidate the biology of lipid diversity and disease control” International Symposium for
Lipid-based Multi-Omics (Daegu, South Korea) October
2022

EventsArita M. “Biology of LipoQuality and Lipidome Atlas”
The 95th Annual Meeting of the Japanese Biochemical
Society (Nagoya, Japan) November 2022

Spatial lipidiomics

Projects

Yoshida M, Ishihara T, Isobe Y, Arita M. Genetic deletionof Cyp4f18 disrupts the omega-3 epoxidation pathway
and results in psoriasis-like dermatitis. FASEB J 36,
e22648 (2022)

Research Highlights

Metabolomics

Arita M. “Advanced non-targeted lipidomics to explore
lipidome changes associated with aging and commensal
microbiota” 62nd International Congress on the Bioscience of Lipids (ICBL2022) (Montreal, Canada) September
2022

51

Laboratory for

Microbiome Sciences
Team Leader: Hiroshi Ohno

Chromosomes

Figure: Reconstructing complete bacterial genomes, plasmids, and viral genomes directlyfrom metagenomic data

Using a long-read sequencing technique, we analyzed
232 fecal metagenomic DNA samples from healthy
Japanese individuals. Obtained reads with an average
length of ~10 kb were brought for de novo assembly
and the resulting contigs showed the average N50 of
416.64 kb. From these high-quality contigs, we identified 1,894 non-redundant complete/near-complete
bacterial chromosomes (≥1 Mb). Among them, 1,693(90%) were assigned to known species based on asimilarity search with full-length 16S rRNA genes; theremaining 201 (10%) were novel species that are notedas ‘undefined’ in the current database.
Furthermore, we identified 593 non-redundant plasmids
and 1,532 non-redundant bacteriophages (phages).
Among them, 559 (94 %) of the plasmids and 1,242 (81%) of the phages were novel.
Recent Major Publications
Nagata N, Takeuchi T, Masuoka H, Aoki R, Ishikane M,
Iwamoto N, Sugiyama M, Suda W, Nakanishi Y, TeradaHirashima J, Kimura M, Nishijima T, Inooka H, MiyoshiAkiyama T, Kojima Y, Shimokawa C, Hisaeda H, Zhang F,
Yeoh YK et al. Human gut Microbiota and its metabolites
impact immune responses in COVID-19 and its complications. Gastroenterology 164, 272-288 (2023)

Li Y, Watanabe E, Kawashima Y, Plichta DR, Wang Z, Ujike
M, Ang QY, Wu R, Furuichi M, Takeshita K, Yoshida K,
Nishiyama K, Kearney SM, Suda W, Hattori M, Sasajima S,
Matsunaga T, Zhang X, Watanabe K et al. Identificationof trypsin-degrading commensals in the large intestine.
Nature 609, 582-589 (2022)
Furuhashi H, Takayasu L, Isshi K, Hara Y, Ono S, Kato M,
Sumiyama K, Suda W. Effect of storage temperatureand flash-freezing on salivary microbiota profiles basedon 16S rRNA-targeted sequencing. Eur J Oral Sci 130,e12852 (2022)
Invited presentations
Suda W. ”Human × Microbiome” Front Line ~Symbiosis
between the human body and micro-organisms, thechallenge of the unknown~, LIFE University Human &Being School (Online) October 2022

Suda W. “Metagenomics of human microbiome” The59th Congress of Japanese Society for Surgical Metabolism and Nutrition (Ibaraki, Japan) July 2022

52

2,166

Long-read NGS

Non-redundant
contigs

Undefined (201)
Plasmids~10kb
subreads

N50 of
417 kbcontigs

Human reads

Plasmid

1,489

593
pOTUs

Phages

Known
6%

Novel
94%
Phage

2,133

1,532
vOTUs

T

Ruminococcus
Bifidobacterium
G_undefined_Lachnospiraceae
Eubacterium
Faecalibacterium
Collinsella
Blautia
Roseburia
Clostridium
Phascolarctobacterium

1,894
contigs

Assemble
Canu

232
Japanese
healthycohortTaxonomic classification 92 genera(FL-16S id% ≥94%)(Top 10 are shown)

Known
19%

Novel
81%

Against ref databases
Known:≥95% id≥80% length coverage
Novel:<95% idor<80% length coverage

he Laboratory for Microbiome Sciences has been engaged in the study ofthe complex interactions between symbiotic microbial ecosystems andtheir hosts. Through the development of original experimental and informatics-based technologies using state-of-the-art sequencers, we aim to comprehensively understand the whole “picture” of microbiome structures.
We have been working on developing a novel pipeline for high-resolution
metagenome analysis using long-read sequencers. These instruments enable us
to reconstruct complete bacterial genomes, plasmids, and viral genomes directly from metagenomic data (Figure). High-quality genome catalogs constructedhere are also expected to serve as references for future meta-transcriptome andmeta-proteome analysis. Furthermore, we optimized protocols for human fecal
DNA extraction and developed the original method for recovering microbial
DNA from extremely low biomass.
These technology developments have given us insights into the relationshipbetween diseases and microbiome. We reported an alteration in gut microbiome in multiple sclerosis patients according to disease severity and, using adata-driven approach, identified and isolated candidate strains correlated withpathogenesis. We also discovered characteristic alterations of gut microbiomes
in COVID-19 patients uniquely found in a Japanese cohort. We further reported that the salivary microbiome could be used for non-invasive diagnosis
of Primary sclerosing cholangitis (PSC) and IgA nephropathy.
We also have been focused on the temporal dynamics of gut microbiomes.
We analyzed the gut microbiome from birth to death in mice and reported thatmost of the lifespan-related microbes are “life-core” and are observed at most of
the periods throughout life. We are now planning to perform a high-resolution
time-series analysis of gut microbiome by developing an automatic sampling
device for disease model mice. Understanding the relationship between microbial dynamics and the host could lead to future control of human health basedon gut microbiome time-course monitoring.

Laboratory for

Research Highlights

Integrated Cellular
Systems
Team Leader: Katsuyuki Yugi

Figure: Differential equation representation ofa trans-omic network and its application to related fields

Signaling (Phosphoproteome)

Typical rate equation

𝑑𝑑[pP𝑟𝑟𝑟𝑟𝑟𝑟]= 𝑣𝑣kinase − 𝑣𝑣phosphatase
𝑑𝑑𝑑𝑑

𝑣𝑣kinase = 𝑘𝑘𝑓𝑓 Kinase [Prot]

𝑑𝑑[RNA]= 𝑣𝑣synthesis − 𝑣𝑣degradation
𝑑𝑑𝑑𝑑

𝑣𝑣synthesis =TF
RNATranscription vs. RNA decay (Transcriptome)

Ribosome

Translation vs proteolysis (Proteome)P

EnzymeMetabolic pathway

Terakawa A, Hu Y, Kokaji T, Yugi K, Morita K, Ohno S, Pan Y,
Bai Y, Parkhitko AA, Ni X, Asara JM, Bulyk ML, Perrimon N,
Kuroda S. Trans-omics analysis of insulin action reveals
a cell growth subnetwork which co-regulates anabolic
processes. iScience 25, 104231 (2022)

Yugi K. “Trans-omic analysis of pharmacological actions”
Niigata University (Niigata, Japan) October 2022
Yugi K. “Integration of multiple omic data on the basisof reaction kinetics and open source intelligence” HURIKEN-OIST Joint Workshop “Understanding Life andPhysical Phenomena using Mathematical Models andAnalysis” (Higashi-hiroshima, Japan) June 2022

Drug action

Immunometabolism

𝑣𝑣degradation =𝑉𝑉ma𝑥𝑥 [S]𝐾𝐾s + [S]Neurometabolism

Metabolism is a biological process involved in various diseases, not only
metabolic diseases such as obesity and diabetes, but also autoimmune
diseases, psychiatric diseases, and cancer. Biochemical metabolic pathways consist of myriad feedback loops and branch points, thereby defying simple causation analyses frequently performed in linear cascades. Furthermore, metabolism undergoes multiplexed regulation from other omic layers: phosphorylationof enzymes by signal transduction (phosphoproteome), transcriptional regulation (transcriptome), translational regulation (expression proteome), etc. Our
research interest is to understand intracellular metabolism and its regulatory
mechanisms as a system of biochemical reactions in dynamic, macroscopic, andquantitative contexts. We employ the methodology of ‘trans-omics’ to reconstruct global metabolic regulatory networks that span multiple omic layers, not
as a group of indirect statistical correlations but as chains of direct mechanistic
interactions on the basis of reaction kinetics (Yugi et al., Trends Biotechnol.,
2016; Yugi and Kuroda, Cell Syst., 2017; Yugi and Kuroda, Curr. Opin. Syst.
Biol., 2018; Yugi et al., Curr. Opin. Syst. Biol., 2019; Okamoto et al., Neurosci.
Res. 2022). Interdisciplinary approaches, such as ‘wet’ biology experiments and‘dry’ data analyses, such as mathematical models and statistical methods, areutilized to characterize the global metabolic regulatory networks. The network
reconstruction is performed based on comprehensive measurement data, public
databases, and a kinetic picture of the cellular processes (Figure). The comprehensive data of multiple omic layers should be measured under identical conditions preferably in a time-series manner so that one can construct mathematicalmodels of the multi-layered network for subsequent systems biological analyses. We eventually aim to reveal the chain of logic from individual biochemical
reactions to omics-scale metabolic regulatory systems.

53

Data and Statistics

Invited presentations
Yugi K. “Integration of multiple omic data on the basis ofreaction kinetics and open source intelligence” The 95th
Annual Meeting of the Japanese Biochemical Society(Nagoya, Japan) November 2022

𝑑𝑑[S]= 𝑣𝑣synthesis − 𝑣𝑣degradation
𝑑𝑑𝑑𝑑

EventsKokaji T, Eto M, Hatano A, Yugi K, Morita K, Ohno S, Fujii
M, Hironaka K, Ito Y, Egami R, Uematsu S, Terakawa A,
Pan Y, Maehara H, Li D, Bai Y, Tsuchiya T, Ozaki H, Inoue H,
Kubota H, Suzuki Y, Hirayama A, Soga T, Kuroda S. In vivotransomic analyses of glucose-responsive metabolism
in skeletal muscle reveal core differences between thehealthy and obese states. Sci Rep 12, 13719 (2022)

𝑣𝑣degradation = 𝑘𝑘d [Prot]

Projects

Recent Major Publications†Okamoto L, †Watanabe S, †Deno S, Nie X, Maruyama
J, Tomita M, Hatano A, Yugi K. Meta-analysis of transcriptional regulatory networks for lipid metabolism inneural cells from schizophrenia patients based on an
open-source intelligence approach. Neurosci Res 175,
82-97 (2022)

𝑉𝑉ma𝑥𝑥 [TF]ℎ𝐾𝐾s + [TF]ℎEnzyme reaction (Metabolome)P

Human genetics

𝑑𝑑[Prot]= 𝑣𝑣synthesis − 𝑣𝑣degradation
𝑑𝑑𝑑𝑑

Lab Activities

We integrate multiple omic data with postulating a
dynamic picture of cellular processes driven by reaction
kinetics. Each reaction rate (terms represented by ‘v ’)is a function of the number of molecules that belong
to the same or other omic layers. We apply this methodology to characterize complex metabolic regulatory
systems related to drug action, the nervous system, theimmune system, human genetics, etc.

P

Laboratory for

Metabolic Networks
Team Leader: Toshimori Kitami

Combinatorial chemical screen
Activator screen

Figure: Schematic of our chemical screening
strategy for uncovering the role of mitochondria in NLRP3 inflammasome activation

Suppressor screens
1280+1
chemicals

1

K+
?

2

3

X ROS Lysosome?

?

NLRP3-PYCARD-CASP1+2

pro-IL-1β

IL-1β
IL-1β

Model building
1

Recent Major Publications
Kobayashi A, Azuma K, Takeiwa T, Kitami T, Horie K,
Ikeda K, Inoue S. FRET-based respirasome assembly
screen defines potential therapeutic intervention that
improves muscle mitochondrial respiration and exercise
performance. Nat Commun 14, 312 (2023)

Kitami T, Fukuda S, Kato T, Yamaguti K, Nakatomi Y,
Yamano E, Kataoka Y, Mizuno K, Tsuboi Y, Kogo Y, Suzuki
H, Itoh M, Morioka MS, Kawaji H, Koseki H, Kikuchi J,
Hayashizaki Y, Ohno H, Kuratsune H, #Watanabe Y. Deepphenotyping of myalgic encephalomyelitis / chronic
fatigue syndrome in Japanese population. Sci Rep 10,
19933 (2020)
Tran UT, Kitami T. Niclosamide activates the NLRP3
inflammasome by intracellular acidification and mitochondrial inhibition. Commun Biol 2, 2 (2019)
Invited presentations
Kitami T. “Dissecting the mitochondrial stress response
network using chemical screening and metabolomics”
Symposium. Japanese Biochemical Society Annual
Meeting (Nagoya, Japan) November 2022

54

2

Ex vivo / in vivo analysis

3

K+

X ROS Lysosome

?

ATP

pH
K+�

NLRP3-PYCARD-CASP1

�
K+�

O2�
�

ATP�
�

Lyso�

pH�
�

NLRP3-PYCARD-CASP1�
pro-IL-1β� IL-1β�

pro-IL-1β

IL-1β
IL-1β

M

IL-1β�

Model refinement

itochondria are dynamic organelles central to energy homeostasis, intermediary metabolism, ion homeostasis, and cell death. Inherited defects
in mitochondria cause the most common inborn errors of metabolism, but agrowing body of evidence also links mitochondria to more complex diseases including type 2 diabetes, cardiovascular disease, and neurodegeneration. Despite
our basic understanding of mitochondrial functions, the precise mechanisms bywhich mitochondria participate in disease pathogenesis remain largely unanswered. The long-term goal of our laboratory is to use our expertise in chemical
biology and genomics to critically evaluate the role of mitochondria in disease
pathways and to develop novel therapeutics centered on mitochondria.
Towards our goal, we initiated chemical screens focusing on the role of mitochondria in inflammation and neuronal cell death, both of which converge
to accelerate neurodegenerative processes such as Parkinson’s disease. In macrophages, we identified small molecules that specifically block mitochondrial
damage-induced activation of the NLRP3 inflammasome pathway. In neuronalcells, we identified small molecules that block neuronal death triggered by mitochondrial inhibitors. We are currently working to test our lead compounds
and molecular insights gained from these studies in mouse models of Parkinson’s disease and rare mitochondrial diseases. We are also working to establish
methods to manipulate cellular metabolism in a cell type-specific manner inmice to dissect and computationally model metabolic cooperativity between
cell types in neurodegeneration. These tools will be useful for understanding
how mitochondrial damage can be buffered by metabolic adaptation of neighboring cells and how disruptions in these interactions accelerate neurodegenerative processes.
In addition, we are examining the role of mitochondria in other complex
disease pathways by taking advantage of large-scale omics datasets generated
at RIKEN IMS. We hope that our multi-omics and chemical biology efforts
will not only help clarify the role of mitochondria in complex diseases but also
point to common therapeutic strategies for a variety of mitochondria-relateddisorders.

Laboratory for

Research Highlights

Epigenome InheritanceTeam Leader: Azusa Inoue

Figure: Parental programming hypothesis

Matoba S*, Kozuka C*, Miura K, Inoue K, Kumon M,
Hayashi R, Ohhata T, Ogura A, Inoue A*†. Noncanonical imprinting sustains embryonic development andrestrains placental overgrowth. Genes Dev 36, 483-494(2022)Mei H*, Kozuka C, Hayashi R, Kumon M, Koseki H, Inoue
A*†. H2AK119ub1 guides maternal inheritance andzygotic deposition of H3K27me3 in mouse embryos.
Nat Genet 53, 539-550 (2021)

Inoue A. “Genomic imprinting by maternal Polycomb repressive complexes” The 20th International Symposiumon Developmental Biotechnology at the Korean Societyof Animal Reproduction and Biotechnology (Korea/
Online) October 2022

Inoue A. “Mechanism and functions of non-canonicalimprinting” EMBO Workshop 2022, Molecular Mechanisms of Developmental and Regenerative Biology(Kyoto, Japan/Online) April 2022
Inoue A. “Maternal epigenetic inheritance by Polycomb
repressive complexes” EMBO meeting CellBio Virtual
2021 (USA/Online) December 2021

55

Data and Statistics

Inoue A. “Genomic imprinting by Polycomb repressive
complexes” University of California at Davis, Microbiology and Molecular Genetics, Invited seminar (USA/
Online) May 2022

EventsInvited presentations
Inoue A. “Genomic imprinting mediated by maternal
histone modifications” The 2nd Subhash Mukhopadhyay
Symposium (India/Online) January 2023

G

enetic information is passed on to the offspring through oocytes andsperms (gametes) and greatly contributes to their phenotypes and diseasesusceptibility. Recent studies have revealed that the parental genomes in mammals are accompanied by epigenetic information that is also passed on to thenext generation. Defects in epigenetic inheritance lead to various phenotypes inprenatal and postnatal growth in mice. This raises the possibility that epigenetic
changes in gametes, possibly induced by the parental environment, might influence disease susceptibility in the offspring via epigenetic inheritance mechanisms across generations.
Our laboratory is studying the mechanisms and functions of transgenerational inheritance of histone post-translational modifications (hPTMs) inmammals. Our specific aims are as follows (Figure): (1) To understand the molecular basis and functions of hPTM establishment and inheritance during gametogenesis and embryogenesis. (2) To link hPTM inheritance to the pre- andperi-conceptional parental environment; (3) To understand how the parental
environment might influence disease susceptibility in the offspring. To addressthese questions, we integrate cutting-edge low-input epigenomic technologies,
reproductive engineering techniques, and genome/epigenome-modified mousemodels. This study will not only reveal how lifestyle influences epigenetic
memory and gene expression in cells but will also call for an evaluation of thecontribution of epigenetic mechanisms to hereditary diseases. It will provide abasis for new approaches to preventive and predictive medicine.

Projects

Recent Major Publications
Inoue A†. Noncanonical imprinting: intergenerational
epigenetic inheritance mediated by Polycomb complexes. Curr Opin Genet Dev 78,102015, 1-9 (2023)

Lab Activities

Parental epigenomes are established during gametogenesis, and partially inherited by embryos to regulate
gene expression in the fetus and placenta. Our lab
investigates the mechanisms and functions of histone
modification inheritance and the effects of the pre-/peri-conceptional parental environment on epigenetic
inheritance and disease predisposition in the offspring.

Drug Discovery Antibody
Platform Unit
Unit Leader: Takashi Saito

A) Infection of epithelial cells by SARS-CoV2 throughbinding of the Spike protein to the ACE2 receptor.
TMPRSS2-mediated cleavage of Spike is required for
ACE2 binding. TMPRSS2 mAbs block the binding andinternalization of multiple SARS-CoV-2 Variants of Concern (VOC).
B) Inhibition of infection of epithelial cells (Cal-3) withvarious SARS-CoV-2 VOC by four representative TMPRSS2
mAbs. Controls for these experiments are mouse IgG(mIgG) and vesicular stomatitis virus G (VSVG), an unrelated virus.

Recent Major Publications
Takemori T, Sugimoto-Ishige A, Nishitsuji H, Futamura
Y, Harada M, Kimura-Someya T, Matsumoto T, Honma T,
Tanaka M, Yaguchi M, Isono K, Koseki H, Osada H, Miki
D, Saito T, Tanaka T, Fukami T, Goto T, Shirouzu M, Shimotohno K, Chayama K. Establishment of a monoclonal
antibody against human NTCP that blocks HBV infection.
J Virol 96, e0168621 (2022) doi: 10.1128/JVI.01686-21

Kumagai A, Nara T, Uematsu M, Kakinuma Y, Saito T, Masuda K. Development and characterization of a uniqueanti-IgE monoclonal antibody cross-reactive between
human and canine IgE. Immun Inflamm Dis 9, 17401748 (2021)
Tanaka M, Ishige A, Yaguchi M, Matsumoto T, Shirouzu M,
Yokoyama S, Ishikawa F, Kitabayashi I, Takemori T, Harada M. Development of a simple new flow cytometricantibody-dependent cellular cytotoxicity (ADCC) assay
with excellent sensitivity. J Immunol Methods 464, 7486 (2019)

56

Spike
protein

TMPRSS2mAb

B
B

TMPRSS2ACE2epithelia
cells

SARS-CoV-2
a b g dκo

VSVG

Figure: TMPRSS2 mAbs inhibit infection by multiple variants of SARS-CoV-2

SARS-CoV-2

Infection (%)

A

2020

2228

100

50

0
mIgG

752

1864

anti-TMPRSS2 mAb ( 1 μg/m l)T

he Drug Discovery Antibody Platform Unit (Ab Platform) is one of nine
Drug Discovery Basic Units in the Drug Discovery and Medical Technology Platform (DMP). DMP develops innovative new pharmaceuticals to transfer the findings from basic research performed at the institute to the clinics.
The Ab Platform creates new monoclonal Abs (mAb) for therapeutic purposesof preventing/modulating various diseases.
We have recently established mAbs against human TMPRSS2 for the purpose of inhibiting infection with SARS-CoV2. TMPRSS2 is critical for viralentry, and small molecule inhibitors of TMPRSS2 have been shown to inhibit
SARS-CoV2 infection, although these compounds also have side effects and are
unstable. Therefore, mAbs against TMPRSS2 may have a more specific inhibitory function and better modulate COVID-19. Indeed, some mAbs showedstrong inhibition of infection by any of the currently circulating SARS-CoV2
variants in vitro. The binding affinity of the mAbs to TMPRSS2 is in the nM
range and the binding epitopes were identified using peptide mapping andcryo-EM. The in vivo blocking function of the mAb was shown using a Cynomolgus monkey infection model; the mAb inhibited expansion of the virus,
particularly in the lung.
We have also developed and analyzed a mAb against a human hepatitis B
virus (HBV) receptor, NTCP (sodium-taurocholate co-transporting polypeptide). Since the preS1-domain of HBV binds to NTCP, it could be a key target
for the development of HBV-blocking agents. Indeed, the established mAb
inhibits the entry of HBV into human liver cells in vitro and inhibits in vivo
infection in human-liver chimeric mice. Since the mAb has the advantage of
not blocking bile acid import by NTCP, it becomes an ideal specific inhibitorof HBV infection without side effects. Currently, humanized NTCP mAbs arebeing developed and a trial to improve the binding affinity is being undertaken
for eventual clinical applications.
We additionally established mAbs against CRTAM (Cytotoxic and Regulatory T Cell Molecule). CRTAM is critical for the development/function of CD4+
cytotoxic T cells (CTL), which are thought to be essential for late-phase induction of experimental autoimmune encephalomyelitis (EAE). Indeed, preliminary results showed significant inhibition of the late phase of EAE induction byadministration of a CRTAM mAb, suggesting its potential therapeutic use.

Division of Cancer Immunology

Division of Cancer Immunology will explore novel principles of theimmune system, focusing on tumor cells, and promote research for theestablishment of novel therapeutics.

Laboratory for

Medical Science
Mathematics
Team Leader: Tatsuhiko Tsunoda

Figure: Results from our analysis of advanced
colorectal canceraa

Tumor immune statusbb(a) Discovery of new subtype of advanced colorectal
tumors and (b) neoantigen status vs. survival. (Sugawara
T., ..., Tsunoda T. iScience 25, 103740 (2022).)

Exome and RNA
sequencing

Hot

Recent Major Publications
Sugawara T, ..., Lysenko A, ..., Boroevich KA, ..., Tsunoda T.
Immune subtypes and neoantigen-related immune evasion in advanced colorectal cancer. iScience 25, 103740(2022)

Matsuo H, Kamatani T, Hamba Y, Boroevich KA, Tsunoda
T. Association between high immune activity and worse
prognosis in uveal melanoma and low-grade glioma
in TCGA transcriptomic data. BMC Genomics 23, 351(2022)
Yamaguchi K, ... Tsunoda T, ..., Kochi Y. Splicing QTL
analysis focusing on coding sequences reveals mechanisms for disease susceptibility loci. Nat Commun 13,4659 (2022)

58

I

Cold

Intermediaten our laboratory, we aim to understand disease dynamics and immunity
at the molecular level to conquer diseases such as cancer. Effective utilization of rapidly developing omic profiling technologies and the introduction of
personalized/precision/preventive medicine have become major goals of medical research, shifting away from traditional approaches that do not adequately
consider the individuality of each patient. Our laboratory develops strategies toaddress these challenges by bringing the ideas and methods from mathematics
and computational sciences to the medical domain. The first part of our approach is driven by integrative analysis of big data such as patient omics, diagnostic images, and clinical data, to discover novel causes/features of diseases.
Next, we classify each disease into finer categories using molecular profiles andclarify underlying causal mechanisms with systems-based approaches. Last, weapply mathematical and machine learning techniques to infer optimal therapy
for each patient to guide treatment decisions by their hospital or clinic. In thisway, we conduct biomedical science research, making full use of state-of-theart omics profiling technologies, mathematics, and computational science. Ourcurrent research projects include (1) tumor microenvironment analysis, (2)contribution to the International Cancer Consortium (ICGC), (3) competitions for cancer multi-omics analyses, (4) an original paradigm for deep learning (DeepInsight suite), (5) prediction models and biomedical analyses withmachine/deep learning, (6) prediction of post-translational modifications, (7)WGS/WES analyses, (8) GWAS, and new projects: (9) chromatin structure andlincRNA functionality, and (10) analysis methods for new experimental technologies, e.g. nanopore and spatial omics.

Laboratory for

Research Highlights

Cancer Genomics
Team Leader: Hidewaki Nakagawa

Figure:Lab Activities

Unsupervised clustering of ESCC tissues by six gene
expression signatures related to immune cells (NK cells,
Monocytes, B cells, CD8+T cells, CD4+T cells, and Neutrophils).

Recent Major Publications
Okawa Y, Iwasaki Y, Johnson TA, Ebata N, Inai C, Endo M,
Maejima K, Sasagawa S, Fujita M, Matsuda K, Murakami
Y, Nakamura T, Hirano S, Momozawa Y*, and Nakagawa
H*. Hereditary cancer variants and homologous recombination deficiency in biliary tract cancers. J Hepatol78, 333-342 (2023)

Sasagawa S, Kato H, Nagaoka K, Sun C, Imano M, Sato T,
Johnson TA, Fujita M, Maejima K, Okawa Y, Kakimi K, Yasuda T, and Nakagawa H*. Immuno-genomic profiling of
biopsy specimens predicts neoadjuvant chemotherapy
response in esophageal squamous cell carcinoma. Cell
Rep Med 3, 100705 (2022)

Okawa Y and Nakagawa H. “Hereditary Cancer Gene
Variants and Homologous Recombination Deficiency in
Biliary Tract Cancer” The 34th Meeting of Japanese Society of Hepato-Biliary-Pancreatic Surgery (Ehime, Japan)
June 2022
Nakagawa H. “Cancer immunogenomics and immune
classification of cancer” The 19th Annual Meeting of theJapan Research Association for Immuno-therapeutics(Tokyo, Japan) May 2022
Nakagawa H. “Proteo-Genomic Characterization of Japanese Primary Liver Cancers Identifies Novel Subtypes
and Therapeutic Strategies” The 57th Annual Meeting ofLiver Cancer Study Group of Japan (Tokyo, Japan) May
2022

59

Data and Statistics

Nakagawa H. “Proteo-Genomic Characterization of Japanese Primary Liver Cancers Identifies Novel Subtypes
and Therapeutic Strategies” The Asian Pacific Association
for the Study of the Liver (Tokyo, Japan) June 2022

EventsInvited presentations
Nakagawa H. “Cancer genomics and genomic medicine
related with tumor immunology” The 26th Annual
Meeting of the Japanese Association of Cancer Immunology (Matsue, Japan) July 2022C

ancer is essentially a “disease of the genome” that develops and evolves
with the accumulation of a variety of mutations in its genetically unstablebackground. Some somatic mutations of driver genes have been successfullytargeted for cancer treatment. Now, genotype-based personalized cancer therapy is in the clinical stage. Understanding of, and attention to, the underlying
genetic diversity in cancer is, therefore, likely to increase the success of newcancer treatment modalities. Recent explosive advances in next-generation sequencing (NGS) and bioinformatics enable us to perform systematic, genomewide identification of all somatic abnormalities by whole genome sequencing(WGS) and RNA sequencing (RNA-seq). Furthermore, cancer also has been
proven to be an “immune disease”, with a variety of features of immune reaction, and immune therapies targeting immune checkpoints and neo-antigens
derived from somatically mutated proteins are also treatment realities. To explore whole genomic and immuno-genomic alterations and their diversity inhuman cancer, we have been utilizing WGS and RNA-seq analysis for cancer.
These approaches, combined with statistical methods and recent single-cell
technologies, can clarify the underlying carcinogenesis and cancer immunology
and achieve a molecular sub-classification of cancer, which will facilitate thediscovery of biomarkers and personalized cancer medicine.

Projects

Fujita M, Chen MM, Siwak DR, Sasagawa S, Arihiro M,
Arihiro K, Ono A, Miura R, Osawa-Tatsuguchi A, Maejima
K, Aikata H, Ueno M, Hayami S, Yamaue H, Chayama K,
Lu Y, Liang H, Nishizuka SS, and Nakagawa H*. Proteogenomic characterization of virus-associated liver cancers reveals potential subtypes and therapeutic targets.
Nat Commun 13, 6481 (2022)

Laboratory for

Immunotherapy
Team Leader: Shin-ichiro Fujii

Figure: Development of therapeutic cellular
drug “artificial adjuvant vector cells”
Since tumors are often composed of a mixture of HLA class
I− and class I+ cells, both innate and adaptive immunity are
crucial for cancer immune surveillance. However, precise therapeutic strategies to restore such surveillance in cancer patients
have yet to be developed. DCs, as “nature’s adjuvants”, play apivotal role in determining the character and magnitude of an
immune response. Therefore, we have studied the role of DCs insitu for anti-tumor immunity by focusing on the link between
innate and adaptive immunity. As an in vivo DC targeting strategy, we have established artificial adjuvant vector cells (aAVCs)
by using CD1d+allogeneic cells loaded with α-GalCer, a ligand
for NKT cells, and transfected with tumor antigen-encoding
mRNA, thus combining the adjuvant effects of NKT cell activation with delivery of antigen to DCs. This approach can leadto the generation of long-term memory T cells and effective
anti-tumor immunity. As a first pipeline of aAVC system, weapplied aAVC-WT1 to refractory or relapsed acute myelogenous
leukemia in phase I clinical trial.

Recent Major Publications
Iyoda T, Shimizu K, Kawamura M, Shing J, Watanabe T, Fukunaga K, Nushiroda T, Saka H, Kitagawa C, Shimamatsu S,
Takenoyama M, Suehiro Y, Imai T, Shingani A, Ito S, Fujii S.
Augmenting Granzyme B-Expressing NK Cells by Invariant NKT
Ligand-Loaded APCs in Patients with Postoperative Early Stage
Non-Small Cell Lung Cancer: Results of a Randomized Phase II
Study. ImmunoHorizons 7, 1-16 (2023)
Fujii S, Kawamata T, Shimizu K, Nakabayashi J, Yamasaki S,
Iyoda T, Shinga J, Nakazato H, Sanpei A, Kawamura M, Ueda
S, Dörrie J, Mojsov S, Dhodapkar MV, Hidaka M, Nojima M,
Nagamura F, Yoshida S, Goto T, Tojo A. Reinvigoration of innate
and adaptive immunity via therapeutic cellular vaccine forpatients with AML. Mol Ther Oncolytics 27, 315-332 (2022)
Shimizu K, Ueda S, Kawamura M, Satoh M, Fujii S. A single
immunization with cellular vaccine confers dual protection
against SARS-CoV-2 and cancer. Cancer Sci 113, 2536-2547(2022)

Invited presentations
Fujii S. “The immunotherapy applicable to cancer and infectious diseases, artificial adjuvant vector cells (aAVCs)” The 37th
Annual meeting of the Japanese Society for the Study of Xenobiotics (Yokohama, Japan) November 2022
Fujii S. “Vaccine design to stimulate T-cell immunity against
infectious diseases” Chemo-Bio Informatic Society Annual
Meeting 2022 (Tokyo, Japan) October 2022
Fujii S. “Development of a new type of therapeutic cancer
vaccine inducing multifunctional immunity, artificial adjuvant
vector cells” 2022 Taiwan-Japan Cancer Immunotherapy Conference (Online) August 2022
Fujii S. “Therapeutic cancer immunotherapy linking innate immunity and adaptive immunity, artificial adjuvant vector cells”
The 43rd Annual Meeting of the Japanese Society of Inflammation and Regeneration (Hyogo, Japan) July 2022
Fujii S. “Development of artificial adjuvant vector cells (aAVCs)”
The 70rh Drug discovery pharmacology forum (Online) January
2022

60

T

he aims of the laboratory are: 1) basic study of cancer immunology and 2)
translational research (TR) in immunotherapy. Immunotherapy can stimulate the activities of specific components of the immune system or counteract
signals produced by cancer cells that suppress immune responses. Although thesuccesses of current immunotherapy represent a clinical turning point, its efficacy is still limited. We have studied several projects based on innate immunitydriven cancer immunology. First, we invented a new type of immunotherapy,
called artificial adjuvant vector cells (aAVC) which is a unique drug delivery
platform composed of NKT cell ligand/CD1d complex and a tumor-associatedantigen. We have accomplished the first in human, investigator-initiated Phase
I clinical trial of aAVC-expressing the Wilms’ tumor 1 antigen (WT1) (aAVCWT1) against relapsed and refractory acute myelogenous leukemia (AML) in
collaboration with the Institute of Medical Science, the University of Tokyo(IMSUT). As a proof of concept, we first verified the safety and immune response of aAVC-WT1 in humans. Subsequently, the Phase II study is ongoingfor patients with AML. In addition, we have been working on some other TR
projects aimed at clinical studies. Second, we are engaged in the multi-omics
analysis of the tumor microenvironment, including neoantigen-specific T cell
responses. Third, we reported a memory-like long-lived invariant NKT cellsubset with strong antitumor effects and have been characterizing these cells interms of intrinsic and extrinsic factors. In addition to our own projects, we havesome collaborative projects; 1) the functional evaluation of the human immune
system as the support institute for vaccine development (SCARDA project) and2) the immunological analysis of the COVID-19 vaccine in cancer patients.

Laboratory for

Research Highlights

Human Disease Models
Team Leader: Fumihiko Ishikawa

PB

BM

SpleenLiver

Figure:Recent Major Publications
Chuprin J, Buettner H, Seedhom MO, Greiner DL, Keck
JG, Ishikawa F, Shultz LD, Brehm MA. Humanized mousemodels for immuno-oncology research. Nat Rev Clin
Oncol 20, 192-206 (2023)

Invited presentations
Itoh-Nakadai A. Educational Session “Elucidation of thepathogenesis and treatment of AML in animal models”
The 84th Annual Meeting of the Japanese Society of
Hematology (Online) October 2022

Hashimoto M. Symposium for AML “Integrative transcriptomic and chemical screening identifies patientspecific vulnerabilities in poor-prognosis AML” The82nd Annual Meeting of the Japanese Society of Hematology (Online) October 2020
Ishikawa F. “Identification of vulnerabilities in genetically-complex AML” Blood Club in Australia (Australia/
Online) October 2020
Ishikawa F. “Creating Treatment Strategies for Poor Prognosis Acute Myeloid Leukemia” Summer School at theJackson Laboratory (USA/Online) August 2020

% chimerism

40
20
0
CAR-T

-

+

+

-

+

+

-

+

+

-

+

+

CXCR4

-

-

+

-

-

+

-

-

+

-

-

+

W

e have developed in vivo models for normal and malignant human hematopoiesis by injecting human stem cells into newborn NOD/SCID/
IL2rγKO (NSG) mice. In mice injected with normal human hematopoietic stem
cells, we have been able to learn how the immune system develops in organs.
On the other hand, the Humanized Mouse model has the caveat of the species
barrier between human blood/immune cells and the mouse microenvironment. Though this system may not completely recapitulate the human immune
system, it has the unique advantage of understanding in vivo kinetics and dynamics of human hematopoiesis and immunity. In the past three years, we havefocused on two topics: First, we have performed single-cell transcriptomics forhuman cells from multiple organs of the Humanized Mice to investigate more
dynamic aspects of human blood cell fate. Second, we have analyzed T cell immunity in the Humanized Mice and in patients.
Malignant cells resist and escape kinase inhibition, apoptosis induction, andimmune surveillance through mutations and chromosomal abnormalities, leading to poor patient outcomes. For malignant human hematopoiesis, we havefocused on understanding of myeloid and lymphocytic leukemia with poor
prognostic factors such as complex karyotypes. We already had robust genomic
data on human malignancies, but it has yet to be addressed how we can achievecomplete remission for the long-term and cure of the diseases. In addition to
the information on mutated genes and proteins, it must be crucial to connect
function with genomics. Patient-derived NSG xenografts have been one of thegold standards for this specific aim worldwide.
Taking advantage of the strengths at RIKEN IMS, we have been working
with non-hematology scientists such as genomics, lipidomics, and iPS researchers. Through such interdisciplinary collaboration, we aim to better understanddisease biology, identify vulnerabilities as therapeutic targets, and develop treatment modalities for poor prognosis leukemia.

61

Data and Statistics

Ishikawa F. “Identification of vulnerabilities in genetically-complex AML” The Annual Conference of European
Hematology Association (Online) May 2021

60

Events

Saito Y, Shultz LD, Ishikawa F*. Understanding normal
and malignant human hematopoiesis using nextgeneration humanized mice. Trends Immunol 41, 706720 (2020)

80

Projects

Hashimoto M, Saito Y, Nakagawa R, Ogahara I, Takagi S,
Takata S, Amitani H, Endo M, Yuki H, Ramilowski JA, Sevverin J, Manabe R, Watanabe T, Ozaki K, Kaneko A, Kajita
H, Fujiki S, Sato K, Honma T, Uchida N, Fukami T, Okazaki
Y, Ohara O, Shultz LD, Yamada M, Taniguchi S, Vyas R, De
Hoon M, Momozawa Y, Ishikawa F*. Combined inhibitionof XIAP and BCL2 drives maximal therapeutic efficacy ingenetically diverse aggressive Acute Myeloid Leukemia.
Nat Cancer 2, 340-356 (2021)

100

Lab Activities

Effect of a single injection of CD25-targeting CAR-T cellswith and without CXCR4 to % human AML cells in peripheral blood (PB), bone marrow (BM), spleen and liverof AML PDX mice. Following 2.5e6 CD25-targeted CART cell injection, treatment efficacy was variable, withresidual AML cells in BM and spleen. With an additional
engineering of CXCR4 expression, CAR-T cell efficacy
improved, eradicating AML cells in BM and liver as well
as PB and spleen (****p<0.0001 and **p<0.01 by two
tailed t-test).

Laboratory forCancer Invasion andMetastasis
Team Leader: Kohei Miyazono

Figure: TNF superfamily protein(s) as moleculartargets for the mesenchymal subtype of glioblastoma

BMP
Type II
receptor

Type I receptor

Loss ofstem cell-like
properties

P
PP

DEGs

Bone morphogenetic proteins (BMPs) induce differentiation of glioma-initiating cells (GICs) As therapeutic
molecular targets for the mesenchymal subtype of glioblastoma multiforme (GBM), tumor necrosis factor (TNF)
superfamily molecule(s) have been identified.

Glioma-Initiating Cells (GICs)

vsRecent Major Publications
Ehata S, Miyazono K. Bone Morphogenetic Protein
Signaling in Cancer; Some Topics in the Recent 10 Years.
Front Cell Dev Biol 10, 883523 (2022)

Takahashi Kei, Abe K, Kubota SI, Fukatsu N, Morishita Y,
Yoshimatsu Y, Hirakawa S, Kubota Y, Watabe T, Ehata S,
Ueda HR, Shimamura T, Miyazono K. An analysis modality for vascular structures combining tissue-clearing
technology and topological data analysis. Nat Commun
13, 5239 (2022)
Takahashi Kazuki, Podyma-Inoue KA, Saito M, Sakakitani
S, Sugauchi A, Iida K, Iwabuchi S, Koinuma D, Kurioka
K, Konishi T, Tanaka S, Kaida A, Miura M, Hashimoto
S, Okada M, Uchihashi T, Miyazono K, Watabe T. TGF-β
generates a population of cancer cells residing in G1
phase with high motility and metastatic potential via
KRTAP2-3. Cell Rep 40, 111411 (2022)
Invited presentations
Miyazono K. “Mechanisms of the differentiation of glioblastoma-initiating cells by BMPs” 13th International
Conference on Bone Morphogenetic Proteins (Dubrovnik,
Croatia) October 2022

Miyazono K. “Plasticity of cancer cells and mechanisms
of TGF-β-induced cancer metastasis” The 81st Annual
Meeting of the Japanese Cancer Association, Symposium: Plasticity and Diversity in Cancer (Yokohama,Japan) September-October 2022
Miyazono K. “Multiple roles of TGF-β signaling in cancer
metastasis” FASEB Science Research Conferences 2022
- The TGF-β Superfamily Conference: Signaling in Development and Disease (Dublin, Ireland) July 2022
Miyazono K. “Regulation of blood and lymph-angiogenesis by TGF-β and their visualization” The 46th General
Meeting of The Japanese Society of Lymphology (Tokyo,
Japan) June 2022
Miyazono K. “TGF-β signaling in progression of cancer”
The 10th Sweden-Japan Academic Network Seminar at
Royal Academy of Sciences, Sweden (Stockholm, Sweden) April 2022

62

Untreated

GBM samples+BMP-4Gene(s) regulatedby BMP-4

Differential gene expression
in malignant GBM tissues

Therapeutic target gene(s)e.g., TNF superfamily molecule(s)The Laboratory for Cancer Invasion and Metastasis started in August2022. Our major research interest is to search for target molecules that
may be used for the treatment of intractable cancers. Bone morphogenetic
proteins (BMPs), members of the transforming growth factor-β family, induce
growth arrest and differentiation of glioma-initiating cells (GICs). ThroughRNA-sequencing analysis of GICs treated or not with BMP-4, we have foundthat expression of some tumor necrosis factor receptor superfamily (TNFRSF)
protein(s) is suppressed by BMP-4 in certain glioblastoma cells. Glioblastoma
is subclassified into four subtypes, i.e., proneural, neural, classical, and mesenchymal subtypes. We have found that one of the TNFRSF proteins is highly
expressed in the mesenchymal subtype of human glioblastoma cells and tissues.
Silencing of the TNFRSF protein expression resulted in reduced proliferationand neurosphere formation of glioblastoma cells in cell culture and decreased
tumorigenic ability and prolonged survival of mice after intracranial injectionof the glioblastoma cells.
We have generated a VHH (variable domain of heavy chain of heavy chain
antibody) against the TNFRSF related protein. The VHH antibody was humanized, and the Fc portion of human IgG was attached. Pre-clinical studies of the
VHH antibody without and with Fc, including pharmacokinetic studies andsafety studies, are ongoing.

Special Program for
Young Leaders
RIKEN Hakubi Fellows Program
RIKEN offers junior PI (Principal Investigator) positions, the RIKEN
Hakubi Fellows, to exceptionally talented researchers for a maximum of 7
years. The RIKEN Hakubi Fellows are expected to engage independently
in creative and ambitious research in natural and mathematical sciences,including research areas bordering the humanities and social sciences.
An important goal of the RIKEN Hakubi Program is to foster stimulatinginteractions among Fellows with diverse backgrounds and to create an
intellectual hub of scientists with different disciplines within and beyond
RIKEN.
“Hakubi” is a phrase derived from classical Chinese story about five
siblings in ancient China, all gifted, but the most brilliant one had white(haku) eyebrows (bi).

Young Chief Investigator Program
The Young Chief Investigator Program (YCI) aims to provide a career
path for young investigators who conduct multidisciplinary research thatwill bridge immunology with other research fields. In this program, theselected Young Chief Investigator (age below 40) will head an independent research laboratory, but will have an access to mentoring by multiple
senior specialists in related research fields. Mentors provide guidance forexperimental design, preparation of papers and presentations, promotionof international visibility, and obtaining research funding. The YCI laboratory will also share space, equipment and facilities with a host laboratory
in IMS.

Genome Immunobiology
RIKEN Hakubi Research
Team
Hakubi Team Leader: Nicholas Parrish

Figure: A LINE-1 insertion in NEDD4 acts as an
isoform-specific enhancer and causes increased
keloid risk

Subjects with and without keloid were recruited andgenotyped by BioBank Japan, and keloid risk variants
were identified by GWAS. Subjects with a LINE-1 insertion in the gene NEDD4 have higher keloid risk. Using
genetic modification of iPSCs and differentiation to
fibroblasts, we showed that this LINE-1 insertion acts
as an enhancer of a keloid-promoting short isoform of
NEDD4.
Recent Major Publications
Ito J, Seita Y, Kojima S, Parrish NF, Sasaki K, Sato, K. A
hominoid-specific endogenous retrovirus may haverewired the gene regulatory network shared between
primordial germ cells and naïve pluripotent cells. PLoS
Genet 18, e1009846 (2022)

Koido M, Hon C, Koyama S, Kawaji H, Murakawa Y, Ishigaki K, Ito K, Sese J, Parrish NF, Kamatani Y, Carninci P,
Terao C. Prediction of the cell-type-specific transcriptionof non-coding RNAs from genome sequences via machine learning. Nat Biomed Eng Online ahead of print
at doi: 10.1038/s41551-022-00961-8 (2022)
Eds. Parrish NF, Iwasaki Y. piRNAs: Methods and Protocols. Methods in Molecular Biology. Springer Nature,
New York. Published May, 2022
Invited presentations
Kojima S, Parrish NF. “Polymorphisms of endogenous
retroviruses in humans: from detection methods to disease risk” 45th Annual Meeting of the Molecular Biology
Society of Japan (Chiba, Japan) November 2022

Hayakawa K, Kojima S, Parrish NF. “Potential involvement of endogenous HHV-6 in lymphangioleiomyomatosis” 45th Annual Meeting of the Molecular Biology
Society of Japan (Chiba, Japan) November 2022
Heaton SM, Parrish NF. “Querying the genotypedependence of stimulus-response phenotypes using
single-cell sequencing of genetically diverse human cell
libraries” 45th Annual Meeting of the Molecular Biology
Society of Japan (Chiba, Japan) November 2022
Kojima S, Parrish NF. “Mobile element variation drives
population-specific genome diversification, gene regulation, and disease risk” Cold Spring Harbor Laboratory
Meeting: Transposable Elements (Long Island, USA)
October 2022
Kojima S, Parrish NF. “Mobile element variation drives
population-specific genome diversification, gene
regulation, and disease risk” 2022 IMS-McGill Workshop(Montreal, Canada) September 2022

64

O

ur research focuses on understanding the biological functions and disease associations of mobile genetic elements (MEs), including transposable elements and endogenous viral elements (EVEs). EVEs are virus-derived
sequences that have become integrated into the host genome through past viralinvasions.
We previously found that mouse and human EVEs derived from Borna disease virus (BoDV), called endogenous bornavirus-like nucleoprotein elements(EBLNs), are transcribed and processed into PIWI-interacting RNAs (piRNAs).
Because piRNAs are known to guide RNA interference against complementary
RNA targets, we hypothesized that EBLN-derived piRNAs may target BoDVmRNAs and function as an antiviral mechanism against BoDV. To test the
hypothesis, we engineered mutant mice lacking piRNA-generating EBLNs. Additionally, we knocked-in modern Borna disease virus sequences into piRNAgenerating loci (piRNA clusters) to simulate the acquisition of a new EBLN-like
EVE. Using these genetically modified animals, we are establishing BoDV testis
infection models to determine whether EBLN-derived piRNAs are involved in
antiviral RNA interference. If so, this could reveal a novel mechanism of germline-encoded innate immune memory in mammals.
Beyond the provocative example provided by EBLNs, we are interested generally in the evolution of novel phenotypes through the activity of MEs, and wehave been using biobank-scale human data to uncover new examples. We madetools to detect and genotype germline insertional polymorphisms of humanherpesvirus 6 (Liu et al., PLoS Genetics 2020), endogenous retroviruses (Kojima et al., PLoS Genetics 2021) and other MEs (Kojima et al., Nature Genetics
2023). Using statistical genetics and molecular biology, we have found examples
in which novel insertions of MEs have generated new human phenotypes, forexample, a LINE-1 transposon insertion that causes an increased risk of keloid
and fasciitis.

YCI Laboratory for

Research Highlights

ImmunologicalTranscriptomics

Young Chief Investigator: Hideyuki Yoshida

Figure: Immunofluorescence analysis of a mousethymic tissue section

Morimoto J, Matsumoto M, Miyazawa R, Yoshida H,
Tsuneyama K, Matsumoto M. Aire suppresses CTLA-4
expression from the thymic stroma to control autoimmunity. Cell Rep 38, 110384 (2022)

Yoshida H. “Gene regulations in immunocytes: datadriven approach employing a wide range of immune
cells” The 94th Annual Meeting of the Japanese Biochemical Society (Japan/Online) November 2021
Yoshida H. “Data-driven Immunology: large scale multiome analysis revealed comprehensive mechanisms fortranscriptional regulation” The 29th Molecular Immunology Forum Tokyo (Japan/Online) March 2021

2) Systematic analysis of the immune system employing a datadriven approach
Bioinformatics has impacted research on gene regulation and is becoming
more potent since it began dealing with big data analysis. To promote datadriven studies, we are collaborating with the ImmGen group.

65

Data and Statistics

Invited presentations
Yoshida H. “mTECs, peripheral tissue-specific antigens,and beyond” The 51st Annual Meeting of the JapaneseSociety for Immunology (Kumamoto, Japan) December
2022

1) Gene regulation in immune tolerance
The negative selection of the self-reactive T cells occurs in the thymus and is
one of the most essential mechanisms to induce immune tolerance. To achievethis, a large number of genes encoding peripheral tissue antigens (PTAs) are expressed in thymic medullary epithelial cells (mTEC), and the developing T cells
are eliminated if they respond to these PTAs. Since the disrupted expressionof PTAs can result in autoimmune disorders, understanding the mechanisms
controlling PTA expression is important to uncover the pathogenesis of autoimmune diseases and to develop new treatments. We are analyzing gene expression in mTEC by employing multiple single-cell profiling methods to reveal
detailed gene regulation along with validations employing mouse models.

EventsNishijima H, Matsumoto M, Morimoto J, Hosomichi K,
Akiyama N, Akiyama T, Oya T, Tsuneyama K, Yoshida H,
Matsumoto M. Aire Controls Heterogeneity of Medullary Thymic Epithelial Cells for the Expression of SelfAntigens. J Immunol 208, 303-320 (2022)

G

ene regulation is one of the most fundamental mechanisms governing cellfunctions and biological processes, including immune cells and the immune system, and has been studied in many contexts. Recent advances in profiling the epigenome and transcriptome, taking advantage of next-generation
sequencing (NGS), enable us to investigate gene regulation in an unprecedented
manner and hence uncharted mechanisms in biology and immunology.
Our research aims to promote the understanding of gene regulation in immune cells and the immune system for better deciphering and treatment of
immune disorders. Transcriptomics can be applied to various studies in immunological settings, and we have been engaged in 1) studies of immune tolerance
and 2) a project for the systematic analysis of immunocytes.

Projects

Recent Major Publications
Miyazawa R, Nagao JI, Arita-Morioka KI, Matsumoto
M, Morimoto J, Yoshida M, Oya T, Tsuneyama K, Yoshida
H, Tanaka Y, Matsumoto M. Dispensable Role of Aire in
CD11c+ Conventional Dendritic Cells for Antigen Presentation and Shaping the Transcriptome. Immunohorizons 7, 140-158 (2023)

Lab Activities

The green color shows cells that are in the process ofdying through apoptosis. This happens because thethymus is sorting out cells that react strongly against
the body’s own tissues through a process called “negative
selection.”

IMS Research and Infrastructure Platforms

I

MS Research and Infrastructure Platforms provide all researchers in the Center with access to the most advanced
equipment and technologies. The platforms consist of six sections; FACS managed by Dr. Takashi Saito, Imaging and Microscopes managed by Dr. Takaharu Okada, Genome Platform andrelated activities managed by Dr. Yukihide Momozawa, Animal
Facility managed by Dr. Haruhiko Koseki, Metabolomics (Lipidomics) managed by Dr. Makoto Arita, and Information Infrastructure managed by Dr. Takeya Kasukawa.

FACS

T

he FACS Laboratory provides a range of support for flow
cytometry and cell sorting, techniques that are essential
for nearly all experiments in immunology, genome research anddisease studies. The Laboratory supports both population andsingle-cell analysis and has upgraded all FACS Aria instruments,
including two Aria Fusions and a FACSymphony for multi-color
analyses/sorting. In addition to FACS instruments, the lab has
a mass spectrometry-based cytometer, HELIOS, which has thepotential to analyze more than 40 markers simultaneously withmetal-labeled antibodies.
In 2022, still in the difficult period due to the coronavirus pandemic, in total 550 analytical and 927 FACS sorting experiments
and 48 analyses with HELIOS were performed.
In the FACS laboratory, a specialized staff member offers various services for users of the equipment (cell analyzers and cell sorters): (1) Technical support and training: In 2022, the facility offered
32 technical courses (four for cell sorting and four for cell analysis).
The courses were held at three different levels, Canto II (7) andAria basic (25). An Aria course was also held in English. A total of
56 researchers participated in these courses in 2022. (2) Cell sorting

operation service: The Laboratory provides a cell sorting operation
service, in which researchers can ask an experienced operator to
conduct the sorting experiment. In 2022, 128 such services were
provided. Advanced cell sorting techniques, such as single-cellsorting, have also been performed. (3) Management/maintenance of
FACS instruments: FACS machines are available for registered users
around the clock and reservations are accepted up to one month inadvance through an internal website. In addition to the in-house
FACS Laboratory staff, engineers from Becton Dickinson visit oncea week to provide maintenance and technical support.
Table: Instruments and their usage in the FACS Laboratory (2022)

Instrument
types

Model

# of
machines# ofanalyses# of training
sessions(# of participants)

FACS cell analyzer Calibur

3

11

1 (0)

Canto II

2

550

3 (7)

FACS cell sorter

Aria IIIu/III/
Fusion/Symphony

7927

3 (25)

Mass cytometer

Helios (CyTOF)

1

48

0 (0)

Imaging and Microscopes

The Microscope Laboratory provides equipment for cell andtissue imaging and coordinates technical support. There are
six fluorescence microscopes and one scanning electron microscope available to researchers at IMS.
(1) Inverted Leica SP8 system equipped with hybrid detectors andthe LIGHTNING super-resolution image extraction module.
(2) Inverted Leica SP8 system with two femtosecond Ti:Sa lasers
for multiphoton excitation. This system is equipped with two
types of scanners (resonant and galvano) and hybrid detectors.
One of the two Ti:Sa lasers is connected to an optical parametric oscillator (OPO) that enables two-photon imaging by longwavelength excitation.
(3) Inverted Leica SP5 system with hybrid detectors.
(4) Inverted Nikon N-SIM/N-STORM super-resolution microscopefor dual color imaging.
(5) GE Healthcare DeltaVision Elite system.
(6) Keyence BZ-X700 all-in-one fluorescence microscope.
(7) Hitachi field emission scanning electron microscope (FE-SEM)

66

Regulus8240. The related devices such as a conventional ultramicrotome Leica EM UC7 and an array tomography ultramicrotome ARTOS 3D are also available.

Figure: Leica SP8 confocal microscope (1), Leica SP8 multiphoton microscope (2), Nikon N-SIM/N-STORM super-resolution microscope (4), GE
Healthcare DeltaVision Elite system (5), Keyence BZ-X700 microscope (6),and Hitachi Regulus8420 FE-SEM (7)Genome Platform and related activities
laboration with the University of Tokyo.
We expect that the intramural interactions fostered by the
Genome Platform among the Divisions of Human Immunology, Disease Systems Biology, Cancer Immunology, and Genome
Medicine will greatly enhance IMS research activities.
Table1: Central services provided by the Genome Platform in 2022

Library Preparation# of Samples

whole genome sequencetarget sequencebulk RNA-seq
SMART-Seq
RamDA-seq
NET-CAGE
10x 3’GE

274
42110
172
864
1156
13
19

Lab Activities

Table2: Next-generation DNA sequencing

Illumina Sequencer# of Runs

NovaSeq6000
NextSeq2000
HiSeq2500
MiSeq

86
27
27
183

PacBio Sequel# of Runs

Sequel II

28

Projects

he Genome Platform was launched in September 2020.
This platform enables users in IMS to obtain DNA libraries, sequence data and analysis data quickly and at a reasonable
cost, thus empowering their research. For library preparation, we
support whole-genome sequencing, targeted sequencing, CAGE,
single-cell RNA-seq, and bulk RNA-seq. For sequencing, we support NovaSeq6000, NextSeq2000, HiSeq2500, MiSeq, and PacBio
Sequel runs. Data analysis is available for whole-genome sequencing, targeted sequencing, CAGE, single-cell RNA-seq, bulk RNAseq, Chip-Seq, and ATAC-seq. In addition, we also support theregistration of data in public databases.
In FY2022, we developed an in-house RamDA-seq analysis
method in collaboration with the Nikaido team at RIKEN Center for Biosystems Dynamics Research. We have also transferred
NET-CAGE technology in cooperation with the Murakawa teamat RIKEN IMS. The genome platform enabled users to receive
analysis data online by using the HOKUSAI SS data science platform. In addition, the Illumina DRAGEN Bio-IT platform maderoutine data analysis fast and easy, and enables data to be provided to users in a short period of time.
This year, we are working on 52 projects. The achievements
in library preparation and sequencing are shown in Table 1. In
one important project, we conducted whole-genome sequencing
analysis of 800 individuals for an Atrial Fibrillation Study in col-Research Highlights

T

Animal Facility
We have generated genetically modified mice to improve theefficiency of transplantation of human hematopoietic stem cells
into NOD.Cg-Prkdcscid Il2rg tm1Wjl/SzJ (NSG) mice by better “humanizing” the host strain. For this purpose, we have introduced
large genomic fragments containing human genes encoding
MHC, cytokines, adhesion molecules, virus receptors, and others
into the NSG mice. We maintain such transgenic and knock-in
mice.

Data and Statistics

e continue to maintain over 60,000 mice in the SPF areaand 1,500 mice in an isolated area. The SPF area also
contains 1,000 germ-free or gnotobiotic mice in vinyl isolator
rooms and in vinyl isolation bio-bubble rooms. The former areused by several IMS research groups, in particular the mucosal
immunologists, and the latter are for “humanized mice”. In addition, for COVID-19 research, a new animal biosafety level 3(ABSL3) room was completed in 2021. The new ABSL3 room has
high negative pressure Individually Vented Cage systems (IVCs)(Figure) and has the capacity to breed 150 mice. We introduce
mouse lines into the SPF area via a combination of in vitro fertilization (IVF) and embryo transfer methods and have also generated cryo-stocks of genetic resources (frozen embryos and sperm)
for 902 lines. We also maintain relatively large colonies of several
commonly used strains, such as Rag1 KO and Cre deleters, andprovide them to users on demand. We have also provided technical assistance to generate knockout and transgenic mice (96lines). In addition, we have created 11 lines of germ-free mice. We
maintain flexibility so that we can provide space for new experiments in the animal facility, e.g., behavioral testing of germ-freemice.

EventsW

Figure: The new ABSL3 room camera image with Individually Vented Cagesystems

67

Metabolomics (Lipidomics)

L

ipids constitute biological membranes and play a variety ofroles as energy sources, signaling molecules and their precursors. Some lipids are biologically active as single molecules,
while others are involved in the formation of membrane domains
as molecular assemblies. In general, the dysregulation of lipid
metabolism is associated with human diseases and, hence, theprecise determination of lipids is quite important for understanding their functions in physiology and disease, and for discoveringnovel bioactive lipids that may have therapeutic benefits.
A powerful method for analyzing lipid metabolites is liquid
chromatography-tandem mass spectrometry (LC-MS/MS).
The Metabolomics Laboratory is equipped with an AQUITYUPLC (Waters) coupled with a TripleTOF 6600, a QTRAP
6500/5500/4500 (Sciex) and a GC-MS TQ8030 (Shimadzu) tocover untargeted and wide-targeted metabolomics. Recently, we
introduced timsTOF flex MALDI-2 (Bruker) for MS imaging(spatial lipidomics) analyses. This state-of-the-art lipidomics
platform together with our original informatics technologies are
powerful tools for elucidating complex lipid structures and visualizing metabolic networks globally and in an unbiased manner.

They also provide an opportunity for data-driven hypotheses tomake the connection between lipid metabolism and biologicalphenotypes.

Figure: LC-MS/MS based Advanced Lipidomics Platform

Information InfrastructureTo promote and support large-scale computation for various research activities in IMS, there are several groups
that manage the information infrastructure and computational
resources. In the West building, we have internal large-scalecomputation systems (total ~1,000 cores, 2.1PB storage) using
RIKEN’s internal network and provide them for IMS researchers.
In FY2021, RIKEN R-IH launched a new private cloud system
named HOKUSAI SS for all RIKEN laboratories. We have utilized HOKUSAI SS to expand the in-house computation systems
by providing a seamless environment. In the East building, we
also have internal large-scale computation systems (total ~3500
cores, 8PB storage) in a closed network and provide them widelyfor IMS researchers, not just in the East building; other buildings
also have access to these servers, especially for controlled access
data, e.g., human-derived data. We are planning to gradually shift
the storage system to HOKUSAI SR to securely store human genomics data. Moreover, two remote access terminals have been
installed in the East building in order to enable IMS researchers
to easily access Tohoku Medical Megabank (ToMMo) data.
Recently, sharing of research data becomes important in the open
science era. We have drafted IMS Research Data Guidelines for the68

treatment of research data obtained in IMS, for discussion in IMS.
Large-scale computation is now essential in biomedical studies
and we continue to provide sufficient and the latest computation
environment and information infrastructure for IMS researchers.

Figure: The computer servers managed in the West building (left) and in
the East building (right)

IMS Bioethics Working Group
offering research ethics education opportunities, and establishinginternational collaborations such as the Multi-Regional Clinical
Trials Center of Brigham and Women’s Hospital and Harvard,
and the Science Policy Think Tank in U.S.
The BWG has set up a help desk to provide researchers withresearch ethics consultations, offered ongoing support for someresearch projects, invited prominent scholars from Japan andoverseas to lecture on the latest knowledge and issues, and held
forums for exchanging opinions among scholars and researchers.
The IMS BWG also provides support related to ELSI, such as
issues of promoting open science while protecting personal information, issues of returning research results, and issues regarding
implication of genomic medicine while preventing genetic discrimination.
In addition, in collaboration with other RIKEN departments,
the IMS BWG has taken the initiative in improving the systems
related to research ethics and conflict of interest. The IMS BWG
has been granted the President’s Discretionary Fund twice, andover the past three years has made significant progress in improving the environment surrounding and supporting research ethics
at IMS.

Lab Activities

MS aims to clarify the mechanisms underlying the development of human diseases and to use this insight to create newtreatments that can improve the well-being of society. More specifically, IMS is engaged in medical research focusing on the elucidation of human immune and genomic functions. Therefore, itis essential to conduct research using human samples and data atvarious levels, including genome, transcriptome, medical record
information, and samples provided by hospitals.
In conducting such research, IMS recognizes the importanceof protecting the rights of research participants, ensuring responsible handling of samples and information provided by research
participants, complying with research-related regulations, returning research results to society including the participants, andpromoting dialogue with the general public. IMS also recognizes
that Ethical, Legal, and Social Implications/Issues (ELSI) must be
addressed while conducting cutting-edge research.
Therefore, the IMS Office of the Center Director has established a Bioethics Working Group (BWG), which began in earnest
in FY2019, to address bioethical challenges facing IMS researchers. Since then, the IMS BWG has focused on providing research
ethics support, conducting ELSI-related surveys and feedback,Research Highlights

I

Projects

IMS Bioethics Working Group

Research
EthicsConsultation

EventsELSIRelated
Survey &Feedback

International
Collaboration

Figure: Four major components of the Bioethics Working Group that interact with society

Data and Statistics
69

RIKEN International Program Associate (IPA)I

MS accepted four international students as RIKEN International Program Associates (IPA). Under this IPA program,
IMS lab heads host international students from collaborating
graduate schools and supervise their Ph.D. program as Joint Supervisors. The students receive a daily living allowance and housing costs for up to a maximum of three years.

The IPA students who studied at IMS in 2022 were

Yan Jun Lan (ETH Zurich, Switzerland) in the Laboratory for

Advanced Genomics Circuit

Jingjie Chang (Tokyo Medical and Dental University, Japan) in

the Laboratory for Transcriptional Regulation
Yali Xu (Nanjing University, China) in the Laboratory for Cellular Function Conversion Technology
Jan Peter Pack (McGill University, Canada) in the Laboratoryfor Human Disease Models

RIKEN Junior Research Associate (JRA) ProgramT

he Junior Research Associate Program was launched in 1996
to encourage young scientists with fresh ideas and youthful
enthusiasm to collaborate with, and learn from, senior scientists
with years of experience. This program provides part-time positions at RIKEN for young researchers enrolled in university Ph.D.
programs. The JRA program serves the dual purpose of fostering
the development of these young scientists while also energizing
RIKEN with their innovative thinking.
This year, 30 JRA students studied in IMS.
Haruki Uchino (Laboratory for Metabolomics)
Umi Tahara (Laboratory for Skin Homeostasis)
Hiroto Horikawa (Laboratory for Gut Homeostasis)
Tomo Kakihara (Laboratory for Microbiome Sciences)
Kentarou Kubota (Laboratory for Innate Immune Systems)
Sayoko Kuroha (Laboratory for Metabolomics)
Zhengzheng Shi (Laboratory for Intestinal Ecosystem)
Yuki Tanaka (Laboratory for Cellular Function Conversion

Technology)

Susumu Toshima (Laboratory for Tissue Dynamics)
Ryo Nakagawa (Laboratory for Human Disease Models)Mio Yoshida (Laboratory for Metabolomics)
Nao Tanaka (Laboratory for Statistical and Translational Genetics)

Taichi Akase (Laboratory for Large-Scale Biomedical Data Tech-

nology)Tatsuya Ishikawa (Laboratory for Immune Homeostasis)
Raku Son (RIKEN-IFOM Joint Laboratory for Cancer Genomics)
Yuichiro Tanaka (Laboratory for Intestinal Ecosystem)
Ritsu Nagata (Laboratory for Intestinal Ecosystem)
Naoto Fujioka (Laboratory for Innate Immune Systems)
Satoshi Morozumi (Laboratory for Metabolomics)
Tatsuro Iwasaki (Laboratory for Skin Homeostasis)
Yuki Okawa (Laboratory for Cancer Genomics)
Fumie Ota (Laboratory for Cardiovascular Genomics and Infor-

matics)Yuta Sakamoto (Laboratory for Cellular Function Conversion

Technology)

Xufeng Shu (Laboratory for Transcriptome Technology)
Yu Terauchi (Laboratory for Metabolomics)
Kaiyuan Deng (Laboratory for Metabolomics)
Mio Hayama (Laboratory for Immune Homeostasis)Tomoya Hirai (RIKEN-IFOM Joint Laboratory for Cancer Ge-

nomics)Rino Maruyama (Laboratory for Cellular Function Conversion
Technology)
Soichiro Yoshino (Laboratory for Statistical and Translational
Genetics)

RIKEN Special Postdoctoral Researcher (SPDR)
Program

R

IKEN’s Special Postdoctoral Researcher Program was instituted to provide young and creative scientists the opportunity to be involved in autonomous and independent researchin line with RIKEN objectives and research fields. The positions
are competitive, but if selected, researchers receive salaries andresearch budgets (1 million yen) from RIKEN and they are able toconduct their research at one of its laboratories.
This year, 8 postdocs conducted their research at IMS throughthe SPDR program.

70

Chisayo Kozuka (Laboratory for Developmental Genetics)
Mari Hashimoto (Laboratory for Human Disease Models)
Baihao Zhang (Laboratory for Mucosal Immunity)
Hideki Terajima (Laboratory for Gut Homeostasis)
Ryota Teramoto (Laboratory for Comprehensive Genomic

Analysis)
Steven Matthew Heaton (Genome Immunobiology RIKEN
Hakubi Research Team)
Shohei Kojima (Genome Immunobiology RIKEN Hakubi Research Team)
Ayako Matsuyama (Laboratory for Tissue Dynamics)

Part 3
Research
Projects

COVID-19 projects in IMSC

oronavirus disease 2019 (COVID-19) caused by SARSCoV-2 continues. While current COVID-19 vaccines haveshown efficacy in many countries, the development of diagnostics
and prevention strategies to protect from severe disease is stillneeded. Here we will introduce several groups in IMS that are
currently working on COVID-19 projects. Fukuyama’s group, in
collaboration with Keio University, have already isolated several
human mAbs from COVID-19 patients. They have patented
these antibodies, which can neutralize several variants of concern
strains of SARS-CoV-2, and started research and developmentwith pharmaceutical companies for formulation of therapeutic
neutralizing antibodies. Yamamoto’s group has established a system for analyzing the whole picture of peripheral blood mononuclear cells (PBMCs) of those who recovered from COVID-19 andare searching for factors that are involved in infection resistance.
They also studied changes in PBMCs and lymphocyte function
before and after vaccination by single-cell analysis. Momozawa’s
group, as a member of the COVID Human Genetic Effort, hasbeen identifying COVID-19 susceptibility genes, genes associated with severe disease and disease resistant genes from clinicalinformation or immunological analysis, and from large-scale
whole genome data. Terao’s group, as a member of the International Joint Research group, reported COVID-19 patients withmosaic chromosomal alterations (mCAs) have an increased riskof developing severe infections. Honda’s group has revealed that
intestinal colonization by trypsin-degrading bacteria suppresses
mouse hepatitis virus. In addition, they showed that people witha large number of microbiome bacterial genes involved in trypsin
degradation had less severe diarrhea symptoms during SARSCoV-2 infection. Ohno’s group searched for gut bacterial markers
involved in the severity of COVID-19 and complications in otherorgans outside the intestine from omics analysis and found thatthe characteristics of the intestinal flora of patients in Japan are
different from those of patients in the United States. Ishikawa’s
group provided human immune cell data to understand how
coronavirus infection affects human immune reactions and differentiation. Several groups are collaborating with the RIKEN
Drug Discovery and Medical Platform (DMP). Miyauchi’s grouppreviously succeeded in generating high-affinity antibodies thatrecognize multiple mutant CoV-2 strains by stimulating T follicular helper cells in the germinal center. Saito’s group has establishedneutralizing antibodies that target TMPRSS2, the host enzymethat activates the viral spike protein and are now conducting preclinical studies. Fujii’s group has identified an HLA-A24-restricted, cross-reactive QYI peptide for CTL induction using human
PBMCs reactive with SARS-CoV-2. Also, since they previously
established the concept of the artificial adjuvant vector cell (aAVC)
system against cancer, they established a SARS-CoV-2-derived
antigen-expressing aAVC (aAVC-CoV-2). In preclinical studies
they obtained evidence for anti-viral cytotoxic T cell induction as
well as anti-SARS-CoV-2 Ab in vaccinated animals.
Recent advances as IMS projects in the fields of diagnostics,
treatment and vaccine development for SARS-CoV-2 infection
are summarized in Table.

Table: COVID-19-related research conducted at IMS

Teams

TitlesHidehiro Fukuyama(Lab. for Lymphocyte Differentiation)

Development of COVID-19 antibody drugs

Kazuhiko Yamamoto(Laboratory for Autoimmune Diseases)

Development of a method for healthy immune cell profiling of individuals recovering from SARS-CoV-2
infection

Yukihide Momozawa(Lab for Genotyping Development)

Genome analysis to identify genes and genome loci associated with individual differences insusceptibility to COVID-19 infection

Kosuke Miyauchi(Lab. for Cytokine Regulation)

Construction of a system to isolate a human monoclonal neutralizing antibodies against SARS-CoV-2(with DMP)

Kenya Honda(Lab. for Gut Homeostasis)

Understanding host-gut microbiota interactions to develop a therapeutic/preventive strategy for
SARS-CoV-2 infection

Hiroshi Ohno
(Lab. for Intestinal Ecosystem)

Screening for an intestinal flora marker for COVID-19 in large databases using Omics analysis

Takashi Saito(Lab. for Cell Signaling)

Development of a TMPRSS monoclonal Ab (with DMP)

Chikashi Terao(Laboratory for Statistical and Translational Genetics)

Elucidating the relationship between somatic cell mosaicism and the risk of COVID-19 infection

Fumihiko Ishikawa(Lab. for Human Disease Models)

Mechanism of COVID-19 severity caused by mutant viruses in the post-vaccination period

Shin-Ichiro Fujii(Lab. for Immunotherapy)

Development of aAVC-CoV-2 (with DMP)

Shin-Ichiro Fujii(Lab. for Immunotherapy)

Identification of SARS-CoV-2 epitopes cross-reactive with seasonal coronaviruses

72

Human Cell Atlasat single-cell resolution (Figure). This analysis framework wasalso extended to the AIDA project, which aims to characterize
the extent of variation in immune cell types from diverse Asian
populations. In the AIDA project, we have profiled the tCREs in>1 million immune cells from 500 individuals collected in Japan,
Korea, and Singapore. In the next phase of the project, we will
extend our efforts to other Asian countries including Thailand,
India, Sri Lanka, Pakistan, and Russia. In summary, these HCA
activities leveraged the single-cell transcriptomics and medical
genetics expertise in RIKEN IMS to further our understanding of
the cellular contexts of human diseases.

a)

Lab Activities

he Human Cell Atlas (HCA) is an international consortium
aiming to create a comprehensive molecular reference mapof human cells as a basis for understanding human health anddiseases. At RIKEN IMS, led by Dr. Piero Carninci, Dr. Jay Shin,and Dr. Chung-Chau Hon, we contribute to HCA by coordinating HCA activities among Asian institutions (e.g., HCA Asia
meetings), developing single-cell experimental and computational methods (e.g., single-cell 5’ RNA-Seq analysis methods)
and generating single-cell molecular atlases from Asian samples(e.g., Asian Immune Diversity Atlas (AIDA)). Specifically, we
devised a method to identify genuine transcribed cis-regulatory
elements (tCREs) from single-cell 5’ RNA-Seq data and used thismethod to generate a single-cell tCRE atlas from 22 human tissues, comprising >500,000 cells. Using this tCRE atlas, we devised
a novel method to estimate the enrichment of disease heritability

Research Highlights

Tb)

Figure: Enrichment of disease heritability at single-cell resolutiona) UMAP of a single-cell tCRE atlas from 22 human tissues, comprising >500,000 cells,
annotated as 21 broad cell types. b) Enrichment of psoriasis heritability across the
single-cell tCRE atlas. Heritability enrichment at single-cell resolution is calculated using a novel method based on tCRE module activities. Psoriasis heritability is enrichedin subpopulations of T-cells, dendritic cells, fibroblasts, blood vessel endothelial cells,
and non-secretary epithelial cells.

Projects

Keio-RIKEN IMS HuMED

Ia) Sorting strategy for the human single-cell RNA-seq:
Lamina propria lymphocytes (LPLs) collected from digested small intestinal tissues were sorted by identifying
7AAD–CD45+TCRB+ cells by FACS. b) UMAP of 12,073 cells
from healthy controls (n=2) and IBD patients [ulcerative
colitis (n=1) and Crohn’s disease (n=1)]. Cells wereclustered into 18 clusters. The hCD4+CD8+, hTreg andhMAIT cluster is considered to be orthologous to mouse
CD4 cytotoxic T cells. c) Expression of CD4 and CD8A. d)
Proportion of each cluster in controls and patients withulcerative colitis (UC) and Crohn’s disease (CD).

a)

c)

b)

d)

73

Data and Statistics

Figure: Identification of cytotoxic CD4+CD8A+
T cells in the human gut and their similarity tomouse CD4 cytotoxic T cells

iPSC-induced motor neurons from an ALS cohort (n=150), andsalivary gland biopsies from a Sjögren’s syndrome cohort (n=30).
In addition, the joint program also includes 10+ other projects including GVHD of colon transplantation, spatial transcriptomicsof brains from Alzheimer’s disease and Schizophrenia disease
patients, skin biopsies of atopic dermatitis, characterization ofhuman gut T cell populations and in vitro differentiation of neural lineages, etc. One of the highlights is the identification of cytotoxic CD4+CD8A+ T cells in the human gut and their similarity
to mouse CD4 cytotoxic T cells (Figure). The joint research lab isa hub for fruitful collaborations between RIKEN IMS and Keio
University, generating highly informative genomic data to transform medicine for a brighter future.

Eventsn 2021, RIKEN IMS embarked on an exciting joint research
program with Keio University School of Medicine, “KeioRIKEN IMS Human Biology and Medicine Program (HuMED)”,aiming to maximize the social benefits of medical knowledge derived from genomic studies. The creation of a Keio-RIKEN IMS
joint laboratory in the Shinanomachi campus, led by Dr. Jay Shin,
Dr. Akiko Minoda and Dr. Chung-Chau Hon, strengthens thealready well-established medical research at Keio University withthe advanced genomic technologies from RIKEN IMS, throughcollaborative projects over the next decade. The HuMED projectfocuses on the applications of single-cell genomics to medical
research, in particular large-scale studies of disease cohorts at single-cell resolution. Notable examples include profiling of colon biopsies from ulcerative colitis and Crohn’s disease cohorts (n=300),

FANTOM ProjectS

ince its start in 2000 in a broad international collaboration,
the FANTOM Project aims to elucidate the function of the
mammalian genome with a focus on the transcriptome. The goalof the FANTOM6 Project is to systematically elucidate the function of long non-coding RNAs (lncRNAs) in the human genome.
FANTOM6 has published an initial functional screening based on
perturbation of the function of lncRNAs and imaging, identifying
function for about ~30% of analyzed lncRNAs (Ramilowski et al.,Genome Research 2020; Yip et al., Cell Reports 2022).
Moving into the second phase of FANTOM6, we aim to decipher the function of lncRNAs and their regulatory elements
by studying their physical interactions with their targets. We are
analyzing an initial set of ~15 biological samples and producing
multi-omics data using various technologies, including RADICLseq to detect RNAs interacting with, and likely regulating, chro-matin activity. In parallel we characterize in detail the lncRNA sequences and the map of promoters and enhancers. Particular initial focus is dedicated to the interactome along the differentiationfrom iPS cells to cortical neurons and the differentiation frommonocytes to macrophages as a pilot before broadly expanding
the biological emphasis.
Given that the majority of RNAs are retained in the nucleus,
and there is a broad set of them interacting with chromatin, theproduced data from this project will be of great help in elucidating the role of lncRNAs to regulate human genome activity.
A

Figure: RNA-chromatin interactome in FANTOM6A) Cell models and FANTOM6 RADICL-seq libraries B) RNA-chromatin interactions
during differentiation from THP-1 monocytes to macrophages: in trans interactions,shown as percentages, increase during the differentiation process. Phorbol 12-myristate 13-acetate (PMA), which activates protein kinase C, was used to induce differentiation. C) Different interaction patterns between protein coding RNAs and longnon-coding RNAs (lncRNAs): lncRNAs mostly show exon-derived interactome in transor distal in cis while protein coding RNAs mostly show intron-derived interactome incis with specific patterns.

BC

Human genome analysis

In 2015, the Japanese government set rare hereditary diseases, cancer, dementia, infection, and pharmacogenomics as priority areas
for the implementation of genomic information for actual medical
practice. To accomplish this goal, a combined analysis of germline
variants with other information including somatic variations, gene
expression profiles and environmental factors would be key.
IMS has analyzed various diseases and phenotypes by genomewide association studies and/or targeted- and whole-genome
sequencing-based association studies. These include cancer (Momozawa & Nakagawa), pharmacogenomics (Mushiroda), boneand joint diseases (Ikegawa), diabetes mellitus (Horikoshi), cardiovascular diseases (Ito), autoimmune diseases (Yamamoto K),
genome immunobiology (Parish), functional genetics (Ishigaki),and integrated analysis of all data and phenotypes (Terao). In addition, we began to extract information about somatic variations
from DNA microarray data, which had previously been used only
to call germline variants. Further, to better understand disease
biology, we integrated our results with knowledge of non-coding
regions and single-cell sequencing approaches obtained by laboFigure: Integration analysis of genomic data with ChIP-seq data identified a new transcription factor involved in the development of atrial
fibrillationa. Volcano plot analysis utilizing the results of genomic analysis with a ChIP-seq database highlighted the ERRg transcription factor in cardiac cells.
b. Motion analysis of iPS-derived cardiomyocytes (iPSCM) using the SI8000 Cell
Motion Imaging System. iPSCMs treated with GSK5182, an inverse agonist of ERRg,
showed an arrhythmic phenotype.

74

ratories of the FANTOM and Human Cell Atlas projects. Finally,
we have established collaborations with large Japanese cohorts
including BioBank Japan (BBJ), Tohoku Medical Megabank anddomestic and international universities.
A key finding in 2022 is the accumulation of new genomicbased evidence for the pathogenesis of atrial fibrillation (AF)and the application of a genetic risk score (GRS). The integrative
analyses suggested that the ERRg transcription factor is involvedin the pathogenesis. We also showed the AF-GRS predicted stroke
even without AF diagnosis, which expanded its potential for clinical application.
abSEAPharm for the establishment of stratified
medicine in Asia
Recently, SEAPharm has started a new project involving targeted next-generation sequencing (NGS) of DNA samples fromthe 12 member countries to clarify the genetic diversity of 100
pharmacokinetics-related genes in individuals. We reported
substantial genetic variations in drug-metabolizing enzymes anddrug-transporter genes among Asian populations. Our findings
show that NGS-derived data coupled with in vitro experimental
metabolic validations can provide useful insights towards clinical
PGx implementation, which would be the basis for integrating
NGS for genetic testing into routine clinical practice.

Lab Activities

IKEN established the Southeast Asian Pharmacogenomics
Research Network (SEAPharm) together with five other
Asian countries (Korea, Indonesia, Malaysia, Taiwan, and Thailand) in 2012 and membership has been steadily increasing, with
Singapore, Vietnam, Nepal, Laos, the Philippines, Brunei, andMyanmar now included. The aims of the collaboration are to
identify pharmacogenomic (PGx) biomarkers associated withadverse drug reactions, such as severe cutaneous adverse drug
reactions (ADRs), including Stevens-Johnson syndrome (SJS),
toxic epidermal necrolysis (TEN) and hepatic injury, to provide
technical assistance and training of young researchers from the
SEAPharm member countries and to hold international seminars
and workshops.

Targeted PGx panel
resequencing

Figure: SEAPharm PGx variation project and proposed clinicalworkflow for future clinical implementation of PGx testing

We genotyped 1,571 genomic DNA samples using an NGS panel thattargets the coding regions of 62 drug-metabolizing enzymes and 37
drug transporter genes. We were able to identify many novel variantsin 20 clinically important drug-metabolizing enzyme genes in the
SEAPharm populations, which were not registered to The Pharmacogene
Variation Consortium (PharmVar, https://www.pharmvar.org/). We wish
to propose an approach consisting of NGS coupled with in vitro validation assays of the wild type and variant protein activities, resulting in acomprehensive final variant report to support the possible pathogenicityof these variants.

Research Highlights

R

Variant annotation
In silico
prediction tools
Clinically actionable
PGx variants

Rare and novel
variants
Functionalin vitro assays

Projects

Summary variant report

eQTL project: Integration of genetic information
into immune functions(D) ChIPsequencing

Qu
an
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, sp
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e

: histone
QTL (hQTL)
Histone modific
ation

C
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Genetic variants

EnhancerE-lncRNA

PromoterP-lncRNA

E-lncRNA(G) CAGE-sequencing(H) Captured HiC-sequencing/MicroC-sequencing:Enhancer activity QTL (eaQTL)

Figure: Integration of genetic information into immune functions: The
eQTL project

Gene(G) CAGE-sequencing:Promoter usage QTL (puQTL)

DNA methylation

H3K4me3

Polymerase ⅡRNA

H3K4me1

H3K9acTranscription factors

H3K27ac

DNase I

H3K27me3
Tn5

75

Data and Statistics

lyzed in the steady state or in further stimulated conditions, suchas with combinations of cytokines and cell surface receptor agonists to capture the dynamic responses of gene regulation. Firstly,
genotyping as well as RNA-seq are performed. With this data, wewill obtain eQTL as well as splicing QTL information. Cap analysis of gene expression (CAGE), assay for transposase-accessible
chromatin using sequencing (ATAC-seq) and several histonemark analyses for each subset are powerful tools to be used for
identifying the causal relationship between genetic variation andgene expression.

s
ATA L
statu
(B) AC-QT
atin
rom
g
: AT
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Ope
que

any disease susceptibility variants have been identified bygenome wide association study (GWAS). Germline genetic variations provide us with evidence into the causal relationshipof an observed phenomenon and its pathogenesis. In this regard,
the majority of GWAS risk variants have been reported to locate
in the non-coding regions on the chromosome and function as
an expression-quantitative trait locus (e-QTL), regulating theexpression levels of genes. Therefore, by integrating genomic information, qualitative and quantitative analyses of transcriptomes
together with cell-specific epigenomes, we will better understandthe causal pathogenic components of immune cells in various
immune-mediated diseases.
We are now setting up a system to identify various subtypesof leukocytes from peripheral blood mononuclear cells (PBMC)
of heathy individuals. We expect to obtain the utmost unbiased
relationship between genotypes and gene expression from healthy
donors. Cell separation is performed by fluorescence-activatedcell sorting into about 30 different subsets. Cells are then ana-

EventsM

Identifying gut microbiota-associated biomarkers that
aggravate insulin resistance (IR) and insulin sensitivity (IS)Tvary metagenomic and metabolomic data, plasma metabolomic data, CAGEbased RNAseq, and whole genome sequencing data of peripheral blood mononuclear cells (PBMCs).
We found that IR and metabolic syndrome were significantly associatedwith fecal monosaccharides and sugar derivatives. We further revealed thatthese fecal monosaccharides and sugar derivatives were strongly associatedwith host inflammatory gene expression in PBMCs and with plasma cytokine
levels (Figure). We also found that order Bacteroidales were negatively correlated with IR and fecal monosaccharides. Order Bacteroidales bacteria, especiallyAristipes indistinctus, consumed a wide variety of carbohydrates in bacterial
cultures. We further showed that high-fat diet-induced obesity and IR wereameliorated by Aristipes and Bacteroides. These results reveal the impact ofcarbohydrate degradation by microbiota on IR and suggest genus Aristipes as apotential therapeutic target for improving IS. This study is now under revision
for publication.

ype 2 diabetes mellitus (T2D) is increasing rapidly and becoming one of
the most prevalent diseases worldwide, in association with changes inlifestyle and social environment. It is estimated that about 1 in 5 Japanese suffer from diabetic or prediabetic (medically defined as glucose intolerance) conditions. Thus, prevention of T2D and control of its progression are importantand urgent needs - medically, socially, as well as economically. We, therefore,
set this issue as one of the center projects to try to identify gut microbial T2Dpredictive biomarkers or factors. In collaboration with the University of Tokyo
Hospital, we recruited volunteers undergoing a complete medical checkup withthe following criteria: 1) no obesity or glucose intolerance (control), 2) obesity(BMI ≥ 25) and 3) glucose intolerance (fasting blood glucose ≥ 110 mg/dl or
HbA1c ≥ 6.0%). Clinical examination data from the medical checkup, as wellas nutritional and physical activity data (brief self-administered diet history
questionnaire (BDHQ) and accelerometry), were done at the University ofTokyo Hospital, while the following were collected in RIKEN: fecal and sali-

Figure: The networks between fecal carbohydrate metabolites,
fecal microbes, plasma hydrophilic metabolites, cytokines, and
PBMC genes in IS and IR individuals

Insulin Insulin
sensitive
sensitive

Fecal carbohydrate metabolites (green), fecal microbes (sky blue), plasma hydrophilic
metabolites (orange), cytokines (yellow), and PBMC genes (purple) are shown. For
fecal and plasma metabolites, cytokines and PBMC genes, those significantly associated with both insulin resistance and metabolic syndrome were selected for the
analysis. For fecal microbes, those that formed co-abundance groups were selected.
To construct the omics network, partial Spearman’s correlation corrected by age, sex,
body mass index, and fasting blood glucose between all elements was calculated,
and the interactions with q values < 0.2 are depicted. Line widths show the absolutevalues of Spearman’s coefficient, and red and grey lines show positive and negative
correlations. Disk sizes indicate the overabundance to the median in IS and IR (Theabundance of each element in IS or IR was divided by the median of all samples).

WHRN

WHRN
TTC31

1_5-Anhydro 1_5-Anhydroglucitolglucitol
Hypotaurine
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Adiponectin
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SUOXCST3 LST1SUOX
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acid
acid
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RTL8C
RTL8C
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ParabacteroidesParabacteroides
Fec.Lactulose Fec.Lactulose
Prevotella
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Blautia Coprococcus
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Subdoligranulum
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Alistipes
Bacteroides

Bacteroides

Dorea

ADDG17007589366.R
ADDG17007589366.R
ADDG06106512751.F
ADDG06106512751.F
SUOXCST3 LST1SUOX
LST1Sarcosine

CST3
RNF135

GlucoseGlucose Tyrosine

TTC31

Adipsin
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SIGIRRSIGIRRADDG17008160447.F
ADDG17008160447.F
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hsCRP
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SerpinE1
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Alistipes

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WDR48
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hsCRP
hsCRP
PIK3CDPIK3CD
RPS12
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Adiponectin
SerpinE1
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Tyrosine

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Fec.Xylose
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acid
acid
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Fec.Mannose Fec.Mannose
LactateLactateADDG09112862005.E
ADDG09112862005.E
Fec.Glucosamine
Fec.Glucosamine
RTL8C
RTL8C
2-Hydroxybutyric
2-Hydroxybutyric
CMTM7
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acid
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Fec.Mannitol Fec.Mannitol
Succinate acid
Succinate acid
Fec.Galactose Fec.Galactose
Fec.N-Acetylmannosamine
Fec.N-Acetylmannosamine
Fec.Inositol
Fec.Inositol

Dorea

Fec.Allose
Fec.Allose
Collinsella
Collinsella
Fec.Glucose
Fec.Glucose
Fec.Fucose
Fec.Fucose
Fec.Lyxose
Fec.Lyxose
ParabacteroidesParabacteroides
Fec.Lactulose Fec.Lactulose
Prevotella
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Blautia Coprococcus
Blautia Coprococcus
Subdoligranulum
Subdoligranulum
Faecalibacterium
Faecalibacterium
Alistipes

Alistipes
Bacteroides

Bacteroides

Dorea

Dorea

Atopic dermatitisA

topic dermatitis (AD) is a heterogeneous and multifactorialdisease. Although it has been suggested that a personalized
approach to each patient is important for understanding AD, appropriate methods for this purpose have not yet been established.
This study aims to clarify the diverse pathophysiology of human
AD by integrating and analyzing the genome, transcriptome andmultimodal clinical information of AD patients, and to establish afoundation for personalized predictive medicine according to thepathophysiology of the disease.
We have collected multi-omics and multi-modal clinical datafrom more than 200 AD patients and 50 healthy controls. By applying machine learning techniques to these data, we have identified immunological signatures that lead to two representative
skin phenotypes, as well as the possibility that clinical symptoms
and endotypes are closely related longitudinally. These findings
suggest that patient stratification focused on endotypes is feasible.
In addition, skin tissue transcriptome analysis revealed immune

dynamics associated with the therapeutic efficacy of an immunotherapeutic (dupilumab, a mAb that blocks IL4 and IL13), suggesting that metagen-specific marker genes derived from our data
analysis may contribute to predicting therapeutic efficacy anddisease monitoring.
We have also collected data from mouse models of AD.
Through human-mouse data integration, we identified several
novel AD drug targets. We are also actively promoting drug
discovery projects and have already obtained seed compounds
through collaborative research with the University of Tokyo, Keio
University School of Medicine, and RIKEN DMP.

Cross-sectional Study

Longitudinal Study

Animal model
GenemeTranscriptome

Clinical data

Figure: Study workflow: Data-driven research for Atopic Dermatitis

Combining cross-sectional and longitudinal studies, omics data, mainly genomic and transcriptomic, and clinical multimodal data were collected fromcooperative clinical research institutes (in collaboration with Keio University).
These will be used for disease stratification and for the development of usefulmarkers for disease monitoring and prediction using machine learning andmathematical techniques. Furthermore, by analyzing these data in combination with animal models, the project also aims to identify new therapeutictargets and develop new therapeutic agents.

76

Disease Stratiﬁcation
Prediction and Disease Monitoring

Drug Discovery
and Development

iPS Project
To maximize the efficacy of iPS-Vα24+iNKT cells, the facility has focused on introduction of Chimeric Antigen Receptors(CARs) into iPS-Vα24+iNKT cells. Among several CARs, thefacility chose CD19 and CD25 CARs to treat leukemia. In 2022,
we showed a proof of concept. CD19-CAR iPS-Vα24+iNKT cells
suppressed leukemia in mice. Currently, we are generating GMP
grade CD19-CAR iPS cells for a future clinical trial.
The facility also has been developing a protocol with shorter
culture times and higher induction efficiency. We have found that
iPS-derived early progenitors are multipotential for cell fate determination prior to lymphoid-lineage commitment in our current
protocol, which possibly causes low induction efficiency. Thus weare going to improve this with chemical compounds and/or cytokines.
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NKT toward the CD19+ NALM-6 human leukemia
40
IFN-γ and GrB production by CD19CAR iPS-NKT and wild-type
20
iPS-NKT cocultured with NALM-6 ± α-galactosylceramidepulsed dendritic cells (DC/Gal).
060

CD19CARno80

Figure: Anti-tumor effects of CD19CAR iPS-NKT

Cytotoxicity (%)

Copy of CD19CAR_killing#1,5
100

Copy of copy of PHA_GrB
8000

Lab Activities

nduced pluripotent stem (iPS) cells possess tremendous therapeutic potential in many areas, including regenerative medicine and immune therapy. On a collaborative basis with individual IMS research laboratories, the core facility for iPS research isaiming to put cancer immunotherapy with iPS-derived NKT cells
into clinical use.
The facility has operated an IMS Cell Manufacturing Unit toproduce iPS-derived human invariant NKT (Vα24+iNKT) cells
under Good Manufacturing Practice/Good Gene, Cellular, andTissue-based Products Manufacturing Practice guidelines. The facility has been conducting a clinical trial of iPS-Vα24+iNKT cells
for head and neck cancer. We have also been planning anotherclinical trial using a combination therapy with iPS-Vα24+iNKT
cells and activated dendritic cells for head and neck cancer and it
will be started in the next year.
A
A

Research Highlights

I

Humanized Micecells targeting CD25, CD19 and CD7, we evaluated to what extent the engineered T cells can eradicate patient leukemic cells
in multiple organs in patient-derived xenografts for AML, CML
and ALL. In particular, the synergistic effect of inhibiting patientspecific vulnerability molecules and of targeting cell surface molecules in the leukemia resulted in robust eradication of patientleukemic cells in multiple organs such as bone marrow, spleen,
liver, and peripheral blood (Figure).
Taking advantage of the Humanized Mice, we found how
CAR-T cells behaved in organs at distinct time points after infusion. We are now connecting Humanized Mice with single-cellgenomics to find out which genes and networks account for potent treatment efficacy of the newly-developed engineered T cells
in vivo.
Patient- and organ-specificleukemia-T cell interactions
Leukemia

Figure: How to achieve long-term remission for patients suffering fromaggressive leukemia

Tumor-associated determinants of leukemia survival include patient-specific criticalmolecules such as BCL2, MCL1 and IAPs, based on distinct mutations and chromosomal abnormalities (Nature Cancer 2021). By identifying and inhibiting patient-specificvulnerabilities, AML cells become primed for apoptosis and cell death. Pretreatment
with inhibitors of patient-specific survival molecules facilitates both immediate andshort-term CAR-T cell efficacy and acquisition of immunological memory leading
to long-term leukemia suppression. Effector-associated determinants of leukemia
eradication include the expression of CXCR4 in CAR-T cells targeting patient-specificcell surface molecules. CXCR4 expression enhances memory CAR-T cell formation andprevents immune checkpoint activation and T cell exhaustion in the context of in vivo
leukemia-T cell interactions.

T cellsvsTumor-associated factors

Patient-specificvulnerabilities

Apoptotic
priming

BCL2
BIRC/IAP

Effector-associated factors

CXCR4(-)

CXCR4+

Exhaustion
Immune checkpoint

Memorymitochondria

11q23
IDH1
FLT3

3q21
11q23
CBL NRAS
FLT3

77
Tumor-associated determinants of leukemia survival include patient-specific critical molecules such as BCL2, MCL1 and
IAPs, based on distinct mutations and chromosomal abnormalities (Nature Cancer 2021). By identifying and inhibiting

Data and Statistics

umanized Mice, a xenograft system reconstituted withnormal or malignant human stem cells, have been utilized
in wide areas of biological and medical sciences. RIKEN IMS
has made an effort to overcome a limitation of the species barrier by inducing the expression of human cytokines or adhesion
molecules, which better recapitulates normal human blood andimmune systems in the mouse.
For the past decade, the engineering of immune cells and immune checkpoint blockade have emerged as promising treatment
modalities to reactivate patient immune cells that have become
dysfunctional or exhausted. In the Humanized Mouse model,
we aim to elucidate whether the xenograft model can be useful
to assess such immune-oncology treatments and to develop new
CAR-T cell therapies for poor prognosis leukemia. Using CAR-T

EventsH

Cancer ImmunologyT

he immune system can recognize tumor cells and mediate
antigen-specific tumor rejection under certain conditions,however the tumors often evade the immune network. Understanding the tumor immune microenvironment (TIME) will leadto a variety of approaches designed to initiate or enhance antitumor immunity (Figure). The groups in Cancer Immunology are
investigating the target molecules and cells and developing a disease stratification system and treatment strategy. Tsunoda’s group(Lab for Medical Science Mathematics) reported that the statusof the tumor microenvironment and its neoantigen composition will be promising new prognostic biomarkers with potential
clinical relevance. Nakagawa’s group (Lab for Cancer Genomics)
analyzed whole genome, RNAseq and single-cell RNAseq datafrom the TIME of several cancers. They found that the presenceof granulocytes is likely to be associated with response to thetreatment. Ishikawa’s group (Lab for Human Disease Models)developed a CAR-T cell therapy for myeloid leukemia targeting

CD25/IL2RA and also found that engineering the CAR-T cells
to express CXCR4 enhances their ability to eradicate leukemic
cells. Fujii’s group (Lab for Immunotherapy) has made progresswith their aAVC projects for cancer. They developed NY-ESO1-expressing aAVC that showed immunological and anti-tumor
effects in a preclinical study. For the aAVC-WT1, they started a
Phase II clinical study as multicenter joint research. In addition,
Koseki’s group (Lab for Developmental Genetics) has started an
iPS-NKT cell clinical trial for head and neck cancer. These translational research projects have been supported by an interaction
between IMS and the RIKEN Program for Drug Discovery andMedical Technology Platforms.

Figure:Our groups work on two strategies by analyzing the tumor immune microenvironment (TIME). One is for the stratification of tumor tissue through an omics analysis oftumor cells and the TIME, the other one is for the establishment of new cancer immunotherapies.

Linkage to RIKEN Program for Drug Discovery andMedical Technology Platforms (DMP)I

MS collaborates with DMP to develop innovative new biologics, pharmaceuticals and medical technologies by facilitating
the transfer of basic research discoveries within the institute.
DMP supports all phases of the development of new therapeutics, from the discovery of promising targets to the identificationof potential lead compounds and the acquisition of intellectual
property rights to drugs and technologies that can then bebrought to the development phase.
DMP established nine Drug Discovery Basic Units, in which
the types of studies being performed are organized according
to the expertise of each PI. IMS has contributed to this effort by
setting up a facility for the development of antibody drugs, theDrug Discovery Antibody Platform Unit, and the artificial Adjuvant Vector Cell (aAVC) Drug Translational Unit. In 2022, IMS

had eight collaborative programs with DMP: Development ofaAVC expressing WT1, human papillomavirus (HPV) or SARSCoV-2 antigen (aAVC-WT1,-HPV and -CoV-2) for cancer andinfectious diseases (Shin-ichiro Fujii), iPS-derived NKT cells forcancer (Haruhiko Koseki), Neutralizing mAb for hepatitis B virus
infection (Kazuaki Chayama), Development of mAb for multiple
sclerosis (Takashi Saito), mAb for TMPRSS to prevent SARSCoV-2 infection (Takashi Saito), and Development of a drug foratopic dermatitis (Tomohiro Miyai). The investigator-initiatedPhase II clinical trial of aAVC-WT1 against AML is ongoing. In
addition, an iPS-NKT cell phase I clinical trial for head and neckcancer has started.

Identification& validationof targets

Seed/Lead
identification

Lead
optimization

・Artificial adjuvant vector cells (WT1)

Phase Ⅱ
Phase Ⅰ・Artificial adjuvant vector cells (HPV)・TMPRSS mAb for SARS-Cov2
・A novel inhibitor for HBV infection
・Therapeutic mAb drugs for multiple sclerosis

78

Clinicaldevelopment

・Cancer therapy with iPS-derived NKT cells

・Artificial adjuvant vector cells (SARS-Cov2)

Figure: Collaboration between IMS and DMP for
the development of innovative new biologics,
pharmaceuticals and medical technologies

Preclinicaldevelopment

・Drug development for atopic dermatitis

In collaboration with pharmaceutical companies

Part 4
EventsRIKEN IMS-Stanford ISCBRM Joint Symposium

I

MS and Stanford University Institute for Stem Cell Biology
and Regenerative Medicine (ISCBRM) have held a series ofjoint symposiums since 2017. The annual joint symposium has
been successfully held in Yokohama and Stanford alternately, andthe 6th joint symposium for FY2022 was hosted by RIKEN IMS.
Due to COVID-19, it was held online on February 21 and 22,2023 in Japan time. The symposium was started with the opening
remarks by the new director of Stanford ISCBRM, Ravi Majeti,
followed by the first session focusing on heart and lung development by Casey Gifford (Stanford), Kaoru Ito (RIKEN), Karen
Gonzalez (Stanford), and Maria Martinez (Stanford). The next
session was on molecular mechanisms of cell differentiation anddisease development by Chengcheng Zou (RIKEN), Sidd Jaiswal(Stanford), and Tetsuro Kobayashi (RIKEN). The third session on
day two was about multi-modal and multi-cellular biology by Kazuyoshi Ishigaki (RIKEN), Berfin Azizoglu (Stanford), and Tatsuya Ishikawa (RIKEN). The final session featured human disease
biology by Yimiao Qu (Stanford), Hiroshi Ohno (RIKEN), andRavi Majeti (Stanford). Despite the distance and time-zone dif-

6th RIKEN IMS-Stanford ISCBRM Joint Symposium
February 21-22, 2023, 9:00 a.m. - 12:00 p.m. Japan Time
(February 20-21, 2023, 4:00 p.m. - 7:00 p.m. Pacific Time)
Online, Zoom Meeting

ference, we had about 50 participants on both days, and had very
active discussions after each talk. The symposium was concluded
with IMS Director Kazuhiko Yamamoto’s closing remarks hoping
to have an in-person meeting for the 7th.

The 5th Tsinghua-RIKEN Joint WorkshopT

he 5th Tsinghua-RIKEN Joint Workshop, “Recent Progressin Immunology,” was held online on November 25, 2022.
This joint workshop was originally planned to be held in Beijing in 2020, but it had to be postponed for 2.5 years because of
the pandemic. The organizers, Dr. Yun-cai Liu of the Instituteof Immunology Tsinghua University (IITU), and Dr. Tomohiro
Kurosaki of RIKEN IMS, decided to hold the joint meeting virtually this time. In the opening remarks, Dr. Xiaoyu Hu, the new
Director of IITU, and Dr. Kazuhiko Yamamoto, the new Director of RIKEN IMS, applauded resuming joint activities. The
meeting gathered 265 participants. The talks covered recent hot
topics in immunology such as T-B cell biology by Drs. Hai Qi,
Cheng Dong, Kurosaki, and Koseki, innate immunity by Drs.
Moro, Coco Chu, and Xiao-Yu Hu, tissue-specific immunology
by Drs. Ohno, Xiao-huan Guo, and Wenwen Zeng, translational
immunology by Drs. Min Peng, Akiyama, Ishigaki, and ChungChau Hon, and finally clinical immunology by Drs. Huji Xu andYamamoto. After each talk, active questions followed orally, andthe discussions continued in the chat. The meeting was closed
by Dr. Hai Qi, the dean of School of Medicine in Tsinghua Uni-

80

versity, and Dr. Tomohiro Kurosaki, sharing their hope for an inperson meeting next time and the mutual visits between the two
institutions. RIKEN-Tsinghua International Summer Program isplanned to be held in Yokohama in June 2023.

Kazuyo Moro

CoCo Chu

Xiao-Yu Hu

TaishinAkiyama

Min Peng

Kazuyoshi
IshigakiChung Chau
Hon

Meng Xu(chair)Zhihua Liu(chair)Yan Shi(chair)Xin Lin(chair)Tomohiro
KurosakiHaruhiko
KosekiHai QiChen Dong

Hiroshi Ohno

Xiao-huanGuo

WenwenZeng

Huji Xu

Kazuhiko
Yamamoto

Yun-Cai Liu(chair)5th Tsinghua-RIKEN Joint Workshop

November 25, 2022, 9:30 a.m. - 6:05 p.m. Japan Time
(8:30 a.m. - 5:05 p.m. China Time)
Online, Zoom MeetingKeio-IMS Joint Symposium

potential for future collaboration. There were 161 participantsthat attended onsite or online and enjoyed active discussions on
studies utilizing state-of-the-art single-cell technologies. The
symposium concluded with a consensus that continued collaboration and interdisciplinary approaches are crucial for driving
progress and growth.

Lab Activities

n July 2022, a Keio-IMS joint symposium titled “Single Cell
Biology and Clinical Applications” was held in collaboration
with Keio University School of Medicine in a hybrid format.
The advances in single-cell profiling technology have opened
up new avenues for analyzing molecular signatures in many cellswith the single-cell-level resolution, thus providing immense
opportunities for the advancement of medicine. RIKEN IMS
launched a research collaboration project with Keio University
School of Medicine (Keio-RIKEN HuMED) in April 2021 to leverage the knowledge gained from single-cell analysis of humanclinical samples for various diseases and maximize the social benefit of human biology and medicine. In order to facilitate this collaboration, the KEIO-RIKEN Joint Research Lab was establishedon Keio University Shinanomachi campus, fostering innovative
collaborations between the advanced genomic profiling technologies of RIKEN IMS and the well-established basic and clinicalresearch at Keio University School of Medicine.
To share the ongoing achievement and stimulate further collaborations, this symposium was held to bring together researchers from RIKEN IMS and Keio University, and featured nine presentations about current collaborations and the latest studies with

Research Highlights

I

Projects

RIKEN-McGill Symposiums
enjoyed discussion in person and realized the merit of holding
the symposium on site to advance this international activity, andwe plan to organize the 6th symposium to be held in Yokohama,Japan in 2023/2024.

Data and Statistics

ince 2016, RIKEN IMS and the McGill University Faculty of
Medicine have established close interactions to pursue research in the areas of genomics, immunology, and cancer acrossa broad range of diseases. The first comprehensive cooperationagreements/MOUs between the two institutes were even earlier,in July 2010. Starting from the first symposium, which was heldin May 2017 at McGill University, Montreal, Canada, we had annual symposia either at McGill University, Montreal or Yokohama, Japan. These past symposia encompassed the research areasof genome biology, human genome medicine, immunology andinfectious disease, and cancers. However, symposia had been impossible to hold in person since 2020 due to the world-wide pandemic of SARS-CoV-2. Therefore, we kept this partnership by organizing a virtual online symposium in 2021. After the pandemic
settled down, we were very pleased to restart on-site symposiumin 2022. The 5th symposium was held on September 19 and 20,
2022 at McGill University in hybrid style. We had 10 people fromRIKEN IMS visit McGill University and 6 people from Japan
present their work online. On the second day, we discussed the
topic of biological ethics to further stimulate international collaborations using human-derived materials/information. In total,
115 people attended the symposium in person or online. We

EventsS

81

RIKEN-KI/SciLifeLab & Student ExchangeT

he 8th RIKEN-KI-SciLifeLab Symposium with the title Preparing for the next pandemic was held October 20, 2022 at
the Science for Life Laboratory (SciLifeLab) in Stockholm. The
all-day symposium started with welcome notes by the Karolinska
Institutet (KI), SciLifeLab, and IMS directors, followed by 16 scientific presentations including the political, organizational, andpractical aspects of preparedness for potentially upcoming pandemics, with a focus on Japan and Sweden.
The first RIKEN-KI Doctoral Exchange was conducted in conjunction with the symposium. Twelve doctoral students from RIKEN
stayed in KI and SciLifeLab host research groups for two weeks. The
exchange students documented their stays on a BLOG website.
https://sites.google.com/view/riken-ki-exchange/home

The day after the symposium, the RIKEN delegation of speakers and doctoral students visited the European Centre for Disease
Prevention and Control (ECDC) in Stockholm (left photo).
The Japanese ambassador to Stockholm invited the symposium speakers, doctoral students, and their Swedish host researchgroup leaders to a reception at the ambassador’s residence (rightphoto). (left to right): Stefan Norén (former Ambassador of Sweden to Japan), Dr. Kazuhiko Yamamoto, Masaki Noke (Ambassador of Japan to Sweden), Dr. Olli Kallioniemi (Director of SciLifeLab), Dr. Kazuyuki Kuroda (Director of JSPS Stockholm Office),
Dr. Ole Petter Ottersen (Director of KI).

Adjunct Professorship Programs

I

MS collaborates with and accepts graduate students from 8
domestic university graduate schools. There are now a total of
33 adjunct professors/associate professors at IMS (Table), and 64
students who had studied at IMS in 2022. On May 21, 2022, IMS

held a briefing session on adjunct graduate school programs toprovide an opportunity for students to visit and talk directly withlab leaders and to consider their future directions.

Table: Joint graduate school programs
Graduate Program

Affiliated IMS Investigator

Graduate Program

Affiliated IMS Investigator

Graduate School of Medicine,
Osaka University

Kazuyo Moro (Professor)
Takashi Saito (Visiting Professor)
Takashi Tanaka (Visiting Professor)
Shiro Ikegawa (Visiting Professor)

Graduate School of Medical
Life Science, Yokohama City
University

Graduate School of Medicine,
Chiba University

Haruhiko Koseki (Professor)
Hiroshi Ohno (Visiting Professor)
Ichiro Taniuchi (Visiting Professor)
Shin-ichiro Fujii (Visiting Professor)
Fumihiko Ishikawa (Visiting Professor)

Hiroshi Ohno (Visiting Professor)
Makoto Arita (Visiting Professor)
Takaharu Okada (Visiting Professor)
Taishin Akiyama (Visiting Professor)
Yukihide Momozawa (Visiting Professor)
Takahiro Suzuki (Visiting Associate Professor)
Takeya Kasukawa (Visiting Associate Professor)
Hazuki Takahashi (Visiting Assistant Professor)

Research Institute of
Biological Sciences, Tokyo
University of Science

Masato Kubo (Professor)
Takashi Saito (Visiting Professor)

Graduate School of Medicine,
Keio University

Masayuki Amagai (Professor)
Kenya Honda (Professor)
Haruhiko Koseki (Visiting Professor)
Takaharu Okada (Visiting Professor)
Ichiro Taniuchi (Visiting Professor)
Sidonia Fagarasan (Visiting Professor)

Graduate School of Science,
Tokyo Metropolitan University

Azusa Inoue (Visiting Associate Professor)

Graduate School of Medical
and Dental Sciences, Tokyo
Medical and Dental University

Ichiro Taniuchi (Visiting Professor)

Graduate School of Medicine,
Yokohama City University

Shiro Ikegawa (Visiting Professor)
Hidewaki Nakagawa (Visiting Professor)
Taisei Mushiroda (Visiting Professor)
Yukihide Momozawa (Visiting Professor)
Kaoru Ito (Visiting Professor)
Momoko Horikoshi (Visiting Professor)

82

Yokohama Campus Open Day 2022
Research Highlights

A

fter two years of only being an online event due to COVID19 restrictions, Yokohama Campus Open Day was a hybrid
event this year. There were five events from IMS for Yokohama
Campus Open Day.
The teams that contributed to the events this year and their contents:
I mmunosurveillance and immunotherapy against cancer andinfectious diseases, from Laboratory for Immunotherapy.

●

 et’s watch the moment of fertilization, from Laboratory for
L
Epigenome Inheritance.

●

 ab tour of the next generation sequencers, from Laboratory
L
for Comprehensive Genomic Analysis.

●

 lcohol patch tests to determine whether you have high or low
Aalcohol tolerance, from Laboratory for Human Immunogenetics.

●

 hat is “Ethics on Genomics”? from Laboratory for GenotypW
ing Development and Office of the Center Director.

Lab Activities●

Projects

IMS Social Implementation Seminar Series
his seminar series, launched this year, aims to help young
researchers develop a mindset that will enable them to consider entrepreneurship as a future development of their research
results. The ultimate goal for this series is to enable young researchers to take action with confidence by providing them witha concrete image of the path to entrepreneurship, the incentives
they will receive if they succeed, and examples of successes andfailures and their causes.
The seminar series featured regular lectures by invited experts
in the field of venture establishment. Each speaker considered
content to arouse young researchers’ interest in social implementation and to give them hope that their own research could also
lead to social implementation.
This year’s seminar arrangements are as follows.

Date

Spekers

9/30

Dr. Atsushi Usami
UTEC (The University of Tokyo Edge Capital Partners Co., Ltd.)

12/9

Dr. Takaaki Nomoto
JST (The Japan Science and Technology Agency)

Data and Statistics

Table: IMS Social Implementation Seminar 2022

EventsT

Dr. Yoji Jokura
Chairman and Exective Director, CoreTissue BioEngineering Inc.

83

Guest Lectures 2022
Table: Guest Lectures Jan-Dec 2022
Date

Speaker

Affiliation

Country

Title

Jan. 11

Prof. Kaori Muto

Dept. of Public Policy, University of Tokyo Medical
Science Research InstituteJapan

Patient Public Involvement (PPI) in basic biomedical
research

Jan. 20

Dr. Taro Kitazawa

Transcriptional and Epigenetic Regulation of
Craniofacial and Neuronal Development Group, Friedrich
Miescher Institute for Biomedical Research

Switzerland

Epigenetic and transcriptional regulation of neuronal
activity-response genes

Jan. 26

Prof. Sonia Sharma

La Jolla Institute for Immunology

USA

Mapping and mining the innate immune response forcancer immunotherapeutics

Feb. 22

Dr. Andrea Cerase

Queen Mary University of London

UnitedKingdom

IncRNAs biology and function: The example of Xist RNA

Jul. 14

Dr. Takuya Yamamoto

National Institutes of Biomedical Innovation, Healthand NutritionJapan

The study of heterogeneity of age-related immune responseby high-dimensional single-cell FACS analysis for vaccine
development

Jul. 20

Dr. Hiroshi Kudoh

Center for Ecological Research, Kyoto University

Japan

Phenology of epigenetic regulation: long-term analyses of
H3K27me3 and H3K4me3 in a natural plant population

Aug. 17

Dr. Yuka W. Iwasaki

Keio University School of Medicine, Japan

Japan

Understanding and reconstructing small RNA mediatedheterochromatin formation

Aug. 29

Dr. Shigeki Nakagome

School of Medicine, Trinity College Dublin

Ireland

A paleogenomic time-travel through agriculturaltransformation at the edge of Asia

Sep. 27

Dr. Tomoichiro Miyoshi

Graduate School of Biostudies, Kyoto University, JapanJapan

Mechanisms of human LINE-1 retrotransposition

Sep. 28

Dr. Nabila Bouatia-NajiParis-Cardiovascular Research Center, Inserm, Universitéde Paris

France

The genetic risks of ischemic heart disease in womenSep. 30

Dr. Atsushi Usami

The University of Tokyo Edge Capital Partners Co., Ltd.

Japan

From social implementation of technologies to creation of
new industries

Oct. 26

Dr. Caeul Lim

Cell Host & Microbe, Cell Press

USA

Communicating your Science with Cell Press

Nov. 7

Dr. Paul Wilmes

Systems Ecology, Luxembourg Centre for Systems
Biomedicine, University of Luxembourg

Luxemburg

The human expobiome in health and disease

Nov. 9Prof. David Torrents
ArenalesICREA Research Professor, Computational Genomics
Group Leader, Barcelona Supercomputing Centre

Spain

Genomics and Biomedical research at the Barcelona
Supercomputing Center

Nov. 29

Prof. Naoto Hirano

University of Toronto/Senior Scientist, Princess Margaret
Cancer Centre

CanadaImmunology Meets Bioengineering: Improving theEffectiveness of Adoptive T Cell Therapy

Dec. 5

Dr. Donna L. Farber

Department of Microbiology and Immunology,
Columbia University

USA

The changing landscape of human tissue immunity over life

Dec. 9

1. Mr. Nomoto Takaaki

1. Japan Science and Technology Agency (JST)Japan

2. Dr. Jokura Yoji

2. Jokura: CoreTissue BioEngineering Inc.

1. Start-ups creation and support program conducted by
Japan Science and Technology Agency

84

2. Productization and commercialization of artificial
ligament derived from the decellularized animal tissue:a challenge for social implementation as an academia
start-up

Part 5
Data andStatistics

IMS PI SeminarI

ing to the development of new medicine for the benefit of society.
“Seminar” is an important venue for publicizing one's own
research to an audience, while the feedback from seminar participants can help uncover new collaboration possibilities and gather
information from different perspectives.
To achieve this purpose, speakers are expected to introduce
their laboratory activities focusing on an emerging topic with abroad introduction and general perspectives. Additionally, a facilitator, who is familiar with the topic and builds a bridge between
a presenter and the audience more tightly, is assigned to promote
the discussion.
There was a total of 20 talks in 2022 and the IMS Crosstalk/PI
Seminar continues to play a significant role to promote the IMS
mission.

MS PI Seminar is a monthly seminar aiming to inform all researchers in IMS what projects are undergoing at IMS. Until
the end of fiscal year 2021, this seminar series was called IMS
CrossTalk, but in the new fiscal year 2022, it was renamed IMSPI Seminar, and the new organizers, Azusa Inoue and Kaoru
Ito, started to hold it in a hybrid style (onsite and online). Thisis expected to facilitate collaboration among IMS. Since RIKEN
IMS was formed through the merger of the previous IMS and theDivision of Genomic Technologies (DGT), IMS became morecomprehensive while centering on genomics and immunology.
As such, interactions and collaborations between the researchers
have become more relevant to achieve our mission in IMS, whichis to elucidate the pathogenesis of human diseases and establish
new diagnostic and therapeutic methods, followed by contribut-

Table: IMS PI Seminar 2022

From January to March in 2022, it was held as the IMS CrossTalk.
Date

Talk 1

Talk 2

Speaker

Facilitator

Theme(s)Speaker

Facilitator

1/21

Fumihiko Ishikawa

C.C. Hon

Hideya Kawaji

M. de Hoon

2/18

Kazuyoshi Ishigaki

C. Terao

Jun Seita

A. Inoue

Immunology/Cancer–

3/18

Toshimori Kitami

K. Yugi

Yukinori Okada

K. Ishigaki

–

5/27

Aki Minoda

S. Fagarasan

Hiroshi Ohno

S. Fagarasan

Epigenetics & Microbiome

6/17

Kaoru Ito

M. Horikoshi

Momoko Horikoshi

K. ItoGenetics

7/15

Takashi Tanaka

I. Taniuchi

Chikashi Terao

K. Ishigaki

Genetics & Immunology

9/16

Fumihiko Ishikawa

M. de Hoon

Michiel de Hoon

F. Ishikawa

Immunology & RNA
RNA & Hematopoiesis

10/28

Jay ShinT. Kasukawa

Haruhiko Koseki

A. Inoue

11/18

Kenya Honda

S. Fagarasan

Makoto Arita

A. Inoue

Microbiome & Metabolome

12/16

Wataru Suda

H. OhnoKiyokazu Kakugawa

I. Taniuchi

Microbiome & Immunology

IMS Researcher Seminar 2022

T

he IMS Researcher Seminar series was held once every
month with the aim of promoting scientific discussions
among young researchers at IMS, introducing research activities conducted in the IMS laboratories, improving presentation
skills of young researchers at IMS, and preparing researchers forpresenting outside of RIKEN. At the seminars, research scientists,
postdocs, research associates, and graduate students presented
their work. They received questions from the audience and comments from the chair at the end of their talks, and intriguing ideas
were exchanged.

Table: IMS Researcher Seminar 2022
Date
1/21

Chair
Yukihide Momozawa

2/18

Makoto Arita

3/18

Taisei Mushiroda

4/15

Yukinori Okada

5/13

Kazuyoshi Ishigaki

6/17

Azusa Inoue

7/15

Tatsuhiko Tsunoda

9/16

Tomohiro Kurosaki

10/14

Toshimori Kitami

11/18

Yasuhiro Murakawa

12/16

Kenya Honda

86

Speakers
Daiki Takewaki
Haruki Uchino
Raku Son
Yusuke Ogata
Saumya Agrawal
Jonathan Moody
Jessica Severin
Imad Abugessaisa
Ryoko Yamada
Xiaoxi Liu
Yuuri Yasuoka
Junichiro Takano
Junichi Maruyama
Satoshi Morozumi
Aneela Nomura
Ryo Nakagawa
Yuya Kiguchi
Aiko Sekita
Julio Jesus Leon Incio
XianYang Qin
Chisayo Kozuka
Takashi Ito

Laboratory
Laboratory for Microbiome Sciences
Laboratory for Metabolomics
RIKEN-IFOM Joint Laboratory for Cancer Genomics
Laboratory for Microbiome Sciences
Laboratory for Applied Computational Genomics
Laboratory for Genome Information Analysis
Laboratory for Applied Computational Genomics
Laboratory for Large-Scale Biomedical Data Technology
Laboratory for Genotyping Development
Laboratory for Statistical and Translational Genetics
Laboratory for Comprehensive Genomic Analysis
Laboratory for Developmental Genetics
Laboratory for Integrated Cellular Systems
Laboratory for Metabolomics
Laboratory for Transcriptional Regulation
Laboratory for Human Disease Models
Laboratory for Microbiome Sciences
Laboratory for Developmental Genetics
Laboratory for Advanced Genomics Circuit
Laboratory for Cellular Function Conversion Technology
Laboratory for Epigenome InheritanceLaboratory for Intestinal Ecosystem

Position
Student Trainee
Junior Research Associate
Junior Research Associate
Research Scientist
Research Scientist
Research Scientist
Technical Scientist
Senior Scientist
Visiting Scientist
Research Scientist
Research Scientist
Postdoctoral Researcher
Research Scientist
Junior Research Associate
Postdoctoral Researcher
Junior Research Associate
Visiting Scientist
Research Scientist
Research Scientist
Research Scientist
Special Postdoctoral Researcher
Visiting ResearcherPublications 2022

1 Abdelhamid RF, Ogawa K, Beck G, Ikenaka K, Takeuchi E, Yasumizu Y, Jinno J, Kimura Y, Baba K, Nagai
Y, Okada Y, Saito Y, Murayama S, Mochizuki H, Nagano S. piRNA/PIWI Protein Complex as a Potential
Biomarker in Sporadic Amyotrophic Lateral Sclerosis. Mol Neurobiol 59, 1693-1705 (2022)

Table: IMS Publications from January to December, 2022

Journal

Impact Factor(2021)

Number of
papersNat Rev Immunol

108.6

1

Nat Med87.2

1

Nature

69.5

7

Cell

66.9

5

Science63.8

2

Nat Rev Genet

59.9

1

Immunity

43.5

1

Nat Genet

41.4

8

Circulation

39.9

1

33.9

2

33.0

1

Annu Rev Immunol

32.5

1

Cell Metab

31.4

1

Nat Immunol

31.3

3

Sci Immunol

30.7

4
1

JAMA Cardiol

30.2

J Hepatol

30.1

1

Nat Biomed Eng

29.2

1

28.2

1

28.0

3
3

Blood

25.7

Nat Hum Behav

24.3

1

Nat Metab

19.9

1

J Clin Invest

19.5

1

Trends Cancer

19.2

1

Nucleic Acids Res

19.2

1

Nat Struct Mol Biol

18.4

1

18.0

1

17.7

17

J Exp Med

17.6

4

Hepatology

17.3

1

Cell Rep Med

17.0

2
2

Arthritis Rheumatol

15.5

Sci Adv

15.0

2

J Autoimmun

14.5

1

Ophthalmology

14.3

1

EMBO J

13.8

1
1

13.6
12.9

1

J Immunother Cancer

12.5

1

Neurology

12.3

1
1

Psychiatry Clin Neurosci

12.1

Int J Infect Dis

12.1

2

BMC Med11.8

1Semin Immunopathol

11.8

1

EBioMedicine

11.2

1

Adv Healthc Mater

11.1

1

Am J Hum Genet

11.0

1
1

Sci Total Environ

10.8

Arterioscler Thromb Vasc Biol

10.5

1

Inflamm Regen

10.4

3

Pharmacol Res

10.3

1

Mol Ther Nucleic Acids

10.2

1

Others

190

Total

296

7 Akita N, Okada R, Mukae K, Sugino RP, Takenobu H, Chikaraishi K, Ochiai H, Yamaguchi Y, Ohira M,
Koseki H, Kamijo T. Polycomb group protein BMI1 protects neuroblastoma cells against DNA damageinduced apoptotic cell death. Exp Cell Res 422, 113412 (2022)
8 Akiyama M, Miyake M, Momozawa Y, Arakawa S, Maruyama-Inoue M, Endo M, Iwasaki Y, Ishigaki K,
Matoba N, Okada Y, Yasuda M, Oshima Y, Yoshida S, Nakao S, Morino K, Mori Y, Kido A, Kato A, Yasukawa T, Obata R, Nagai Y, Takahashi K, Fujisawa K, Miki A, Nakamura M, Honda S, Ushida H, Yasuma T,
Nishiguchi K, Mori R, Tanaka K, Wakatsuki Y, Yamashiro K, Kadonosono K, Terao C, Chikashi T, Tsujikawa
A, Sonoda K, Kubo M, Kamatani Y. GWAS of age-related macular degeneration reveals two new loci
implying shared genetic components with central serous chorioretinopathy. Ophthalmology 130,361-372 (2022)
9 Al-Jawahiri R, Foroutan A, Kerkhof J, McConkey H, Levy M, Haghshenas S, Rooney K, Turner J, Shears
D, Holder M, Lefroy H, Castle B, Reis LM, Semina EV, University of Washington Centre for Mendelian
Genomics (UW-CMG); Lachlan K, Chandler K, Wright T, Clayton-Smith J, Hug FP, Pitteloud N, Bartoloni
L, Hoffjan S, Park S, Thankamony A, Lees M, Wakeling E, Naik S, Hanker B, Girisha KM, Agolini E,
Giuseppe Z, Alban Z, Tessarech M, Keren B, Afenjar A, Zweier C, Reis A, Smol T, Tsurusaki Y, Nobuhiko O,
Sekiguchi F, Tsuchida N, Matsumoto N, Kou I, Yonezawa Y, Ikegawa S, Callewaert B, Freeth M, Genomics England Research Consortium; Lotte Kleinendorst L, Donaldson A, Alders M, Paepe AD, Sadikovic
B, McNeill A. SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile. Genet Med
24, 1261-1273 (2022)
10 Andrew TW, Koepke LS, Wang Y, Lopez M, Steininger H, Struck D, Boyko T, Ambrosi TH, Tong X, Sun
Y, Gulati GS, Murphy MP, Marecic O, Telvin R, Schallmoser K, Strunk D, Seita J, Goodman SB, Yang F,
Longaker MT, Yang GP, Chan CK. Sexually dimorphic estrogen sensing in skeletal stem cells controls
skeletal regeneration. Nat Commun 13, 6491 (2022)
11 Aoki H, Isobe Y, Yoshida M, Kang JX, Maekawa M, Arita M. Enzymatically-epoxidized docosahexaenoic
acid, 19,20-EpDPE, suppresses hepatic crown-like structure formation and nonalcoholic steatohepatitis fibrosis through GPR120. Biochim Biophys Acta Mol Cell Biol Lipids 1868, 159275 (2022)
12 Aragam KG, Jiang T, Goel A, Kanoni S, Wolford BN, Atri DS, Weeks EM, Wang M, Hindy G, Zhou W, Grace
C, Roselli C, Marston NA, Kamanu FK, Surakka I, Venegas LM, Sherliker P, Koyama S, Ishigaki K, Åsvold
BO, Brown MR, Brumpton B, de Vries PS, Giannakopoulou O, Giardoglou P, Gudbjartsson DF, Güldener U,
Haider SM, Helgadottir A, Ibrahim M, Kastrati A, Kessler T, Kyriakou T, Konopka T, Li L, Ma L, Meitinger
T, Mucha S, Munz M, Murgia F, Nielsen JB, Nöthen MM, Pang S, Reinberger T, Schnitzler G, Smedley
D, Thorleifsson G, von Scheidt M, Ulirsch JC, Arnar DO, Burtt NP, Costanzo MC, Flannick J, Ito K, Jang D,
Kamatani Y, Khera AV, Komuro I, Kullo IJ, Lotta LA, Nelson CP, Roberts R, Thorgeirsson G, Thorsteinsdottir U, Webb TR, Baras A, Björkegren JL, Boerwinkle E, Dedoussis G, Holm H, Hveem K, Melander O,
Morrison AC, Orho-Melander M, Rallidis LS, Ruusalepp A, Sabatine MS, Stefansson K, Zalloua P, Ellinor
PT, Farrall M, Danesh J, Ruff CT, Finucane HK, Hopewell JC, Clarke R, Gupta RM, Erdmann J, Samani NJ,
Schunkert H, Watkins H, Willer CJ, Deloukas P, Kathiresan S, Butterworth AS. Discovery and systematiccharacterization of risk variants and genes for coronary artery disease in over a million participants.
Nat Genet 54, 1803-1815 (2022)
13 Ariyasu Y, Sato Y, Isobe Y, Taniguchi K, Yanagita M, Arita M. Sterol O-Acyltransferase Inhibition Ameliorates High-Fat Diet-Induced Renal Fibrosis and Tertiary Lymphoid Tissue Maturation after Ischemic
Reperfusion Injury. Int J Mol Sci 23, 15465 (2022)
14 Asano F, Tsuboi A, Moriya S, Kato T, Tsuji N, Nakaguma T, Ohno H, Miyamoto H, Kodama H. Amendmentof a thermophile-fermented compost to humus improves the growth of female larvae of the Hercules
beetle Dynastes hercules (Coleoptera: scarabaeidae). J Appl Microbiol 134, lxac006 (2022)
15 Baba R, Kabata H, Shirasaki Y, Kamatani T, Yamagishi M, Irie M, Watanabe R, Matsusaka M, Masaki K,
Miyata J, Moro K, Uemura S, Fukunaga K. Upregulation of IL-4 receptor signaling pathway in circulating ILC2s from asthma patients. J Allergy Clin Immunol Glob 1, 299-304 (2022)
16 Baranasic D, Hortenhuber M, Balwierz PJ, Zehnder T, Mukarram AK, Nepal C, Varnai C, Hadzhiev Y,
Jimenez-Gonzalez A, Li N, Wragg J, D’Orazio FM, Relic D, Pachkov M, Diaz N, Hernandez-Rodriguez
B, Chen Z, Stoiber M, Dong M, Stevens I, Ross SE, Eagle A, Martin R, Obasaju O, Rastegar S, McGarvey
AC, Kopp W, Chambers E, Wang D, Kim HR, Acemel RD, Naranjo S, Lapinski M, Chong V, Mathavan
S, Peers B, Sauka-Spengler T, Vingron M, Carninci P, Ohler U, Lacadie SA, Burgess SM, Winata C, van
Eeden F, Vaquerizas JM, Luis Gomez-Skarmeta J, Onichtchouk D, Brown BJ, Bogdanovic O, van Nimwegen E, Westerfield M, Wardle FC, Daub CO, Lenhard B, Muller F. Multiomic atlas with functional
stratification and developmental dynamics of zebrafish cis-regulatory elements. Nat Genet 54,
1037-1050 (2022)
17 Battenberg K, Kelly ST, Ras RA, Hetherington NA, Hayashi M, Minoda A. A flexible cross-platform
single-cell data processing pipeline. Nat Commun 13, 6847 (2022)

87

Data and Statistics

Clin Gastroenterol Hepatol
Genes Dev

6 Akamine Y, Millman JF, Uema T, Okamoto S, Yonamine M, Uehara M, Kozuka C, Kaname T, Shimabukuro M, Kinjo K, Mitsuta M, Watanabe H, Masuzaki H. Fermented brown rice beverage distinctively
modulates the gut microbiota in Okinawans with metabolic syndrome: A randomized controlled tria.
Nutrition Research 103, 68-81 (2022)

EventsGenome Biol
Nat Commun

5 Akamatsu S, Terada N, Takata R, Kinoshita H, Shimatani K, Momozawa Y, Yamamoto M, Tada H, Kawamorita N, Narita S, Kato T, Nitta M, Kandori S, Koike Y, Inazawa J, Kimura T, Kimura H, Kojima T, TerachiT, Sugimoto M, Habuchi T, Arai Y, Yamamoto S, Matsuda T, Obara W, Kamoto T, Inoue T, Nakagawa H,
Ogawa O, group ob. Clinical Utility of Germline Genetic Testing in Japanese Men Undergoing Prostate
Biopsy. JNCI Cancer Spectr 6, pkac001 (2022)

Projects

Nat Cell Bio
Ann Rheum Dis

4 Adachi Y, Ueda K, Nomura S, Ito K, Katoh M, Katagiri M, Yamada S, Hashimoto M, Zhai B, Numata G,
Otani A, Hinata M, Hiraike Y, Waki H, Takeda N, Morita H, Ushiku T, Yamauchi T, Takimoto E, Komuro I.
Beiging of perivascular adipose tissue regulates its inflammation and vascular remodeling. Nat Commun 13, 5117 (2022)

Lab Activities

Gastroenterology
JAMA Oncol

3 Adachi Y, Ueda K, Ito K, Nomura S, Takimoto E, Komuro I. Beiging Of Perivascular Adipose Tissue
Regulates Its Inflammation And Vascular Remodeling. Arteriosclerosis Thrombosis and Vascular
Biology 42, a354-a354 (2022)

Research Highlights

2 Abe K, Kitago M, Kosaki K, Yamada M, Iwasaki E, Kawasaki S, Mizukami K, Momozawa Y, Terao C, Yagi
H, Abe Y, Hasegawa Y, Hori S, Tanaka M, Nakano Y, Kitagawa Y. Genomic analysis of familial pancreaticcancers and intraductal papillary mucinous neoplasms: A cross-sectional study. Cancer Sci 113, 18211829 (2022)

18 Bjornsdottir G, Stefansdottir L, Thorleifsson G, Sulem P, Norland K, Ferkingstad E, Oddsson, Zink F, Lund
SH, Nawaz MS, Walters G, Skuladottir AT, Gudjonsson SA, Einarsson G, Halldorsson GH, Bjarnadottir V,
Sveinbjornsson G, Helgadottir A, Styrkarsdottir U, J Gudmundsson L, Pedersen OB, Hansen TF, Werge,
Banasik K, Troelsen A, Skou ST, Thørner LW, Erikstrup C, Nielsen KR, Mikkelsen, D, Bjornsson, Olafsson
IH, Ulfarsson E, Blondal, Vikingsson, Brunak S, Ostrowski SR, Ullum H, Thorsteinsdottir U, Stefansson H,
Gudbjartsson DF, Thorgeirsson E, Stefansson K, Ikegawa S. Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology. Nat Commun 13, 634-634 (2022)
19 Bo C, Barker CS, Mengle S, Qianbin Z, Rana GK, Wu Y. Multilayered omics reveal sex- and depotdependent adipose progenitor cell heterogeneity. Cell Metab 34, 783-799 (2022)
20 Bono H, Sakamoto T, Kasukawa T, Tabunoki H. Systematic Functional Annotation Workflow for Insects.
Insects 13, 586 (2022)
21 Butler-Laporte G, Povysil G, Kosmicki JA, Cirulli ET, Drivas T, Furini S, Saad C, Schmidt A, Olszewski P,
Korotko U, Quinodoz M, Çelik E, Kundu K, Walter K, Jung J, Stockwell AD, Sloofman LG, Jordan DM,
Thompson RC, Del Valle D, Simons N, Cheng E, Sebra R, Schadt EE, Kim-Schulze S, Gnjatic S, Merad
M, Buxbaum JD, Beckmann ND, Charney AW, Przychodzen B, Chang T, Pottinger TD, Shang N, Brand F,
Fava F, Mari F, Chwialkowska K, Niemira M, Pula S, Baillie JK, Stuckey A, Salas A, Bello X, Pardo-Seco J,
Gómez-Carballa A, Rivero-Calle I, Martinón-Torres F, Ganna A, Karczewski KJ, Veerapen K, Bourgey M,
Bourque G, Eveleigh RJ, Forgetta V, Morrison D, Langlais D, Lathrop M, Mooser V, Nakanishi T, Frithiof R,
Hultström M, Lipcsey M, Marincevic-Zuniga Y, Nordlund J, Barrett KM, Lee W, Bolze A, White S, Riffle S,
Tanudjaja F, Sandoval E, Neveux I, Dabe S, Casadei N, Motameny S, Alaamery M, Massadeh S, Aljawini
N, Almutairi MS, Arabi YM, Alqahtani SA, Harthi FS, Almutairi A, Alqubaishi F, Alotaibi S, Binowayn
A, Alsolm EA, Bardisy HE, Fawzy M, Cai F, Soranzo N, Butterworth A, Initiative CH, Group DH, Study
GM, Center MS, consortium G, Consortium G, Force JC, Center RG, Geschwind DH, Arteaga S, Stephens
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92 Johnson TA, Maekawa S, Fujita M, An J, Ju Y, Maejima K, Kanazashi Y, Jikuya R, Okawa Y, Sasagawa S,
Yagi K, Okazaki Y, Kuroda N, Takata R, Obara W, Nakagawa H. Genomic features of renal cell carcinoma
developed during end-stage renal disease and dialysis. Hum Mol Genet 32, 290-303 (2022)
93 Kabata H, Motomura Y, Kiniwa T, Kobayashi T, Moro K. ILCs and Allergy. Adv Exp Med Biol 1365, 75-95(2022)
94 Kageyama Y, Nakamura M, Igari Y, Yamaguchi S, Oguchi A, Murakawa Y, Hattori Y, Sasano Y. Expression of matrix metalloproteinase‐3 and ‐10 is up‐regulated in the periodontal tissues of aged mice. J
Periodontal Res 57, 733-741 (2022)
95 Kai Y, Mei H, Kawano H, Nakajima N, Takai A, Kumon M, Inoue A, Yamashita N. Transcriptomic signatures in trophectoderm and inner cell mass of human blastocysts classified according to developmental potential, maternal age and morphology. PLoS One 17, e0278663 (2022)
96 Kanki Y, Muramatsu M, Miyamura Y, Kikuchi K, Higashijima Y, Nakaki R, Suehiro J, Sasaki Y, Kubota Y,
Koseki H, Morioka H, Kodama T, Nakao M, Kurotaki D, Aburatani H, Minami T. Bivalent-histone-marked
immediate-early gene regulation is vital for VEGF-responsive angiogenesis. Cell Rep 38, 110332 (2022)
97 Kanoni S, Graham SE, Wang Y, Surakka I, Ramdas S, Zhu X, Clarke SL, Bhatti KF, Vedantam S, Winkler
TW, Locke AE, Marouli E, Zajac GJ, Wu KH, Ntalla I, Hui Q, Klarin D, Hilliard AT, Wang Z, Xue C, Thorleifsson G, Helgadottir A, Gudbjartsson DF, Holm H, Olafsson I, Hwang MY, Han S, Akiyama M, Sakaue S,
Terao C, Kanai M, Zhou W, Brumpton BM, Rasheed H, Havulinna AS, Veturi Y, Pacheco JA, Rosenthal
EA, Lingren T, Feng Q, Kullo IJ, Narita A, Takayama J, Martin HC, Hunt KA, Trivedi B, Haessler J, Giulianini F, Bradford Y, Miller JE, Campbell A, Lin K, Millwood IY, Rasheed A, Hindy G, Faul JD, Zhao W,
Weir DR, Turman C, Huang H, Graff M, Choudhury A, Sengupta D, Mahajan A, Brown MR, Zhang W,
Yu K, Schmidt EM, Pandit A, Gustafsson S, Yin X, Luan J, Zhao J, Matsuda F, Jang H, Yoon K, MedinaGomez C, Pitsillides A, Hottenga JJ, Wood AR, Ji Y, Gao Z, Haworth S, Yousri NA, Mitchell RE, Chai JF,
Aadahl M, Bjerregaard AA, Yao J, Manichaikul A, Hwu C, Hung Y, Warren HR, Ramirez J, Bork-JensenJ, Kårhus LL, Goel A, Sabater-Lleal M, Noordam R, Mauro P, Matteo F, McDaid AF, Marques-Vidal P,
Wielscher M, Trompet S, Sattar N, Møllehave LT, Munz M, Zeng L, Huang J, Yang B, Poveda A, Kurbasic
A, Lamina C, Forer L, Scholz M, Galesloot TE, Bradfield JP, Ruotsalainen SE, Daw E, Zmuda JM, Mitchell
JS, Fuchsberger C, Christensen H, Brody JA, Vazquez-Moreno M, Feitosa MF, Wojczynski MK, Wang Z,
Preuss MH, Mangino M, Christofidou P, Verweij N, Benjamins JW, Engmann J, Tsao NL, Verma A, Slieker

89

Data and Statistics

73 Ishigaki K, Sakaue S, Terao C, Luo Y, Sonehara K, Yamaguchi K, Amariuta T, Too CL, Laufer VA, ScottIC, Viatte S, Takahashi M, Ohmura K, Murasawa A, Hashimoto M, Ito H, Hammoudeh M, Emadi SA,
Masri BK, Halabi H, Badsha H, Uthman IW, Wu X, Lin L, Li T, Plant D, Barton A, Orozco G, Verstappen
SM, Bowes J, MacGregor AJ, Honda S, Koido M, Tomiduka K, Kamatani Y, Tanaka H, Tanaka E, Suzuki
A, Maeda Y, Yamamoto K, Miyawaki S, Xie G, Zhang J, Amos CI, Keystone E, Wolbink G, van der HorstBruinsma I, Cui J, Liao KP, Carroll RJ, Lee H, Bang S, Siminovitch KA, de Vries N, Alfredsson L, RantapääDahlqvist S, Karlson EW, Bae S, Kimberly RP, Edberg JC, Mariette X, Huizinga T, Dieudé P, Schneider M,
Kerick M, Denny JC, Matsuda K, Matsuo K, Mimori T, Matsuda F, Fujio K, Tanaka Y, Kumanogoh A, Traylor M, Lewis CM, Eyre S, Xu H, Saxena R, Arayssi T, Kochi Y, Ikari K, Harigai M, Gregersen PK, Yamamoto K,
Louis Bridges S, Padyukov L, Martin J, Klareskog L, Okada Y, Raychaudhuri S. Multi-ancestry genomewide association analyses identify novel genetic mechanisms in rheumatoid arthritis. Nat Genet 54,
1640-1651 (2022)

87 Jansen C, Paraiso KD, Zhou JJ, Blitz IL, Fish MB, Charney RM, Cho JS, Yasuoka Y, Sudou N, Bright AR,
Wlizla M, Veenstra GJ, Taira M, Zorn AM, Mortazavi A, Cho KW. Uncovering the mesendoderm gene
regulatory network through multi-omic data integration. Cell Rep 38, 10364 (2022)

Events71 Inoue T, Shinnakasu R, Kawai C, Yamamoto H, Sakakibara S, Ono C, Itoh Y, Terooatea T, Yamashita
K, Okamoto T, Hashii N, Ishii-Watabe A, Butler NS, Matsuura Y, Matsumoto H, Otsuka S, Hiraoka K,
Teshima T, Murakami M, Kurosaki T. Antibody feedback contributes to facilitating the development of
Omicron-reactive memory B cells in SARS-CoV-2 mRNA vaccinees. J Exp Med 220, e20221786 (2022)

86 Jangid A, Fukuda S, Suzuki Y, Taylor TD, Ohno H, Yadav TP. Shotgun metagenomic sequencing revealed
the prebiotic potential of a grain-based diet in mice. Sci Rep 12, 6748 (2022)

Projects

67 Imianowski CJ, Whiteside SK, Lozano T, Evans AC, Benson JD, Courreges CJ, Sadiyah F, Lau CM, Zandhuis ND, Grant FM, Schuijs MJ, Vardaka P, Kuo P, Soilleux EJ, Yang J, Sun JC, Kurosaki T, Okkenhaug
K, Halim TY, Roychoudhuri R. BACH2 restricts NK cell maturation and function, limiting immunity tocancer metastasis. J Exp Med 219, e20211476 (2022)

85 Jangid A, Fukuda S, Seki M, Suzuki Y, Taylor TD, Ohno H, Prakash T. Gut microbiota alternation under
the intestinal epithelium-specific knockout of mouse Piga gene. Sci Rep 12, 10812 (2022)

Lab Activities

61 Horikawa H, Amagai M. T Helper 17/T Helper 22-Skewed Inflammation with Epidermal Barrier Dysfunction in Nonmajor Inherited Ichthyosis Subtypes. J Invest Dermatol 142, 2303-2305 (2022)

Research Highlights

58 Hayashi R, Inoue A. Low-input CUT&RUN for Mouse Oocytes and Preimplantation Embryos. Methods
Mol Biol 2577, 83-92 (2022)

78 Ito S, Das ND, Umehara T, Koseki H. Factors and Mechanisms That Influence Chromatin-MediatedEnhancer-Promoter Interactions and Transcriptional Regulation. Cancers 14, 5404 (2022)

RC, Lo KS, Zilhao NR, Le P, Kleber ME, Delgado GE, Huo S, Ikeda DD, Iha H, Yang J, Liu J, Demirkan A,
Leonard HL, Marten J, Frank M, Schmidt B, Smyth LJ, Cañadas-Garre M, Wang C, Nakatochi M, Wong
A, Hutri-Kähönen N, Sim X, Xia R, Huerta-Chagoya A, Fernandez-Lopez JC, Lyssenko V, Nongmaithem
SS, Bayyana S, Stringham HM, Irvin MR, Oldmeadow C, Kim H, Ryu S, Timmers PR, Arbeeva L, Dorajoo
R, Lange LA, Prasad G, Lorés-Motta L, Pauper M, Long J, Li X, Theusch E, Takeuchi F, Spracklen CN,
Loukola A, Bollepalli S, Warner SC, Wang YX, Wei WB, Nutile T, Ruggiero D, Sung YJ, Chen S, Liu F, Yang J,
Kentistou KA, Banas B, Nardone GG, Meidtner K, Bielak LF, Smith JA, Hebbar P, Farmaki A, Hofer E, Lin
M, Concas MP, Vaccargiu S, van der Most PJ, Pitkänen N, Cade BE, van der Laan SW, Chitrala KN, Weiss S,
Bentley AR, Doumatey AP, Adeyemo AA, Lee JY, Petersen ER, Nielsen AA, Choi HS, Nethander M, Freitag-Wolf S, Southam L, Rayner NW, Wang CA, Lin S, Wang J, Couture C, Lyytikäinen L, Nikus K, CuellarPartida G, Vestergaard H, Hidalgo B, Giannakopoulou O, Cai Q, Obura MO, van Setten J, Li X, Liang J,
Tang H, Terzikhan N, Shin JH, Jackson RD, Reiner AP, Martin LW, Chen Z, Li L, Kawaguchi T, Thiery J, Bis
JC, Launer LJ, Li H, Nalls MA, Raitakari OT, Ichihara S, Wild SH, Nelson CP, Campbell H, Jäger S, Nabika
T, Al-Mulla F, Niinikoski H, Braund PS, Kolcic I, Kovacs P, Giardoglou T, Katsuya T, de Kleijn D, de Borst
GJ, Kim EK, Adams HH, Ikram MA, Zhu X, Asselbergs FW, Kraaijeveld AO, Beulens JW, Shu X, Rallidis
LS, Pedersen O, Hansen T, Mitchell P, Hewitt AW, Kähönen M, Pérusse L, Bouchard C, Tönjes A, Chen YI,
Pennell CE, Mori TA, Lieb W, Franke A, Ohlsson C, Mellström D, Cho YS, Lee H, Yuan J, Koh W, Rhee SY,
Woo J, Heid IM, Stark KJ, Zimmermann ME, Völzke H, Homuth G, Evans MK, Zonderman AB, Polasek O,
Pasterkamp G, Hoefer IE, Redline S, Pahkala K, Oldehinkel AJ, Snieder H, Biino G, Schmidt R, Schmidt
H, Bandinelli S, Dedoussis G, Thanaraj TA, Kardia SL, Peyser PA, Kato N, Schulze MB, Girotto G, Böger
CA, Jung B, Joshi PK, Bennett DA, De Jager PL, Lu X, Mamakou V, Brown M, Caulfield MJ, Munroe PB,
Guo X, Ciullo M, Jonas JB, Samani NJ, Kaprio J, Pajukanta P, Tusié-Luna T, Aguilar-Salinas CA, Adair LS,
Bechayda SA, de Silva HJ, Wickremasinghe AR, Krauss RM, Wu J, Zheng W, Hollander AI, Bharadwaj
D, Correa A, Wilson JG, Lind L, Heng C, Nelson AE, Golightly YM, Wilson JF, Penninx B, Kim H, Attia J,
Scott RJ, Rao DC, Arnett DK, Hunt SC, Walker M, Koistinen HA, Chandak GR, Mercader JM, Costanzo
MC, Jang D, Burtt NP, Villalpando CG, Orozco L, Fornage M, Tai E, van Dam RM, Lehtimäki T, Chaturvedi
N, Yokota M, Liu J, Reilly DF, McKnight AJ, Kee F, Jöckel K, McCarthy MI, Palmer CN, Vitart V, Hayward C,
Simonsick E, van Duijn CM, Jin Z, Qu J, Hishigaki H, Lin X, März W, Gudnason V, Tardif J, Lettre G, Hart
LM, Elders PJ, Damrauer SM, Kumari M, Kivimaki M, van der Harst P, Spector TD, Loos RJ, Province MA,
Parra EJ, Cruz M, Psaty BM, Brandslund I, Pramstaller PP, Rotimi CN, Christensen K, Ripatti S, Widén E,
Hakonarson H, Grant SF, Kiemeney LA, de Graaf J, Loeffler M, Kronenberg F, Gu D, Erdmann J, Schunkert H, Franks PW, Linneberg A, Jukema JW, Khera AV, Männikkö M, Jarvelin M, Kutalik Z, Francesco
C, Mook-Kanamori DO, van Dijk KW, Watkins H, Strachan DP, Grarup N, Sever P, Poulter N, Chuang L,
Rotter JI, Dantoft TM, Karpe F, Neville MJ, Timpson NJ, Cheng C, Wong T, Khor CC, Li H, Sabanayagam
C, Peters A, Gieger C, Hattersley AT, Pedersen NL, Magnusson PK, Boomsma DI, Willemsen AH, Cupples
L, van Meurs JB, Ghanbari M, Gordon-Larsen P, Huang W, Kim YJ, Tabara Y, Wareham NJ, Langenberg C,
Zeggini E, Kuusisto J, Laakso M, Ingelsson E, Abecasis G, Chambers JC, Kooner JS, de Vries PS, Morrison
AC, Hazelhurst S, Ramsay M, North KE, Daviglus M, Kraft P, Martin NG, Whitfield JB, Abbas S, Saleheen
D, Walters RG, Holmes MV, Black C, Smith BH, Baras A, Justice AE, Buring JE, Ridker PM, Chasman DI,
Kooperberg C, Tamiya G, Yamamoto M, van Heel DA, Trembath RC, Wei W, Jarvik GP, Namjou B, Hayes
MG, Ritchie MD, Jousilahti P, Salomaa V, Hveem K, Åsvold BO, Kubo M, Kamatani Y, Okada Y, Murakami
Y, Kim B, Thorsteinsdottir U, Stefansson K, Zhang J, Chen Y, Ho Y, Lynch JA, Rader DJ, Tsao PS, Chang K,
Cho K, O’Donnell CJ, Gaziano JM, Wilson PW, Frayling TM, Hirschhorn JN, Kathiresan S, Mohlke KL, Sun
YV, Morris AP, Boehnke M, Brown CD, Natarajan P, Deloukas P, Willer CJ, Assimes TL, Peloso GM. Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry metaanalysis. Genome Biol 23, 268 (2022)
98 Karnes JH, Rollin J, Giles JB, Martinez KL, Steiner HE, Shaffer CM, Momozawa Y, Inai C, Bombin A, Shi M,
Mosley JD, Stanaway I, Selleng K, Thiele T, Mushiroda T, Pouplard C, Heddle NM, Kubo M, Phillips EJ,
Warkentin TE, Gruel Y, Greinacher A, Roden DM. ABO O blood group as a risk factor for platelet reactivity in heparin-induced thrombocytopenia. Blood 140, 274-284 (2022)
99 Katayama Y, Yokota R, Akiyama T, Kobayashi TJ. Machine Learning Approaches to TCR Repertoire
Analysis. Front Immunol 13, 858057 (2022)
100 Kato D, Mitsuhashi S, Miya F, Saitoh S, Okamoto N, Tsunoda T, Kochi Y. Utility of tissue-specific gene
expression scores for gene prioritization in Mendelian diseases. J Hum Genet 67, 739-742 (2022)
101 Kato T, Kagawa M, Suda W, Tsuboi Y, Inoue-Suzuki S, Kikuchi J, Hattori M, Ohta T, Ohno H. Integrated
Multi-Omics Analysis Reveals Differential Effects of Fructo-Oligosaccharides (FOS) Supplementationon the Human Gut Ecosystem. Int J Mol Sci 23, 11728 (2022)
102 Kausar M, Ain NU, Hayat F, Fatima H, Azim S, Ullah H, Mushtaq M, Khalid S, Hussain S, Naz S, Janjua J,
Amjad SB, Baig RM, Makitie O, Qamar R, Ikegawa S, Gen N, Khor CC, Foo JN, Siddiqi S. Biallelic variantsin CHST3 cause Spondyloepiphyseal dysplasia with joint dislocations in three Pakistani kindreds. BMC
Musculoskelet Disord 23, 818 (2022)

110 Kishikawa T, Tomofuji Y, Inohara H, Okada Y. OMARU: a robust and multifaceted pipeline for metagenome-wide association study. NAR Genom Bioinform 4, lqac019 (2022)
111 Kiyose H, Nakagawa H, Ono A, Aikata H, Ueno M, Hayami S, Yamaue H, Chayama K, Shimada M, Wong
JH, Fujimoto A. Comprehensive analysis of full-length transcripts reveals novel splicing abnormalities
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112 Kobayashi S, Nagafuchi Y, Okubo M, Sugimori Y, Hatano H, Yamada S, Nakano M, Yoshida R, Takeshima
Y, Ota M, Tsuchida Y, Iwasaki Y, Setoguchi K, Kubo K, Okamura T, Yamamoto K, Shoda H, Fujio K. Dysregulation of the gene signature of effector regulatory T cells in the early phase of systemic sclerosis.
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113 Kobayashi T, Moro K. A hairy situation for ILC2s. Immunity 55, 1756-1758 (2022)
114 Kobayashi T, Moro K. Tissue-Specific Diversity of Group 2 Innate Lymphoid Cells in the Skin. Front Immunol 13, 885642 (2022)
115 Koda Y, Sato S, Yamamoto H, Niwa H, Watanabe H, Watanabe C, Sato T, Nakamura K, Tanaka A, Shirouzu M, Honma T, Fukami T, Koyama H, Umehara T. Design and Synthesis of Tranylcypromine-Derived
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116 Koido M, Hon C, Koyama S, Kawaji H, Murakawa Y, Ishigaki K, Ito K, Sese J, Parrish NF, Kamatani Y,
Carninci P, Terao C. Prediction of the cell-type-specific transcription of non-coding RNAs from genome
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117 Koike T, Fujii K, Kometani K, Butler NS, Funakoshi K, Yari S, Kikuta J, Ishii M, Kurosaki T, Ise W. Progressive differentiation toward the long-lived plasma cell compartment in the bone marrow. J Exp Med
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118 Kokaji T, Eto M, Hatano A, Yugi K, Morita K, Ohno S, Fujii M, Hironaka K, Ito Y, Egami R, Uematsu S,
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119 Kouno T, Carninci P, Shin J. Complete Transcriptome Analysis by 5’-End Single-Cell RNA-Seq with Random Priming. Methods Mol Biol 2490, 141-156 (2022)
120 Kozuka C, Efthymiou V, Sales VM, Zhou L, Osataphan S, Yuchi Y, Chimene-Weiss J, Mulla C, Isganaitis E,
Desmond J, Sanechika S, Kusuyama J, Goodyear L, Shi X, Gerszten RE, Aguayo-Mazzucato C, Carapeto
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121 Kunishima N, Takeda Y, Hirose R, Kume S, Maeda M, Oguchi A, Yanagita M, Shibuya H, Tamura M,
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122 Kusuyama J, Makarewicz NS, Albertson BG, Alves-Wagner AB, Conlin RH, Prince NB, Alves CR, Ramachandran K, Kozuka C, Xiudong Y, Xia Y, Hirshman MF, Hatta T, Nagatomi R, Nozik ES, Goodyear LJ.
Maternal Exercise-Induced SOD3 Reverses the Deleterious Effects of Maternal High Fat Diet on Offspring Metabolism Through Stabilization of H3K4me3 and Protection Against WDR82 Carbonylation.
Diabetes 71, 1170-1181 (2022)
123 Lagattuta KA, Kang JB, Nathan A, Pauken KE, Jonsson AH, Rao DA, Sharpe AH, Ishigaki K, Raychaudhuri S. Repertoire analyses reveal T cell antigen receptor sequence features that influence T cell fate.
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124 Langlois AW, El-Boraie A, Fukunaga K, Mushiroda T, Kubo M, Lerman C, Knight J, Scherer SE, Chenoweth MJ, Tyndale RF. Accuracy and applications of sequencing and genotyping approaches for
CYP2A6 and homologous genes. Pharmacogenet Genomics 32, 159-172 (2022)
125 Lee H, Chubachi S, Namkoong H, Asakura T, Tanaka H, Otake S, Nakagawara K, Morita A, Fukushima T,
Watase M, Kusumoto T, Masaki K, Kamata H, Ishii M, Hasegawa N, Harada N, Ueda T, Ueda S, Ishiguro T,
Arimura K, Saito F, Yoshiyama T, Nakano Y, Mutoh Y, Suzuki Y, Murakami K, Okada Y, Koike R, Kitagawa
Y, Kimura A, Imoto S, Miyano S, Ogawa S, Kanai T, Fukunaga K. Characteristics of hospitalized patientswith COVID-19 during the first to fifth waves of infection: a report from the Japan COVID-19 Task
Force. BMC Infect Dis 22, 935 (2022)

103 Kawano Y, Edwards M, Huang Y, Bilate AM, Araujo LP, Tanoue T, Atarashi K, Ladinsky MS, Reiner SL,
Wang HH, Mucida D, Honda K, Ivanov II. Microbiota imbalance induced by dietary sugar disrupts
immune-mediated protection from metabolic syndrome. Cell 185, 3501-3519.e20 (2022)

126 Lee H, Chubachi S, Namkoong H, Tanaka H, Otake S, Nakagawara K, Morita A, Fukushima T, Watase M,
Kusumoto T, Masaki K, Kamata H, Ishii M, Hasegawa N, Harada N, Ueda T, Ueda S, Ishiguro T, Arimura K,
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104 Kawasaki T, Takeda Y, Edahiro R, Shirai Y, Nogami-Itoh M, Matsuki T, Kida H, Enomoto T, Hara R, Noda
Y, Adachi Y, Niitsu T, Amiya S, Yamaguchi Y, Murakami T, Kato Y, Morita T, Yoshimura H, Yamamoto M,
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127 Li Y, Watanabe E, Kawashima Y, Plichta DR, Wang Z, Ujike M, Ang QY, Wu R, Furuichi M, Takeshita K,
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105 Keiji W, Kitamura T, Ogata Y, Shindo C, Suda W. Flavobacterium ammonificans sp. nov. and Flavobacterium ammoniigenes sp. nov., ammonifying bacteria isolated from surface river water. Int J Syst Evol
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128 Lisa BA, Micheal CJ, Masayuki A, Anna BD, Kenji K, Jennifer HD, Ana RB. Type 2 Inflammation Contributes to Skin Barrier Dysfunction in Atopic Dermatitis. JID Innovations 2, 100131 (2022)

106 Kerick M, Acosta-Herrera M, Pilar Simeon-Aznar C, Luis Callejas J, Assassi S, Proudman SM, Nikpour M,
Hunzelmann N, Moroncini G, de Vries-Bouwstra JK, Orozco G, Barton A, Herrick AL, Terao C, Allanore
Y, Fonseca C, Eugenia Alarcon-Riquelme M, Radstake TR, Beretta L, Denton CP, Mayes MD, Martin
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107 Kikuchi A, Onoda H, Yamaguchi K, Kori S, Matsuzawa S, Chiba Y, Tanimoto S, Yoshimi S, Sato H,
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108 Kimura H, Mizuno K, Shiota M, Narita S, Terada N, Fujimoto N, Ogura K, Hatano S, Iwasaki Y, Hakozaki
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109 Kırkgöz T, Özkan B, Hazan F, Acar S, Nalbantoğlu Ö, Özkaya B, Kulalı MA, Gürsoy S, Ikegawa S, Guo L. A Null
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130 Liu Z, Sattabongkot J, White M, Chotirat S, Kumpitak C, Takashima E, Harbers M, Tham W, Healer J,
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132 Lopez-Vicario C, Sebastian D, Casulleras M, Duran-Guell M, Flores-Costa R, Aguilar F, Jose Lozano J, Zhang
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135 Maekawa M, Natsume R, Arita M. Functional significance of ion channels during macropinosome
resolution in immune cells. Front Physiol 13, 1037758 (2022)

139 Maquat L, Johnson R, Valadkhan S, Carninci P. Lessons from the functional characterization of lncRNAs:
introduction to mammalian genome special issue. Mamm Genome 33, 245-247 (2022)
140 Mars N, Kerminen S, Feng YA, Kanai M, Läll K, Thomas LF, Skogholt AH, della Briotta Parolo P, Project
TB, FinnGen, Neale BM, Smoller JW, Gabrielsen ME, Hveem K, Mägi R, Matsuda K, Okada Y, Pirinen
M, Palotie A, Ganna A, Martin AR, Ripatti S. Genome-wide risk prediction of common diseases acrossancestries in one million people. Cell Genomics 2, 100118 (2022)

142 Masuda T, Tanaka N, Takamatsu K, Hakozaki K, Takahashi R, Anno T, Kufukihara R, Shojo K, Mikami S,
Shinojima T, Kakimi K, Tsunoda T, Aimono E, Nishihara H, Mizuno R, Oya M. Unique characteristics oftertiary lymphoid structures in kidney clear cell carcinoma: prognostic outcome and comparison withbladder cancer. J Immunother Cancer 10, e003883 (2022)
143 Matoba S, Kozuka C, Miura K, Inoue K, Kumon M, Hayashi R, Ohhata T, Ogura A, Inoue A. Noncanonicalimprinting sustains embryonic development and restrains placental overgrowth. Genes Dev 36, 483494 (2022)
144 Matsuo H, Kamatani T, Hamba Y, Boroevich KA, Tsunoda T. Association between high immune activity
and worse prognosis in uveal melanoma and low-grade glioma in TCGA transcriptomic data. BMC
Genomics 23, 351 (2022)

150 Miyajima Y, Noguchi S, Tanaka Y, Li J, Nishimura H, Kishima M, Lim J, Furuhata E, Suzuki T, Kasukawa
T, Suzuki H. Prediction of transcription factors associated with DNA demethylation during human cellular development. Chromosome Res 30, 109-121 (2022)
151 Miyamoto A, Kawasaki H, Lee S, Yokota T, Amagai M, Someya T. Highly Precise, Continuous, Long-term
Monitoring of Skin Electrical Resistance by Nanomesh Electrodes. Adv Healthc Mater 11, e2102425(2022)

145 McDonald JG, Ejsing CS, Kopczynski D, Holcapek M, Aoki J, Arita M, Arita M, Baker ES, Bertrand-Michel
J, Bowden JA, Brugger B, Ellis SR, Fedorova M, Griffiths WJ, Han X, Hartler J, Hoffmann N, Koelmel
JP, Kofeler HC, Mitchell TW, O’Donnell VB, Saigusa D, Schwudke D, Shevchenko A, Ulmer CZ, Wenk
MR, Witting M, Wolrab D, Xia Y, Ahrends R, Liebisch G, Ekroos K. Introducing the Lipidomics Minimal
Reporting Checklist. Nat Metab 4, 1086-1088 (2022)

152 Miyamoto H, Asano F, Ishizawa K, Suda W, Miyamoto H, Tsuji N, Matsuura M, Tsuboi A, Ishii C, Nakaguma T, Shindo C, Kato T, Kurotani A, Shima H, Moriya S, Hattori M, Kodama H, Ohno H, Kikuchi J.
A potential network structure of symbiotic bacteria involved in carbon and nitrogen metabolism ofwood-utilizing insect larvae. Sci Total Environ 836, 155520 (2022)

146 Mi-ichi F, Tsugawa H, Arita M, Yoshida H. Pleiotropic Roles of Cholesteryl Sulfate during Entamoeba
Encystation: Involvement in Cell Rounding and Development of Membrane Impermeability. mSphere7, e0029922 (2022)

153 Miyamoto H, Kawachi N, Kurotani A, Moriya S, Suda W, Suzuki K, Matsuura M, Tsuji N, Nakaguma T,
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91

Data and Statistics

141 Marston NA, Pirruccello JP, Melloni GE, Koyama S, Kamanu FK, Weng L, Roselli C, Kamatani Y, Komuro
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Events138 Manavi F, Sharma A, Sharma R, Tsunoda T, Shatabda S, Dehzangi I. CNN-Pred: Prediction of singlestranded and double-stranded DNA-binding protein using convolutional neural networks. Gene 853,
147045 (2022)

Projects

137 Makishima M, Saiki R, Nannya N, Korotev S, Gurnari C, Takeda J, Momozawa Y, Best S, Krishnamurthy
P, Yoshizato T, Atsuta Y, Shiozawa Y, Iijima-Yamashita Y, Yoshida K, Shiraishi Y, Nagata Y, Kakiuchi N,
ONIZUKA M, Chiba K, Tanaka H, Kon A, Ochi Y, Nakagawa MM, Okuda O, Mori T, Yoda A, Itonaga H,
Miyazaki Y, Sanada M, Ishikawa T, Chiba S, Tsurumi H, Kasahara S, Müller-Tidow C, Takaori-Kondo A,
Ohyashiki K, Kiguchi T, Matsuda F, Jansen JH, Polprasert C, Blombery P, Kamatani Y, Miyano S, Malcovati L, Haferlach T, Kubo M, Cazzola M, Kulasekararaj AG, Godley LA, Maciejewski JP, Ogawa S. Germline DDX41 mutations define a unique subtype of myeloid neoplasms. Blood 141, 534-549 (2022)

149 Mishra A, Malik R, Hachiya T, Jurgenson T, Namba S, Posner DC, Kamanu FK, Koido M, Le Grand Q, Shi M,
He Y, Georgakis MK, Caro I, Krebs K, Liaw Y, Vaura FC, Lin K, Winsvold BS, Srinivasasainagendra V, Parodi L, Bae H, Chauhan G, Chong MR, Tomppo L, Akinyemi R, Roshchupkin GV, Habib N, Jee YH, Thomassen JQ, Abedi V, Carcel-Marquez J, Nygaard M, Leonard HL, Yang C, Yonova-Doing E, Knol MJ, Lewis AJ,
Judy RL, Ago T, Amouyel P, Armstrong ND, Bakker MK, Bartz TM, Bennett DA, Bis JC, Bordes C, Borte
S, Cain A, Ridker PM, Cho K, Chen Z, Cruchaga C, Cole JW, de Jager PL, de Cid R, Endres M, Ferreira LE,
Geerlings MI, Gasca NC, Gudnason V, Hata J, He J, Heath AK, Ho Y, Havulinna AS, Hopewell JC, Hyacinth
HI, Inouye M, Jacob MA, Jeon CE, Jern C, Kamouchi M, Keene KL, Kitazono T, Kittner SJ, Konuma T, Kumar A, Lacaze P, Launer LJ, Lee K, Lepik K, Li J, Li L, Manichaikul A, Markus HS, Marston NA, Meitinger T,
Mitchell BD, Montellano FA, Morisaki T, Mosley TH, Nalls MA, Nordestgaard BG, O’Donnell MJ, Okada Y,
Onland-Moret NC, Ovbiagele B, Peters A, Psaty BM, Rich SS, Rosand J, Sabatine MS, Sacco RL, Saleheen
D, Sandset EC, Salomaa V, Sargurupremraj M, Sasaki M, Satizabal CL, Schmidt CO, Shimizu A, Smith
NL, Sloane KL, Sutoh Y, Sun YV, Tanno K, Tiedt S, Tatlisumak T, Torres-Aguila NP, Tiwari HK, Tregouet D,
Trompet S, Tuladhar AM, Tybjaerg-Hansen A, van Vugt M, Vibo R, Verma SS, Wiggins KL, Wennberg P,
Woo D, Wilson PW, Xu H, Yang Q, Yoon K, Bis JC, Bis JC, Lee J, Cheng Y, Meschia JF, Chen WM, Sale MM,
Zonderman AB, Evans MK, Wilson JG, Correa A, Traylor M, Lewis CM, Carty CL, Reiner A, Haessler J,
Langefeld CD, Gottesman RF, Yaffe K, Liu YM, Kooperberg C, Lange LA, Furie KL, Arnett DK, Benavente
OR, Grewal RP, Peddareddygari LR, Kooperberg C, Kooperberg C, Hveem K, Lindstrom S, Wang L, Smith
EN, Gordon W, van Hylckama Vlieg A, de Andrade M, Brody JA, Pattee JW, Haessler J, Brumpton BM,
Suchon P, Chen M, Frazer KA, Turman C, Germain M, MacDonald J, Braekkan SK, Armasu SM, Pankratz
N, Jackson RD, Nielsen JB, Giulianini F, Puurunen MK, Ibrahim M, Heckbert SR, Bammler TK, McCauley
BM, Taylor KD, Pankow JS, Reiner AP, Gabrielsen ME, Deleuze J, O’Donnell CJ, Kim J, McKnight B, Kraft
P, Hansen J, Rosendaal FR, Heit JA, Tang W, Morange P, Johnson AD, Kabrhel C, van Dijk EJ, van Dijk EJ,
Koudstaal PJ, Luijckx G, Nederkoorn PJ, van Oostenbrugge RJ, Visser MC, Wermer MJ, Kappelle LJ, Esko T,
Esko T, Metspalu A, Magi R, Nelis M, Irvin MR, Irvin MR, de Leeuw F, Levi CR, Maguire J, Jimenez-CondeJ, Sharma P, Sudlow CL, Rannikmae K, Schmidt R, Slowik A, Pera J, Thijs VN, Lindgren AG, Ilinca A, Melander O, Engstrom G, Rexrode KM, Rothwell PM, Stanne TM, Johnson JA, Danesh J, Butterworth AS,
Heitsch L, Boncoraglio GB, Kubo M, Pezzini A, Rolfs A, Giese A, Weir D, Jackson RD, Ross OA, Lemmons
R, Soderholm M, Cushman M, Jood K, McDonough CW, Bell S, Linkohr B, Lee T, Putaala J, Anderson
CD, Anderson CD, Lopez OL, Jian X, Schminke U, Cullell N, Delgado P, Ibanez L, Krupinski J, Lioutas V,
Matsuda K, Montaner J, Muino E, Roquer J, Sarnowski C, Sattar N, Sibolt G, Teumer A, Rutten-Jacobs
L, Kanai M, Giese A, Gretarsdottir S, Rost NS, Yusuf S, Almgren P, Ay H, Bevan S, Brown RD, Carrera C,
Buring JE, Chen W, Cotlarciuc I, de Bakker PI, DeStefano AL, den Hoed M, Duan Q, Engelter ST, Falcone
GJ, Gottesman RF, Gustafsson S, Hassan A, Holliday EG, Howard G, Hsu F, Ingelsson E, Harris TB, Kissela
BM, Kleindorfer DO, Langenberg C, Lemmens R, Leys D, Lin W, Lorentzen E, Magnusson PK, McArdle
PF, Pulit SL, Rice K, Sakaue S, Sapkota BR, Tanislav C, Thorleifsson G, Thorsteinsdottir U, Tzourio C, vanDuijn CM, Walters M, Wareham NJ, Amin N, Aparicio HJ, Attia J, Beiser AS, Berr C, Bustamante M, Caso
V, Choi SH, Chowhan A, Dartigues J, Delavaran H, Dorr M, Ford I, Gurpreet WS, Hamsten A, Hozawa A,
Ingelsson M, Iwasaki M, Kaffashian S, Kalra L, Kjartansson O, Kloss M, Labovitz DL, Laurie CC, Li L, Lind L,
Lindgren CM, Makoto H, Minegishi N, Morris AP, Muller-Nurasyid M, Norrving B, Ogishima S, Parati EA,
Pedersen NL, Perola M, Jousilahti P, Pileggi S, Rabionet R, Riba-Llena I, Ribases M, Romero JR, Rudd
AG, Sarin A, Sarju R, Satoh M, Sawada N, Sigurdsson A, Smith A, Stine OC, Stott DJ, Strauch K, Takai
T, Tanaka H, Touze E, Tsugane S, Uitterlinden AG, Valdimarsson EM, van der Lee SJ, Wakai K, Williams
SR, Wolfe CD, Wong Q, Yamaji T, Sanghera DK, Stefansson K, Taylor KD, Martinez-Majander N, Sobue
K, Soriano-Tarraga C, Volzke H, Akpa O, Akpa O, Sarfo FS, Akpalu A, Obiako R, Wahab K, Osaigbovo G,
Owolabi L, Komolafe M, Jenkins C, Arulogun O, Ogbole G, Adeoye AM, Akinyemi J, Agunloye A, Fakunle
AG, Uvere E, Olalere A, Adebajo OJ, Chen J, Chen J, Clarke R, Collins R, Guo Y, Wang C, Lv J, Peto R, Chen
Y, Fairhurst-Hunter Z, Hill M, Pozarickij A, Schmidt D, Stevens B, Turnbull I, Yu C, Le Grand Q, Le Grand Q,
Ferreira LE, Nagai A, Nagai A, Murakami Y, Geerlings MI, Geerlings MI, Gasca NC, Gudnason V, van Vugt
M, Gottesman RF, Shiroma EJ, Sigurdsson S, Ghanbari M, Boerwinkle E, Beiser AS, Fongang B, Wang R,
Ikram MK, Volker U, de Jager PL, de Jager PL, de Cid R, Nordestgaard BG, Sargurupremraj M, Verma SS,
de Laat KF, de Laat KF, van Norden AG, de Kort PL, Vermeer SE, Brouwers PJ, Gons RA, Nederkoorn PJ,
den Heijer T, van Dijk GW, van Rooij FG, Aamodt AH, Aamodt AH, Skogholt AH, Brumpton BM, Willer
CJ, Heuch I, Hagen K, Fritsche LG, Pedersen LM, Gabrielsen ME, Ellekjaer H, Zhou W, Martinsen AE,
Kristoffersen ES, Nielsen JB, Hveem K, Thomas LF, Kleinschnitz C, Kleinschnitz C, Frantz S, Ungethum K,
Gallego-Fabrega C, Gallego-Fabrega C, Lledos M, Llucia-Carol L, Sobrino T, Campos F, Castillo J, Freijo M,
Arenillas JF, Obach V, Alvarez-Sabin J, Molina CA, Ribo M, Munoz-Narbona L, Lopez-Cancio E, Millan
M, Diaz-Navarro R, Vives-Bauza C, Serrano-Heras G, Segura T, Delgado P, Dhar R, Delgado-Mederos
R, Prats-Sanchez L, Camps-Renom P, Blay N, Sumoy L, Marti-Fabregas J, Schnohr P, Schnohr P, Jensen
GB, Benn M, Afzal S, Kamstrup PR, van Setten J, van Setten J, van der Laan SW, Vonk JM, Kim B, Kim
B, Curtze S, Curtze S, Tiainen M, Kinnunen J, Menon V, Menon V, Sung YJ, Yang C, Saillour-Glenisson
F, Gravel S, Onland-Moret NC, Onland-Moret NC, Heath AK, Millwood IY, Gieger C, Ninomiya T, Grabe
HJ, Jukema JW, Rissanen IL, Strbian D, Kim YJ, Chen P, Mayerhofer E, Howson JM, Irvin MR, Adams H,
Wassertheil-Smoller S, Christensen K, Ikram MA, Rundek T, Worrall BB, Lathrop GM, Riaz M, Simonsick
EM, Korv J, Franca PH, Zand R, Prasad K, Frikke-Schmidt R, de Leeuw F, Liman T, Haeusler KG, Ruigrok
YM, Heuschmann PU, Longstreth WT, Jung KJ, Bastarache L, Pare G, Damrauer SM, Chasman DI, Rotter
JI, Anderson CD, Zwart J, Niiranen TJ, Fornage M, Liaw Y, Seshadri S, Fernandez-Cadenas I, Walters
RG, Ruff CT, Owolabi MO, Huffman JE, Milani L, Kamatani Y, Dichgans M, Debette S. Stroke genetics
informs drug discovery and risk prediction across ancestries. Nature 611, 115-123 (2022)

Lab Activities

136 Mahajan A, Spracklen CN, Zhang W, Ng MC, Petty LE, Kitajima H, Yu GZ, Rüeger S, Speidel L, Kim YJ,
Horikoshi M, Mercader JM, Taliun D, Moon S, Kwak S, Robertson NR, Rayner NW, Loh M, Kim B, Chiou
J, Miguel-Escalada I, della Briotta Parolo P, Lin K, Bragg F, Preuss MH, Takeuchi F, Nano J, Guo X, Lamri
A, Nakatochi M, Scott RA, Lee J, Huerta-Chagoya A, Graff M, Chai J, Parra EJ, Yao J, Bielak LF, Tabara Y,
Hai Y, Steinthorsdottir V, Cook JP, Kals M, Grarup N, Schmidt EM, Pan I, Sofer T, Wuttke M, Sarnowski C,
Gieger C, Nousome D, Trompet S, Long J, Sun M, Tong L, Chen W, Ahmad M, Noordam R, Lim VJ, Tam
CH, Joo YY, Chen C, Raffield LM, Lecoeur C, Prins BP, Nicolas A, Yanek LR, Chen G, Jensen RA, Tajuddin
S, Kabagambe EK, An P, Xiang AH, Choi HS, Cade BE, Tan J, Flanagan J, Abaitua F, Adair LS, Adeyemo
A, Aguilar-Salinas CA, Akiyama M, Anand SS, Bertoni A, Bian Z, Bork-Jensen J, Brandslund I, Brody
JA, Brummett CM, Buchanan TA, Canouil M, Chan JC, Chang L, Chee M, Chen J, Chen S, Chen Y, Chen
Z, Chuang L, Cushman M, Das SK, de Silva HJ, Dedoussis G, Dimitrov L, Doumatey AP, Du S, Duan Q,
Eckardt K, Emery LS, Evans DS, Evans MK, Fischer K, Floyd JS, Ford I, Fornage M, Franco OH, Frayling
TM, Freedman BI, Fuchsberger C, Genter P, Gerstein HC, Giedraitis V, González-Villalpando C, GonzálezVillalpando ME, Goodarzi MO, Gordon-Larsen P, Gorkin D, Gross M, Guo Y, Hackinger S, Han S, Hattersley AT, Herder C, Howard A, Hsueh W, Huang M, Huang W, Hung Y, Hwang MY, Hwu C, Ichihara S, Ikram
MA, Ingelsson M, Islam MT, Isono M, Jang H, Jasmine F, Jiang G, Jonas JB, Jørgensen ME, Jørgensen
T, Kamatani Y, Kandeel FR, Kasturiratne A, Katsuya T, Kaur V, Kawaguchi T, Keaton JM, Kho AN, KhorC, Kibriya MG, Kim D, Kohara K, Kriebel J, Kronenberg F, Kuusisto J, Läll K, Lange LA, Lee M, Lee NR,
Leong A, Li L, Li Y, Li-Gao R, Ligthart S, Lindgren CM, Linneberg A, Liu C, Liu J, Locke AE, Louie T, Luan
J, Luk AO, Luo X, Lv J, Lyssenko V, Mamakou V, Mani KR, Meitinger T, Metspalu A, Morris AD, Nadkarni
GN, Nadler JL, Nalls MA, Nayak U, Nongmaithem SS, Ntalla I, Okada Y, Orozco L, Patel SR, Pereira MA,
Peters A, Pirie FJ, Porneala B, Prasad G, Preissl S, Rasmussen-Torvik LJ, Reiner AP, Roden M, Rohde R,
Roll K, Sabanayagam C, Sander M, Sandow K, Sattar N, Schönherr S, Schurmann C, Shahriar M, Shi J,
Shin DM, Shriner D, Smith JA, So WY, Stančáková A, Stilp AM, Strauch K, Suzuki K, Takahashi A, Taylor
KD, Thorand B, Thorleifsson G, Thorsteinsdottir U, Tomlinson B, Torres JM, Tsai F, Tuomilehto J, TusieLuna T, Udler MS, Valladares-Salgado A, van Dam RM, van Klinken JB, Varma R, Vujkovic M, WacherRodarte N, Wheeler E, Whitsel EA, Wickremasinghe AR, van Dijk KW, Witte DR, Yajnik CS, Yamamoto K,
Yamauchi T, Yengo L, Yoon K, Yu C, Yuan J, Yusuf S, Zhang L, Zheng W, Raffel LJ, Igase M, Ipp E, Redline
S, Cho YS, Lind L, Province MA, Hanis CL, Peyser PA, Ingelsson E, Zonderman AB, Psaty BM, Wang Y,
Rotimi CN, Becker DM, Matsuda F, Liu Y, Zeggini E, Yokota M, Rich SS, Kooperberg C, Pankow JS, Engert
JC, Chen YI, Froguel P, Wilson JG, Sheu WH, Kardia SL, Wu J, Hayes MG, Ma RC, Wong T, Groop L, MookKanamori DO, Chandak GR, Collins FS, Bharadwaj D, Paré G, Sale MM, Ahsan H, Motala AA, Shu X, ParkK, Jukema JW, Cruz M, McKean-Cowdin R, Grallert H, Cheng C, Bottinger EP, Dehghan A, Tai E, Dupuis
J, Kato N, Laakso M, Köttgen A, Koh W, Palmer CN, Liu S, Abecasis G, Kooner JS, Loos RJ, North KE,
Haiman CA, Florez JC, Saleheen D, Hansen T, Pedersen O, Mägi R, Langenberg C, Wareham NJ, Maeda
S, Kadowaki T, Lee J, Millwood IY, Walters RG, Stefansson K, Myers SR, Ferrer J, Gaulton KJ, Meigs JB,
Mohlke KL, Gloyn AL, Bowden DW, Below JE, Chambers JC, Sim X, Boehnke M, Rotter JI, McCarthy MI,
Morris AP. Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations
for discovery and translation. Nat Genet 54, 560-572 (2022)

148 Misawa T, Wagner M, Koyasu S. ILC2s and adipose tissue homeostasis: Progress to date and the roadahead. Front Immunol 13, 876029 (2022)

Research Highlights

134 Lv Z, Han J, Li J, Guo H, Fei Y, Sun Z, Dong J, Wang M, Fan C, Li W, Xie Y, Sun W, Chen J, Liu Y, Chen F, Liu
Z, Liu A, Wu R, Xu X, Yan W, Jiang Q, Ikegawa S, Chen X, Shi D. Single cell RNA-seq analysis identifies
ferroptotic chondrocyte cluster and reveals TRPV1 as an anti-ferroptotic target in osteoarthritis. EBioMedicine 84, 104258 (2022)

147 Miki Y, Taketomi Y, Kidoguchi Y, Yamamoto K, Muramatsu K, Nishito Y, Park J, Hosomi K, Mizuguchi K,
Kunisawa J, Soga T, Boilard E, Gowda SG, Ikeda K, Arita M, Murakami M. Group IIA secreted phospholipase A (2) controls skin carcinogenesis and psoriasis by shaping the gut microbiota. JCI Insight 7,e152611 (2022)

154 Miyao T, Miyauchi M, Kelly ST, Terooatea TW, Ishikawa T, Oh E, Hirai S, Horie K, Takakura Y, Ohki H, Hayama
M, Maruyama Y, Seki T, Ishii H, Yabukami H, Yoshida M, Inoue A, Sakaue-Sawano A, Miyawaki A, Muratani
M, Minoda A, Akiyama N, Akiyama T. Integrative analysis of scRNA-seq and scATAC-seq revealed transitamplifying thymic epithelial cells expressing autoimmune regulator. Elife 11, e73998 (2022)
155 Miyauchi E, Shimokawa C, Steimle A, Desai MS, Ohno H. The impact of the gut microbiome on extraintestinal autoimmune diseases. Nat Rev Immunol 23, 9-23 (2022)
156 Momozawa Y, Sasai R, Usui Y, Shiraishi K, Iwasaki Y, Taniyama Y, Parsons MT, Mizukami K, Sekine Y,
Hirata M, Kamatani Y, Endo M, Inai C, Takata S, Ito H, Kohno T, Matsuda K, Nakamura S, Sugano K,
Yoshida T, Nakagawa H, Matsuo K, Murakami Y, Spurdle AB, Kubo M. Expansion of Cancer Risk Profile
for BRCA1 and BRCA2 Pathogenic Variants. JAMA Oncol 8, 871-878 (2022)
157 Moody J, Kouno T, Chang J, Ando Y, Carninci P, Shin J, Hon C. SCAFE: a software suite for analysis oftranscribed cis-regulatory elements in single cells. Bioinformatics 38, 5126-5128 (2022)
158 Mori K, Kuroha S, Hou J, Jeong H, Ogawa M, Ikeda S, Kang JX, Negishi K, Torii H, Arita M, Kurihara T,
Tsubota K. Lipidomic analysis revealed n-3 polyunsaturated fatty acids suppressed choroidal thinningand myopia progression in mice. FASEB J 36, e22312 (2022)
159 Mori T, Rai A, Tsugawa H, Yamada Y, Saito K. A liquid chromatography-mass spectrometry-based metabolomics strategy to explore plant metabolic diversity. Methods Enzymol 680, 247-273 (2022)
160 Morimoto A, Fukuda K, Ito Y, Tahara U, Sasaki T, Shiohama A, Kawasaki H, Kawakami E, Naganuma T,
Arita M, Sasaki H, Koseki H, Matsui T, Amagai M. Microbiota-Independent Spontaneous Dermatitis
Associated with Increased Sebaceous Lipid Production in Tmem79-Deficient Mice. J Invest Dermatol
142, 2864-2872.e6 (2022)
161 Morozumi S, Ueda M, Okahashi N, Arita M. Structures and functions of the gut microbial lipidome.
Biochim Biophys Acta Mol Cell Biol Lipids 1867, 159110 (2022)
162 Mukai H, Miki N, Yamada H, Goto H, Kawakami T, Suzuki A, Yamamoto K, Nakanishi Y, Takahashi K.
Pannexin1 channel-dependent secretome from apoptotic tumor cells shapes immune-escape microenvironment. Biochem Biophys Res Commun 628, 116-122 (2022)
163 Mukai Y, Horie M, Kojima S, Kawasaki J, Maeda K, Tomonaga K. An endogenous bornavirus-like nucleoprotein in miniopterid bats retains the RNA-binding properties of the original viral protein. FEBS
Lett 596, 323-337 (2022)
164 Mushiroda T. Avoidance of cutaneous adverse drug reactions induced by antiepileptic drugs based on
pharmacogenomics. J Hum Genet 68, 227-230 (2022)
165 Mutai H, Momozawa Y, Kamatani Y, Nakano A, Sakamoto H, Takiguchi T, Nara K, Kubo M, Matsunaga
T. Whole exome analysis of patients in Japan with hearing loss reveals high heterogeneity among
responsible and novel candidate genes. Orphanet J Rare Dis 17, 114 (2022)
166 Nagafuchi Y, Ota M, Hatano H, Inoue M, Kobayashi S, Okubo M, Sugimori Y, Nakano M, Yamada S,
Yoshida R, Tsuchida Y, Iwasaki Y, Shoda H, Okada Y, Yamamoto K, Ishigaki K, Okamura T, Fujio K. Control
of naive and effector CD4 T cell receptor repertoires by rheumatoid-arthritis-risk HLA alleles. J Autoimmun 133, 102907 (2022)
167 Nagano M, Hu B, Yokobayashi S, Yamamura A, Umemura F, Coradin M, Ohta H, Yabuta Y, Ishikura Y,
Okamoto I, Ikeda H, Kawahira N, Nosaka Y, Shimizu S, Kojima Y, Mizuta K, Kasahara T, Imoto Y, Meehan
K, Stocsits R, Wutz G, Hiraoka Y, Murakawa Y, Yamamoto T, Tachibana K, Peters J, Mirny LA, Garcia BA,
Majewski J, Saitou M. Nucleome programming is required for the foundation of totipotency in mammalian germline development. EMBO J 41, e110600 (2022)
168 Naganuma T, Fujinami N, Arita M. Polyunsaturated Fatty Acid-Derived Lipid Mediators That Regulate
Epithelial Homeostasis. Biol Pharm Bull 45, 998-1007 (2022)
169 Nagata N, Nishijima S, Kojima Y, Hisada Y, Imbe K, Miyoshi-Akiyama T, Suda W, Kimura M, Aoki R,
Sekine K, Ohsugi M, Miki K, Osawa T, Ueki K, Oka S, Mizokami M, Kartal E, Schmidt TS, Molina-Montes E,
Estudillo L, Malats N, Trebicka J, Kersting S, Langheinrich M, Bork P, Uemura N, Itoi T, Kawai T. Metagenomic Identification of Microbial Signatures Predicting Pancreatic Cancer From a Multinational Study.
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Mangino M, Christofidou P, Verweij N, Benjamins JW, Engmann J, Noah TL, Verma A, Slieker RC, Lo KS,
Zilhao NR, Kleber ME, Delgado GE, Huo S, Ikeda DD, Iha H, Yang J, Liu J, Demirkan A, Leonard HL, Marten J, Emmel C, Schmidt B, Smyth LJ, Cañadas-Garre M, Wang C, Nakatochi M, Wong A, Hutri-Kähönen
N, Sim X, Xia R, Huerta-Chagoya A, Fernandez-Lopez JC, Lyssenko V, Nongmaithem SS, Sankareswaran
A, Irvin MR, Oldmeadow C, Kim H, Ryu S, Timmers PR, Arbeeva L, Dorajoo R, Lange LA, Prasad G,
Lorés-Motta L, Pauper M, Long J, Li X, Theusch E, Takeuchi F, Spracklen CN, Loukola A, Bollepalli S,
Warner SC, Wang YX, Wei WB, Nutile T, Ruggiero D, Sung YJ, Chen S, Liu F, Yang J, Kentistou KA, Banas B,
Morgan A, Meidtner K, Bielak LF, Smith JA, Hebbar P, Farmaki A, Hofer E, Lin M, Concas MP, Vaccargiu
S, van der Most PJ, Pitkänen N, Cade BE, van der Laan SW, Chitrala KN, Weiss S, Bentley AR, Doumatey
AP, Adeyemo AA, Lee JY, Petersen ER, Nielsen AA, Choi HS, Nethander M, Freitag-Wolf S, Southam L,
Rayner NW, Wang CA, Lin S, Wang J, Couture C, Lyytikäinen L, Nikus K, Cuellar-Partida G, Vestergaard
H, Hidalgo B, Giannakopoulou O, Cai Q, Obura MO, van Setten J, He KY, Tang H, Terzikhan N, Shin JH,
Jackson RD, Reiner AP, Martin LW, Chen Z, Li L, Kawaguchi T, Thiery J, Bis JC, Launer LJ, Li H, Nalls
MA, Raitakari OT, Ichihara S, Wild SH, Nelson CP, Campbell H, Jäger S, Nabika T, Al-Mulla F, Niinikoski
H, Braund PS, Kolcic I, Kovacs P, Giardoglou T, Katsuya T, de Kleijn D, de Borst GJ, Kim EK, Adams HH,
Ikram MA, Zhu X, Asselbergs FW, Kraaijeveld AO, Beulens JW, Shu X, Rallidis LS, Pedersen O, Hansen T,
Mitchell P, Hewitt AW, Kähönen M, Pérusse L, Bouchard C, Tönjes A, Chen YI, Pennell CE, Mori TA, Lieb
W, Franke A, Ohlsson C, Mellström D, Cho YS, Lee H, Yuan J, Koh W, Rhee SY, Woo J, Heid IM, Stark KJ,

208 Sabate-Soler S, Nickels S, Saraiva C, Berger E, Dubonyte U, Barmpa K, Lan Y, Kouno T, Jarazo J, Robertson G,
Sharif J, Koseki H, Thome C, Shin J, Cowley S, Schwamborn J. Microglia integration into human midbrainorganoids leads to increased neuronal maturation and functionality. Glia 70, 1267-1288 (2022)

Events204 Pirruccello JP, Di Achille P, Nauffal V, Nekoui M, Friedman SF, Klarqvist MD, Chaffin MD, Weng L, Cunningham JW, Khurshid S, Roselli C, Lin H, Koyama S, Ito K, Kamatani Y, Komuro I, Jurgens SJ, Benjamin
EJ, Batra P, Natarajan P, Ng K, Hoffmann U, Lubitz SA, Ho JE, Lindsay ME, Philippakiss AA, Ellinor PT.
Genetic analysis of right heart structure and function in 40,000 people. Nat Genet 54, 792-803 (2022)

207 Ruotsalainen SE, Surakka I, Mars N, Karjalainen J, Kurki M, Kanai M, Krebs K, Graham S, Mishra PP,
Mishra BH, Sinisalo J, Palta P, Lehtimaki T, Raitakari O, Milani L, Okada Y, Palotie A, Widen E, Daly MJ,
Ripatti S. Inframe insertion and splice site variants in MFGE8 associate with protection against coronary atherosclerosis. Commun Biol 5, 802 (2022)

Projects

200 Parrish NF, Gaston DC. Metagenomics in infectious disease diagnostics: Toward best‐use practices tooptimize actionable results. Transpl Infect Dis 25, e13959 (2022)

206 Robbe P, Ridout KE, Vavoulis DV, Dreau H, Kinnersley B, Denny N, Chubb D, Appleby N, Cutts A, Cornish
AJ, Lopez-Pascua L, Clifford R, Burns A, Stamatopoulos B, Cabes M, Alsolami R, Antoniou P, Oates M,
Cavalieri D, Consortium GE, Consortium CP, Gibson J, Prabhu A, Schwessinger R, Jennings D, James T,
Maheswari U, Duran-Ferrer M, Carninci P, Knight SJ, Mansson R, Hughes J, Davies J, Ross M, Bentley
D, Strefford JC, Devereux S, Pettitt AR, Hillmen P, Caulfield MJ, Houlston RS, Martin-Subero J, Schuh
A. Whole-genome sequencing of chronic lymphocytic leukemia identifies subgroups with distinct
biological and clinical features. Nat Genet 54, 1675-1689 (2022)

Lab Activities

195 Okuyama K, Taniuchi I. Three residues in the BTB domain promote a good partnership between NuRD
and Thpok. Sci Immunol 7, eabq1408 (2022)

Research Highlights

189 Ohinata Y, Endo TA, Sugishita H, Watanabe T, Iizuka Y, Kawamoto Y, Saraya A, Kumon M, Koseki Y,
Kondo T, Ohara O, Koseki H. Establishment of mouse stem cells that can recapitulate the developmental potential of primitive endoderm. Science 375, 574-578 (2022)

Zimmermann ME, Völzke H, Homuth G, Evans MK, Zonderman AB, Polasek O, Pasterkamp G, Hoefer IE,
Redline S, Pahkala K, Oldehinkel AJ, Snieder H, Biino G, Schmidt R, Schmidt H, Bandinelli S, Dedoussis
G, Thanaraj TA, Peyser PA, Kato N, Schulze MB, Girotto G, Böger CA, Jung B, Joshi PK, Bennett DA, De
Jager PL, Lu X, Mamakou V, Brown M, Caulfield MJ, Munroe PB, Guo X, Ciullo M, Jonas JB, Samani NJ,
Kaprio J, Pajukanta P, Tusié-Luna T, Aguilar-Salinas CA, Adair LS, Bechayda SA, de Silva HJ, Wickremasinghe AR, Krauss RM, Wu J, Zheng W, Hollander AI, Bharadwaj D, Correa A, Wilson JG, Lind L, Heng
C, Nelson AE, Golightly YM, Wilson JF, Penninx B, Kim H, Attia J, Scott RJ, Rao D, Arnett DK, Walker M,
Scott LJ, Koistinen HA, Chandak GR, Mercader JM, Villalpando CG, Orozco L, Fornage M, Tai ES, vanDam RM, Lehtimäki T, Chaturvedi N, Yokota M, Liu J, Reilly DF, McKnight AJ, Kee F, Jöckel K, McCarthy
MI, Palmer CN, Vitart V, Hayward C, Simonsick E, van Duijn CM, Jin Z, Lu F, Hishigaki H, Lin X, März W,
Gudnason V, Tardif J, Lettre G, Hart LM, Elders PJ, Rader DJ, Damrauer SM, Kumari M, Kivimaki M, vander Harst P, Spector TD, Loos RJ, Province MA, Parra EJ, Cruz M, Psaty BM, Brandslund I, Pramstaller PP,
Rotimi CN, Christensen K, Ripatti S, Widén E, Hakonarson H, Grant SF, Kiemeney L, de Graaf J, Loeffler
M, Kronenberg F, Gu D, Erdmann J, Schunkert H, Franks PW, Linneberg A, Jukema JW, Khera AV, Männikkö M, Jarvelin M, Kutalik Z, Francesco C, Mook-Kanamori DO, van Dijk KW, Watkins H, Strachan DP,
Grarup N, Sever P, Poulter N, Sheu WH, Rotter JI, Dantoft TM, Karpe F, Neville MJ, Timpson NJ, Cheng C,
Wong T, Khor CC, Li H, Sabanayagam C, Peters A, Gieger C, Hattersley AT, Pedersen NL, Magnusson PK,
Boomsma DI, de Geus EJ, Cupples LA, van Meurs JB, Ikram A, Ghanbari M, Gordon-Larsen P, Huang W,
Kim YJ, Tabara Y, Wareham NJ, Langenberg C, Zeggini E, Tuomilehto J, Kuusisto J, Laakso M, Ingelsson
E, Abecasis G, Chambers JC, Kooner JS, de Vries PS, Morrison AC, Hazelhurst S, Ramsay M, North KE,
Daviglus M, Kraft P, Martin NG, Whitfield JB, Abbas S, Saleheen D, Walters RG, Holmes MV, Black C,
Smith BH, Baras A, Justice AE, Buring JE, Ridker PM, Chasman DI, Kooperberg C, Tamiya, Yamamoto M,
van Heel DA, Trembath RC, Wei W, Jarvik GP, Namjou B, Hayes MG, Ritchie MD, Jousilahti P, Salomaa V,
Hveem K, Åsvold BO, Kubo M, Kamatani Y, Okada Y, Murakami Y, Kim B, Thorsteinsdottir U, Stefansson K,
Zhang J, Chen YE, Ho Y, Lynch JA, Tsao PS, Chang K, Cho K, O’Donnell CJ, Gaziano JM, Wilson P, Mohlke
KL, Frayling TM, Hirschhorn JN, Kathiresan S, Boehnke M, Program MV, Consortium GL, Grant S, Natarajan P, Sun YV, Morris AP, Deloukas P, Peloso G, Assimes TL, Willer CJ, Zhu X, Brown CD. A multi-layer
functional genomic analysis to understand noncoding genetic variation in lipids. Am J Hum Genet
109, 1366-1387 (2022)

Walters RG, Weir DR, Weiss ST, White WB, Whitfield JB, Wiggins KL, Willemsen G, Willer CJ, Winsvold BS,
Xu H, Yanek LR, Yin J, Young KL, Young KA, Yu B, Zhao W, Zhou W, Zöllner S, Zuccolo L, Batini C, Bergen AW,
Bierut LJ, David SP, Gagliano Taliun SA, Hancock DB, Jiang B, Munafò MR, Thorgeirsson TE, Liu DJ, Vrieze S.
Genetic diversity fuels gene discovery for tobacco and alcohol use. Nature 612, 720-724 (2022)
217 Sekine Y, Iwasaki Y, Aoi T, Endo M, Hirata M, Kamatani Y, Matsuda K, Sugano K, Yoshida T, Murakami Y,
Fukui T, Akamatsu S, Ogawa O, Nakagawa H, Numakura K, Narita S, Habuchi T, Momozawa Y. Different
risk genes contribute to clear cell and non-clear cell renal cell carcinoma in 1532 Japanese patientsand 5996 controls. Hum Mol Genet 31, 1962-1969 (2022)
218 Sekine Y, Iwasaki Y, Hakozaki N, Endo M, Kamatani Y, Matsuda K, Murakami Y, Sano T, Akamatsu S,
Kobayashi T, Nakagawa H, Numakura K, Narita S, Habuchi T, Momozawa Y. Prevalence and risk estimation of cancer-predisposing genes for upper urinary tract urothelial carcinoma in Japanese. Jpn J Clin
Oncol 52, 1441-1445 (2022)
219 Seo W, Nomura A, Taniuchi I. The Roles of RUNX Proteins in Lymphocyte Function and Anti-Tumor Immunity. Cells 11, 3116 (2022)
220 Sheehan A, Goldfine A, Bajwa M, Wolfs D, Kozuka C, Piper J, Fowler K, Patti M. Pramlintide for postbariatric hypoglycaemia. Diabetes Obes Metab 24, 1021-1028 (2022)
221 Shi Z, Takeuchi T, Nakanishi Y, Kato T, Beck K, Nagata R, Kageyama T, Ito A, Ohno H, Satoh-Takayama
N. A Japanese Herbal Formula, Daikenchuto, Alleviates Experimental Colitis by Reshaping Microbial
Profiles and Enhancing Group 3 Innate Lymphoid Cells. Front Immunol 13, 903459 (2022)
222 Shimizu K, Ueda S, Kawamura M, Satoh M, Fujii S. A single immunization with cellular vaccine confers
dual protection against SARS‐CoV‐2 and cancer. Cancer Sci 113, 2536-2547 (2022)

240 Takeuchi T, Ohno H. Analysis of Peripherally Derived Treg in the Intestine. Methods Mol Biol 2559, 4145 (2022)
241 Takeuchi T, Ohno H. IgA in human health and diseases: Potential regulator of commensal microbiota.
Front Immunol 13, 1024330 (2022)
242 Tanaka J, Senpuku H, Ogawa M, Yasuhara R, Ohnuma S, Takamatsu K, Watanabe T, Mabuchi Y, Nakamura S, Ishida S, Sadaoka T, Takaki T, Shirota T, Shimane T, Inoue T, Sakai T, Mori M, Tsuji T, Saito I,
Mishima K. Human induced pluripotent stem cell-derived salivary gland organoids model SARS-CoV-2
infection and replication. Nat Cell Biol 24, 1595-1605 (2022)
243 Tanaskovic N, Dalsass M, Filipuzzi M, Ceccotti G, Verrecchia A, Nicoli P, Doni M, Olivero D, Pasini D,
Koseki H, Sabò A, Bisso A, Amati B. Polycomb group ring finger protein 6 suppresses Myc-induced
lymphomagenesis. Life Sci Alliance 5, e202101344 (2022)
244 Tanemoto S, Sujino T, Miyamoto K, Moody J, Yoshimatsu Y, Ando Y, Koya I, Harada Y, Okuzawa Tojo
A, Ono K, Hayashi Y, Takabayashi K, Okabayashi K, Teratani T, Mikami Y, Nakamoto N, Hosoe N, Ogata
H, Hon C, Shin JW, Kanai T. Single-cell transcriptomics of human gut T cells identifies cytotoxic
CD4+CD8A+ T cells related to mouse CD4 cytotoxic T cells. Front Immunol 13, 977117 (2022)
245 Tayipto Y, Rosado J, Gamboa D, White MT, Kiniboro B, Healer J, Opi HD, Beeson JG, Takashima E,
Takafumi T, Harbers M, Robinson L, Mueller I, Longley R. Assessment of IgG3 as a serological exposure
marker for Plasmodium vivax in areas with moderate-high malaria transmission intensity. Front Cell
Infect Microbiol 12, 950909 (2022)

224 Shirai Y, Nakanishi Y, Suzuki A, Konaka H, Nishikawa R, Sonehara K, Namba S, Tanaka H, Masuda T, Yaga M,
Satoh S, Izumi M, Mizuno Y, Jo T, Maeda Y, Nii T, Oguro-Igashira E, The Biobank Japan Project, Morisaki T,
Kamatani Y, Nakayamada S, Nishigori C, Tanaka Y, Takeda Y, Yamamoto K, Kumanogoh A, Okada Y. Multitrait and cross-population genome-wide association studies across autoimmune and allergic diseases
identify shared and distinct genetic component. Ann Rheum Dis 81, 1301-1312 (2022)

246 Tcheandjieu C, Zhu X, Hilliard AT, Clarke SL, Napolioni V, Ma S, Lee KM, Fang H, Chen F, Lu Y, Tsao NL,
Raghavan S, Koyama S, Gorman BR, Vujkovic M, Klarin D, Levin MG, Sinnott-Armstrong N, Wojcik GL,
Plomondon ME, Maddox TM, Waldo SW, Bick AG, Pyarajan S, Huang J, Song R, Ho Y, Buyske S, Kooperberg C, Haessler J, Loos RJ, Do R, Verbanck M, Chaudhary K, North KE, Avery CL, Graff M, Haiman CA,
Le Marchand L, Wilkens LR, Bis JC, Leonard H, Shen B, Lange LA, Giri A, Dikilitas O, Kullo IJ, Stanaway
IB, Jarvik GP, Gordon AS, Hebbring S, Namjou B, Kaufman KM, Ito K, Ishigaki K, Kamatani Y, VermaSS, Ritchie MD, Kember RL, Baras A, Lotta LA, Kathiresan S, Hauser ER, Miller DR, Lee JS, Saleheen
D, Reaven PD, Cho K, Gaziano JM, Natarajan P, Huffman JE, Voight BF, Rader DJ, Chang K, Lynch JA,
Damrauer SM, Wilson PW, Tang H, Sun Y, Tsao PS, O’Donnell CJ, Assimes TL. Large-scale genome-wide
association study of coronary artery disease in genetically diverse populations. Nat Med 28, 16791692 (2022)

225 Shirai Y, Nakayama A, Kawamura Y, Toyoda Y, Nakatochi M, Shimizu S, Shinomiya N, Okada Y, Matsuo H,
Consortium JG. Coffee Consumption Reduces Gout Risk Independently of Serum Uric Acid Levels: Mendelian Randomization Analyses Across Ancestry Populations. ACR Open Rheumatol 4, 534-539 (2022)

247 Terakawa A, Hu Y, Kokaji T, Yugi K, Morita K, Ohno S, Pan Y, Bai Y, Parkhitko AA, Ni X, Asara JM, Bulyk
ML, Perrimon N, Kuroda S. Trans-omics analysis of insulin action reveals a cell growth subnetwork
which co-regulates anabolic processes. iSCIENCE 25, 104231 (2022)

226 Siamoglou S, Koromina M, Hishinuma E, Yamazaki S, Tsermpini E, Kordou Z, Fukunaga K, Chantratita W,
Zhou Y, Lauschke VM, Mushiroda T, Hiratsuka M, Patrinos GP. Identification and functional validationof novel pharmacogenomic variants using a next-generation sequencing-based approach for clinicalpharmacogenomics. Pharmacol Res 176, 106087 (2022)

248 Teshima T, Kobayashi Y, Kawai T, Kushihara Y, Nagaoka K, Miyakawa J, Akiyama Y, Yamada Y, Sato Y,
Yamada D, Tanaka N, Tsunoda T, Kume H, Kakimi K. Principal component analysis of early immune cell
dynamics during pembrolizumab treatment of advanced urothelial carcinoma. Oncol Lett 24, 265 (2022)

223 Shiraga K, Ogawa Y, Kikuchi S, Amagai M, Matsui T. Increase in the Intracellular Bulk Water Content in
the Early Phase of Cell Death of Keratinocytes, Corneoptosis, as Revealed by 65 GHz Near-Field CMOS
Dielectric Sensor. Molecules 27, 2886 (2022)

227 Singh H, Shipra, Sharma, Sharma, Sharma A, Modeel S, Gupta N, Gupta G, Pandita AK, Butt MF, Sharma R, Pandita S, Singh V, Rai E, Ikegawa S, Sharma S. The first study of epidemiology of adolescentidiopathic scoliosis shows lower prevalence in females of Jammu and Kashmir, India. Am J Transl Res
14, 1100-1106 (2022)
228 Sonehara K, Kimura Y, Nakano Y, Ozawa T, Takahashi M, Suzuki K, Fujii T, Matsushita Y, Tomiyama A,
Kishikawa T, Yamamoto K, Naito T, Suzuki T, Yamaguchi S, Miwa T, Sasaki H, Kitagawa M, Ohe N, Fukai
J, Ogiwara H, Kawamura A, Miyawaki S, Matsuda F, Kiyokawa N, Ichimura K, Nishikawa R, Okada Y,
Terashima K. A common deletion at BAK1 reduces enhancer activity and confers risk of intracranial
germ cell tumors. Nat Commun 13, 4478 (2022)
229 Suda W, Ogata Y, Shindo C, Watanabe K. Complete Genome Sequences of Two Flavobacterium ammonificans Strains and a Flavobacterium ammoniigenes Strain of Ammonifying Bacterioplankton
Isolated from Surface River Water. Microbiol Resour Announc 11, e0017622 (2022)
230 Sugawara T, Miya F, Ishikawa T, Lysenko A, Nishino J, Kamatani T, Boroevich KA, Kakimi K, Kinugasa
Y, Tanabe M, Tsunoda T. Immune subtypes and neoantigen-related immune evasion in advanced
colorectal cancer. iScience 25, 103740 (2022)
231 Sun C, Nagaoka K, Kobayashi Y, Nakagawa H, Nakajima J, Kakimi K. Immunotherapies targeting neoantigens are effective in PD-1 blockade-resistant tumors. Int J Cancer 152, 1463-1475 (2022)
232 Sun H, Tang C, Chung S, Ye X, Makusheva Y, Han W, Kubo M, Shichino S, Ueha S, Matsushima K, Ikeo K,
Asano M, Iwakura Y. Blocking DCIR mitigates colitis and prevents colorectal tumors by enhancing the
GM-CSF-STAT5 pathway. Cell Rep 40, 111158 (2022)
233 Suzuki K, Abe MS, Kumakura D, Nakaoka S, Fujiwara F, Miyamoto H, Nakaguma T, Okada M, Sakurai
K, Shimizu S, Iwata H, Masuya H, Nihei N, Ichihashi Y. Chemical-Mediated Microbial Interactions Can
Reduce the Effectiveness of Time-Series-Based Inference of Ecological Interaction Networks. Int J
Environ Res Public Health 19, 1228 (2022)
234 Suzuki T, Furuhata E, Maeda S, Kishima M, Miyajima Y, Tanaka Y, Lim J, Nishimura H, Nakanishi Y,
shojima A, Suzuki H. GATA6 is predicted to regulate DNA methylation in an in vitro model of humanhepatocyte differentiation. Commun Biol 5, 414 (2022)
235 Suzuki T, Hoshina M, Nishijima S, Hoshina N, Chisato K, Tomohiro T, Fukao A, Fujiwara T, Yamamoto
T. Regulation of CCR4-NOT complex deadenylase activity and cellular responses by MK2-dependent
phosphorylation of CNOT2. RNA Biol 19, 234-246 (2022)
236 Tachibana N, Chijimatsu R, Okada H, Oichi T, Taniguchi Y, Maenohara Y, Miyahara J, Ishikura H, Iwanaga
Y, Arino Y, Nagata K, Nakamoto H, Kato S, Doi T, Matsubayashi Y, Oshima Y, Terashima A, Omata Y, Yano
F, Maeda S, Ikegawa S, Seki M, Suzuki Y, Tanaka S, Saito T. RSPO2 defines a distinct undifferentiatedprogenitor in the tendon/ligament and suppresses ectopic ossification. Sci Adv 8, eabn2138 (2022)
237 Takano J, Ito S, Dong Y, Sharif J, Nakajima-Takagi Y, Umeyama T, Han Y, Isono K, Kondo T, Iizuka Y, Miyai
T, Koseki Y, Ikegaya M, Sakihara M, Nakayama M, Ohara O, Hasegawa Y, Hashimoto K, Arner E, Klose
RJ, Iwama A, Koseki H, Ikawa T. PCGF1-PRC1 links chromatin repression with DNA replication during
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238 Takeshima Y, Iwasaki Y, Nakano M, Narushima Y, Ota M, Nagafuchi Y, Sumitomo S, Okamura T, Elkon K,
Ishigaki K, Suzuki A, Kochi Y, Yamamoto K, Fujio K. Immune cell multiomics analysis reveals contribution of oxidative phosphorylation to B-cell functions and organ damage of lupus. Ann Rheum Dis 81,
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239 Takeuchi C, Moe Y, Shu K, Aoi S, Kuniaki S, Takashi F, Haruhiko, Yuka IW. Mod (mdg4) variants repress
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94

249 Thibord F, Klarin D, Brody JA, Chen M, Levin MG, Chasman D, Goode EL, Hveem K, Teder-Laving M,
Martinez-Perez A, Aissi D, Daian-Bacq D, Ito K, Natarajan P, Lutsey PL, Nadkarni GN, de Vries PS, Cuellar-Partida G, Wolford BN, Pattee JW, Kooperberg C, Braekkan SK, Li-Gao R, Saut N, Sept C, Germain
M, Judy RL, Wiggins KL, Ko D, O’Donnell CJ, Taylor KD, Giulianini F, De Andrade M, Nost TH, Boland A,
Empana J, Koyama S, Gilliland T, Do R, Huffman JE, Wang X, Zhou W, Soria JM, Souto JC, Pankratz N,
Haessler J, Hindberg K, Rosendaal FR, Turman C, Olaso R, Kember RL, Bartz TM, Lynch JA, Heckbert SR,
Armasu SM, Brumpton B, Smadja DM, Jouven X, Komuro I, Clapham KR, Loos RJ, Willer CJ, SabaterLleal M, Pankow JS, Reiner AP, Morelli VM, Ridker PM, Vlieg Av, Deleuze J, Kraft P, Rader DJ, Lee KM,
Psaty BM, Skogholt AH, Emmerich J, Suchon P, Rich SS, Vy HM, Tang W, Jackson RD, Hansen J, Morange
P, Kabrhel C, Tregouet D, Damrauer SM, Johnson AD, Smith NL. Cross-Ancestry Investigation of Venous
Thromboembolism Genomic Predictors. Circulation 146, 1225-1242 (2022)
250 Tomiaki C, Miyauchi K, Ki S, Suzuki Y, Suzuki N, Morimoto H, Mukoyama Y, Kubo M. Role of FK506sensitive signals in asthmatic lung inflammation. Front Immunol 13, 1014462 (2022)
251 Tomofuji Y, Kishikawa T, Maeda Y, Ogawa K, Otake-Kasamoto Y, Kawabata S, Nii T, Okuno T, OguroIgashira E, Kinoshita M, Takagaki M, Oyama N, Todo K, Yamamoto K, Sonehara K, Yagita M, Hosokawa
A, Motooka D, Matsumoto Y, Matsuoka H, Yoshimura M, Ohshima S, Shinzaki S, Nakamura S, Iijima H,
Inohara H, Kishima H, Takehara T, Mochizuki H, Takeda K, Kumanogoh A, Okada Y. Prokaryotic and viralgenomes recovered from 787 Japanese gut metagenomes revealed microbial features linked to diets,
populations, and diseases. Cell Genom 2, 100219 (2022)
252 Toyofuku E, Takeshita K, Ohnishi H, Kiridoshi Y, Masuoka H, Kadowaki T, Nishikomori R, Nishimura K,
Kobayashi C, Ebato T, Shigemura T, Inoue Y, Suda W, Hattori M, Morio T, Honda K, Kanegane H. Dysregulation of the Intestinal Microbiome in Patients With Haploinsufficiency of A20. Front Cell InfectMicrobiol 11, 787667 (2022)
253 Tripathi LP, Arakawa M, Morita E. Flavivirus recruits the valosin-containing protein (VCP)/NPL4
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254 Trubetskoy V, Pardiñas AF, Qi T, Panagiotaropoulou G, Awasthi S, Bigdeli TB, Bryois J, Chen C, Dennison
CA, Hall LS, Lam M, Watanabe K, Frei O, Ge T, Harwood JC, Koopmans F, Magnusson S, Richards AL,
Sidorenko J, Wu Y, Zeng J, Grove J, Kim M, Li Z, Voloudakis G, Zhang W, Adams M, Agartz I, Atkinson
EG, Agerbo E, Al Eissa M, Albus M, Alexander M, Alizadeh BZ, Alptekin K, Als TD, Amin F, Arolt V, Arrojo
M, Athanasiu L, Azevedo MH, Bacanu SA, Bass NJ, Begemann M, Belliveau RA, Bene J, Benyamin B,
Bergen SE, Blasi G, Bobes J, Bonassi S, Braun A, Bressan RA, Bromet EJ, Bruggeman R, Buckley PF,
Buckner RL, Bybjerg-Grauholm J, Cahn W, Cairns MJ, Calkins ME, Carr VJ, Castle D, Catts SV, Chambert
KD, Chan RC, Chaumette B, Cheng W, Cheung EF, Chong SA, Cohen D, Consoli A, Cordeiro Q, Costas J,
Curtis C, Davidson M, Davis KL, de Haan L, Degenhardt F, DeLisi LE, Demontis D, Dickerson F, Dikeos
D, Dinan T, Djurovic S, Duan J, Ducci G, Dudbridge F, Eriksson JG, Fañanás L, Faraone SV, Fiorentino A,
Forstner A, Frank J, Freimer NB, Fromer M, Frustaci A, Gadelha A, Genovese G, Gershon ES, Giannitelli
M, Giegling I, Giusti-Rodríguez P, Godard S, Goldstein JI, González Peñas J, González-Pinto A, Gopal
S, Gratten J, Green MF, Greenwood TA, Guillin O, Gülöksüz S, Gur RE, Gur RC, Gutiérrez B, Hahn E,
Hakonarson H, Haroutunian V, Hartmann AM, Harvey C, Hayward C, Henskens FA, Herms S, HoffmannP, Howrigan DP, Ikeda M, Iyegbe C, Joa I, Julià A, Kähler AK, Kam-Thong T, Kamatani Y, KarachanakYankova S, Kebir O, Keller MC, Kelly BJ, Khrunin A, Kim S, Klovins J, Kondratiev N, Konte B, Kraft J, Kubo
M, Kučinskas V, Kučinskiene ZA, Kusumawardhani A, Kuzelova-Ptackova H, Landi S, Lazzeroni LC, Lee
PH, Legge SE, Lehrer DS, Lencer R, Lerer B, Li M, Lieberman J, Light GA, Limborska S, Liu C, Lönnqvist
J, Loughland CM, Lubinski J, Luykx JJ, Lynham A, Macek M, Mackinnon A, Magnusson PK, Maher BS,
Maier W, Malaspina D, Mallet J, Marder SR, Marsal S, Martin AR, Martorell L, Mattheisen M, McCarley
RW, McDonald C, McGrath JJ, Medeiros H, Meier S, Melegh B, Melle I, Mesholam-Gately RI, Metspalu
A, Michie PT, Milani L, Milanova V, Mitjans M, Molden E, Molina E, Molto MD, Mondelli V, Moreno C,
Morley CP, Muntané G, Murphy KC, Myin-Germeys I, Nenadić I, Nestadt G, Nikitina-Zake L, Noto C,

256 Tsuji K, Shimada W, Kishino S, Ogawa J, Arita M. Comprehensive analysis of fatty acid metabolites
produced by gut microbiota using LC-MS/MS-based lipidomics. Medical Mass Spectrometry 6, 112125 (2022)
257 Tsumagari K, Sato Y, Shimozawa A, Aoyagi H, Okano H, Kuromitsu J. Co-expression network analysis
of human tau-transgenic mice reveals protein modules associated with tau-induced pathologies.
iSCIENCE 25, 104832 (2022)

271 Wang Z, Xue J, Nishimura, Kometani M, Wilnai Y, Zeitlin L, Kinoshita A, Yoshiura K, Imamura T, Ohashi
H, Kawai S, Shiina M, Ogata K, Miyake N, Toguchida J, Superti-Furga A, Matsumoto N, Ikegawa S.
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273 Weissbrod O, Kanai M, Shi H, Gazal S, Peyrot WJ, Khera AV, Okada Y, Martin AR, Finucane HK, Price AL.
Leveraging fine-mapping and multipopulation training data to improve cross-population polygenic
risk scores. Nat Genet 54, 450-458 (2022)

262 Udagawa C, Kuah S, Shimoi T, Kato K, Yoshida T, Nakano MH, Shimo A, Kojima Y, Yoshie R, Tsugawa
K, Mushiroda T, Tan EY, Zembutsu H. Replication Study for the Association of Five SNPs Identified by
GWAS and Trastuzumab-Induced Cardiotoxicity in Japanese and Singaporean Cohorts. Biol Pharm
Bull 45, 1198-1202 (2022)

274 Winkler TW, Rasheed H, Teumer A, Gorski M, Rowan BX, Stanzick KJ, Thomas LF, Tin A, Hoppmann
A, Chu AY, Tayo B, Thio CH, Cusi D, Chai J, Sieber KB, Horn K, Li M, Scholz M, Cocca M, Wuttke M,
van der Most PJ, Yang Q, Ghasemi S, Nutile T, Li Y, Pontali G, Günther F, Dehghan A, Correa A, Parsa
A, Feresin A, de Vries AP, Zonderman AB, Smith AV, Oldehinkel AJ, De Grandi A, Rosenkranz AR,
Franke A, Teren A, Metspalu A, Hicks AA, Morris AP, Tönjes A, Morgan A, Podgornaia AI, Peters A,
Körner A, Mahajan A, Campbell A, Freedman BI, Spedicati B, Ponte B, Schöttker B, Brumpton B,
Banas B, Krämer BK, Jung B, Åsvold BO, Smith BH, Ning B, Penninx BW, Vanderwerff BR, Psaty BM,
Kammerer CM, Langefeld CD, Hayward C, Spracklen CN, Robinson-Cohen C, Hartman CA, Lindgren
CM, Wang C, Sabanayagam C, Heng C, Lanzani C, Khor C, Cheng C, Fuchsberger C, Gieger C, Shaffer
CM, Schulz C, Willer CJ, Chasman DI, Gudbjartsson DF, Ruggiero D, Toniolo D, Czamara D, Porteous
DJ, Waterworth DM, Mascalzoni D, Mook-Kanamori DO, Reilly DF, Daw EW, Hofer E, Boerwinkle E,
Salvi E, Bottinger EP, Tai E, Catamo E, Rizzi F, Guo F, Rivadeneira F, Guilianini F, Sveinbjornsson G,
Ehret G, Waeber G, Biino G, Girotto G, Pistis G, Nadkarni GN, Delgado GE, Montgomery GW, Snieder
H, Campbell H, White HD, Gao H, Stringham HM, Schmidt H, Li H, Brenner H, Holm H, Kirsten
H, Kramer H, Rudan I, Nolte IM, Tzoulaki I, Olafsson I, Martins J, Cook JP, Wilson JF, Halbritter J,
Felix JF, Divers J, Kooner JS, Lee JJ, O’Connell J, Rotter JI, Liu J, Xu J, Thiery J, Ärnlöv J, Kuusisto J,
Jakobsdottir J, Tremblay J, Chambers JC, Whitfield JB, Gaziano JM, Marten J, Coresh J, Jonas JB,
Mychaleckyj JC, Christensen K, Eckardt K, Mohlke KL, Endlich K, Dittrich K, Ryan KA, Rice KM, Taylor
KD, Ho K, Nikus K, Matsuda K, Strauch K, Miliku K, Hveem K, Lind L, Wallentin L, Yerges-Armstrong
LM, Raffield LM, Phillips LS, Launer LJ, Lyytikäinen L, Lange LA, Citterio L, Klaric L, Ikram MA, Ising
M, Kleber ME, Francescatto M, Concas MP, Ciullo M, Piratsu M, Orho-Melander M, Laakso M, Loeffler M, Perola M, de Borst MH, Gögele M, Bianca ML, Lukas MA, Feitosa MF, Biggs ML, Wojczynski
MK, Kavousi M, Kanai M, Akiyama M, Yasuda M, Nauck M, Waldenberger M, Chee M, Chee M,
Boehnke M, Preuss MH, Stumvoll M, Province MA, Evans MK, O’Donoghue ML, Kubo M, Kähönen
M, Kastarinen M, Nalls MA, Kuokkanen M, Ghanbari M, Bochud M, Josyula NS, Martin NG, Tan NY,
Palmer ND, Pirastu N, Schupf N, Verweij N, Hutri-Kähönen N, Mononen N, Bansal N, Devuyst O, Melander O, Raitakari OT, Polasek O, Manunta P, Gasparini P, Mishra PP, Sulem P, Magnusson PK, Elliott
P, Ridker PM, Hamet P, Svensson PO, Joshi PK, Kovacs P, Pramstaller PP, Rossing P, Vollenweider P,
van der Harst P, Dorajoo R, Sim RZ, Burkhardt R, Tao R, Noordam R, Mägi R, Schmidt R, de Mutsert R,
Rueedi R, van Dam RM, Carroll RJ, Gansevoort RT, Loos RJ, Felicita SC, Sedaghat S, Padmanabhan
S, Freitag-Wolf S, Pendergrass SA, Graham SE, Gordon SD, Hwang S, Kerr SM, Vaccargiu S, Patil SB,
Hallan S, Bakker SJ, Lim S, Lucae S, Vogelezang S, Bergmann S, Corre T, Ahluwalia TS, Lehtimäki T,
Boutin TS, Meitinger T, Wong T, Bergler T, Rabelink TJ, Esko T, Haller T, Thorsteinsdottir U, Völker U,
Foo VH, Salomaa V, Vitart V, Giedraitis V, Gudnason V, Jaddoe VW, Huang W, Zhang W, Wei WB, Kiess
W, März W, Koenig W, Lieb W, Gao X, Sim X, Wang YX, Friedlander Y, Tham Y, Kamatani Y, Okada Y,
Milaneschi Y, Yu Z, Stark KJ, Stefansson K, Böger CA, Hung AM, Kronenberg F, Köttgen A, Pattaro
C, Heid IM. Differential and shared genetic effects on kidney function between diabetic and nondiabetic individuals. Commun Biol 5, 580 (2022)

263 Udagawa C, Nakano MH, Yoshida T, Ohe Y, Kato K, Mushiroda T, Zembutsu H. Association between
genetic variants and the risk of nivolumab-induced immune-related adverse events. Pharmacogenomics 23, 887-901 (2022)
264 Umehara T, Arita H, Miya F, Achiha T, Shofuda T, Yoshioka E, Kanematsu D, Nakagawa T, Kinoshita M,
Kagawa N, Fujimoto Y, Hashimoto N, Kiyokawa H, Morii E, Tsunoda T, Kanemura Y, Kishima H. Revisiting the definition of glioma recurrence based on a phylogenetic investigation of primary and reemerging tumor samples: a case report. Brain Tumor Pathol 39, 218-224 (2022)
265 Usui Y, Iwasaki Y, Matsuo K, Endo M, Kamatani Y, Hirata M, Sugano K, Yoshida T, Matsuda K, Murakami
Y, Maeda Y, Nakagawa H, Momozawa Y. Association between germline pathogenic variants in cancerpredisposing genes and lymphoma risk. Cancer Sci 113, 3972-3979 (2022)
266 Valentini P, Pierattini B, Zacco E, Mangoni D, Espinoza S, Webster NA, Andrews B, Carninci P, Tartaglia
G, Pandolfini L, Gustincich S. Towards SINEUP-based therapeutics: Design of an in vitro synthesized
SINEUP RNA. Mol Ther Nucleic Acids 27, 1092-1102 (2022)
267 Vincent SA, Kim J, Pérez-Salamó I, To TK, Torii C, Ishida J, Tanaka M, Endo TA, Bhat P, Devlin PF, Seki M,
Devoto A. Jasmonates and Histone deacetylase 6 activate Arabidopsis genome-wide histone acetylation and methylation during the early acute stress response. BMC Biol 20, 83 (2022)
268 Wagner M, Koyasu S. Cancer immunosurveillance by ILC2s. Trends Cancer 8, 792-794 (2022)
269 Walker S, Abugessaisa I, Kasukawa T. Single Cell Databases: An Emerging and Essential Tool. Practical
Guide to Life Science Databases (2022)
270 Wang QS, Edahiro R, Namkoong H, Hasegawa T, Shirai Y, Sonehara K, Tanaka H, Lee H, Saiki R,
Hyugaji T, Shimizu E, Katayama K, Kanai M, Naito T, Sasa N, Yamamoto K, Kato Y, Morita T, Takahashi K, Harada N, Naito T, Hiki M, Matsushita Y, Takagi H, Ichikawa M, Nakamura A, Harada S,
Sandhu Y, Kabata H, Masaki K, Kamata H, Ikemura S, Chubachi S, Okamori S, Terai H, Morita A,
Asakura T, Sasaki J, Morisaki H, Uwamino Y, Nanki K, Uchida S, Uno S, Nishimura T, Ishiguro T, Isono
T, Shibata S, Matsui Y, Hosoda C, Takano K, Nishida T, Kobayashi Y, Takaku Y, Takayanagi N, Ueda S,
Tada A, Miyawaki M, Yamamoto M, Yoshida E, Hayashi R, Nagasaka T, Arai S, Kaneko Y, Sasaki K,
Tagaya E, Kawana M, Arimura K, Takahashi K, Anzai T, Ito S, Endo A, Uchimura Y, Miyazaki Y, Honda
T, Tateishi T, Tohda S, Ichimura N, Sonobe K, Sassa CT, Nakajima J, Nakano Y, Nakajima Y, Anan R,
Arai R, Kurihara Y, Harada Y, Nishio K, Ueda T, Azuma M, Saito R, Sado T, Miyazaki Y, Sato R, Haruta Y,
Nagasaki T, Yasui Y, Hasegawa Y, Mutoh Y, Kimura T, Sato T, Takei R, Hagimoto S, Noguchi Y, Yamano
Y, Sasano H, Ota S, Nakamori Y, Yoshiya K, Saito F, Yoshihara T, Wada D, Iwamura H, Kanayama S,
Maruyama S, Yoshiyama T, Ohta K, Kokuto H, Ogata H, Tanaka Y, Arakawa K, Shimoda M, Osawa
T, Tateno H, Hase I, Yoshida S, Suzuki S, Kawada M, Horinouchi H, Saito F, Mitamura K, Hagihara
M, Ochi J, Uchida T, Baba R, Arai D, Ogura T, Takahashi H, Hagiwara S, Nagao G, Konishi S, Nakachi

275 Xue J, Ikegawa S, Guo L. SLC4A2, another gene involved in acid-base balancing machinery of osteoclasts, causes osteopetrosis. Bone 167, 116603 (2022)

95

Data and Statistics

261 Uchiyama J, Roy R, Wang DO, Morikawa K, Kawahara Y, Iwasaki M, Yoshino C, Mishima Y, Ishihama
Y, Imami K. pSNAP: Proteome-wide analysis of elongating nascent polypeptide chains. iScience 25,104516 (2022)

259 Tuganbaev T, Yoshida K, Honda K. The effects of oral microbiota on health. Science 376, 934-936 (2022)

Events260 Uchino H, Tsugawa H, Takahashi H, Arita M. Computational mass spectrometry accelerates C = C
position-resolved untargeted lipidomics using oxygen attachment dissociation. Commun Chem 5,
162 (2022)

272 Watase M, Masaki K, Chubachi S, Namkoong H, Tanaka H, Lee H, Fukushima T, Otake S, Nakagawara K,
Kusumoto T, Asakura T, Kamata H, Ishii M, Hasegawa N, Oyamada Y, Harada N, Ueda T, Ueda S, Ishiguro T,
Arimura K, Saito F, Yoshiyama T, Nakano Y, Mutoh Y, Suzuki Y, Edahiro R, Sano H, Sato Y, Okada Y, Koike
R, Kitagawa Y, Tokunaga K, Kimura A, Imoto S, Miyano S, Ogawa S, Kanai T, Fukunaga K, Force JC.
Impact of accumulative smoking exposure and chronic obstructive pulmonary disease on COVID-19
outcomes: Report based on findings from the Japan COVID-19 Task Force. Int J Infect Dis 128, 121127 (2022)

Projects

258 Tsuo K, Zhou W, Wang Y, Kanai M, Namba S, Gupta R, Majara L, Nkambule LL, Morisaki T, Okada Y,
Neale BM, Initiative GB, Daly MJ, Martin AR. Multi-ancestry meta-analysis of asthma identifies novelassociations and highlights the value of increased power and diversity. Cell Genom 2, 100212 (2022)

Lab Activities

255 Tsuchida Y, Shoda H, Nakano M, Ota M, Okamura T, Yamamoto K, Kurano M, Yatomi Y, Fujio K, Sawada T.
Autotaxin is a potential link between genetic risk factors and immunological disturbances of plasmacytoid dendritic cells in systematic lupus erythematosus. Lupus 31, 1578-1585 (2022)

I, Murakami K, Yamada M, Sugiura H, Sano H, Matsumoto S, Kimura N, Ono Y, Baba H, Suzuki Y,
Nakayama S, Masuzawa K, Namba S, Shiroyama T, Noda Y, Niitsu T, Adachi Y, Enomoto T, Amiya S,
Hara R, Yamaguchi Y, Murakami T, Kuge T, Matsumoto K, Yamamoto Y, Yamamoto M, Yoneda M, Tomono K, Kato K, Hirata H, Takeda Y, Koh H, Manabe T, Funatsu Y, Ito F, Fukui T, Shinozuka K, Kohashi
S, Miyazaki M, Shoko T, Kojima M, Adachi T, Ishikawa M, Takahashi K, Inoue T, Hirano T, Kobayashi
K, Takaoka H, Watanabe K, Miyazawa N, Kimura Y, Sado R, Sugimoto H, Kamiya A, Kuwahara N,
Fujiwara A, Matsunaga T, Sato Y, Okada T, Hirai Y, Kawashima H, Narita A, Niwa K, Sekikawa Y,
Nishi K, Nishitsuji M, Tani M, Suzuki J, Nakatsumi H, Ogura T, Kitamura H, Hagiwara E, Murohashi
K, Okabayashi H, Mochimaru T, Nukaga S, Satomi R, Oyamada Y, Mori N, Baba T, Fukui Y, Odate M,
Mashimo S, Makino Y, Yagi K, Hashiguchi M, Kagyo J, Shiomi T, Fuke S, Saito H, Tsuchida T, Fujitani S,
Takita M, Morikawa D, Yoshida T, Izumo T, Inomata M, Kuse N, Awano N, Tone M, Ito A, Nakamura Y,
Hoshino K, Maruyama J, Ishikura H, Takata T, Odani T, Amishima M, Hattori T, Shichinohe Y, Kagaya
T, Kita T, Ohta K, Sakagami S, Koshida K, Hayashi K, Shimizu T, Kozu Y, Hiranuma H, Gon Y, Izumi N,
Nagata K, Ueda K, Taki R, Hanada S, Kawamura K, Ichikado K, Nishiyama K, Muranaka H, Nakamura
K, Hashimoto N, Wakahara K, Koji S, Omote N, Ando A, Kodama N, Kaneyama Y, Maeda S, Kuraki T,
Matsumoto T, Yokote K, Nakada T, Abe R, Oshima T, Shimada T, Harada M, Takahashi T, Ono H, Sakurai T, Shibusawa T, Kimizuka Y, Kawana A, Sano T, Watanabe C, Suematsu R, Sageshima H, Yoshifuji
A, Ito K, Takahashi S, Ishioka K, Nakamura M, Masuda M, Wakabayashi A, Watanabe H, Ueda S,
Nishikawa M, Chihara Y, Takeuchi M, Onoi K, Shinozuka J, Sueyoshi A, Nagasaki Y, Okamoto M, Ishihara S, Shimo M, Tokunaga Y, Kusaka Y, Ohba T, Isogai S, Ogawa A, Inoue T, Fukuyama S, Eriguchi
Y, Yonekawa A, Kan-o K, Matsumoto K, Kanaoka K, Ihara S, Komuta K, Inoue Y, Chiba S, Yamagata
K, Hiramatsu Y, Kai H, Asano K, Oguma T, Ito Y, Hashimoto S, Yamasaki M, Kasamatsu Y, Komase Y,
Hida N, Tsuburai T, Oyama B, Takada M, Kanda H, Kitagawa Y, Fukuta T, Miyake T, Yoshida S, Ogura
S, Abe S, Kono Y, Togashi Y, Takoi H, Kikuchi R, Ogawa S, Ogata T, Ishihara S, Kanehiro A, Ozaki S,
Fuchimoto Y, Wada S, Fujimoto N, Nishiyama K, Terashima M, Beppu S, Yoshida K, Narumoto O,
Nagai H, Ooshima N, Motegi M, Umeda A, Miyagawa K, Shimada H, Endo M, Ohira Y, Watanabe M,
Inoue S, Igarashi A, Sato M, Sagara H, Tanaka A, Ohta S, Kimura T, Shibata Y, Tanino Y, Nikaido T,
Minemura H, Sato Y, Yamada Y, Hashino T, Shinoki M, Iwagoe H, Takahashi H, Fujii K, Kishi H, Kanai
M, Imamura T, Yamashita T, Yatomi M, Maeno T, Hayashi S, Takahashi M, Kuramochi M, Kamimaki
I, Tominaga Y, Ishii T, Utsugi M, Ono A, Tanaka T, Kashiwada T, Fujita K, Saito Y, Seike M, Watanabe
H, Matsuse H, Kodaka N, Nakano C, Oshio T, Hirouchi T, Makino S, Egi M, Omae Y, Nannya Y, Ueno
T, Takano T, Katayama K, Ai M, Kumanogoh A, Sato T, Hasegawa N, Tokunaga K, Ishii M, Koike R,
Kitagawa Y, Kimura A, Imoto S, Miyano S, Ogawa S, Kanai T, Fukunaga K, Okada Y. The whole bloodtranscriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task
Force. Nat Commun 13, 4830 (2022)

Research Highlights

Nuechterlein KH, O’Brien NL, O’Neill FA, Oh S, Olincy A, Ota VK, Pantelis C, Papadimitriou GN, Parellada
M, Paunio T, Pellegrino R, Periyasamy S, Perkins DO, Pfuhlmann B, Pietiläinen O, Pimm J, Porteous D,
Powell J, Quattrone D, Quested D, Radant AD, Rampino A, Rapaport MH, Rautanen A, Reichenberg A,
Roe C, Roffman JL, Roth J, Rothermundt M, Rutten BP, Saker-Delye S, Salomaa V, Sanjuan J, Santoro
ML, Savitz A, Schall U, Scott RJ, Seidman LJ, Sharp SI, Shi J, Siever LJ, Sigurdsson E, Sim K, Skarabis N,
Slominsky P, So H, Sobell JL, Söderman E, Stain HJ, Steen NE, Steixner-Kumar AA, Stögmann E, Stone
WS, Straub RE, Streit F, Strengman E, Stroup TS, Subramaniam M, Sugar CA, Suvisaari J, Svrakic DM,
Swerdlow NR, Szatkiewicz JP, Ta TM, Takahashi A, Terao C, Thibaut F, Toncheva D, Tooney PA, Torretta S,
Tosato S, Tura GB, Turetsky BI, Üçok A, Vaaler A, van Amelsvoort T, van Winkel R, Veijola J, Waddington
J, Walter H, Waterreus A, Webb BT, Weiser M, Williams NM, Witt SH, Wormley BK, Wu JQ, Xu Z, Yolken
R, Zai CC, Zhou W, Zhu F, Zimprich F, Atbaşoğlu EC, Ayub M, Benner C, Bertolino A, Black DW, Bray NJ,
Breen G, Buccola NG, Byerley WF, Chen WJ, Cloninger CR, Crespo-Facorro B, Donohoe G, Freedman R,
Galletly C, Gandal MJ, Gennarelli M, Hougaard DM, Hwu H, Jablensky AV, McCarroll SA, Moran JL, MorsO, Mortensen PB, Müller-Myhsok B, Neil AL, Nordentoft M, Pato MT, Petryshen TL, Pirinen M, Pulver
AE, Schulze TG, Silverman JM, Smoller JW, Stahl EA, Tsuang DW, Vilella E, Wang S, Xu S, Adolfsson R,
Arango C, Baune BT, Belangero SI, Børglum AD, Braff D, Bramon E, Buxbaum JD, Campion D, Cervilla
JA, Cichon S, Collier DA, Corvin A, Curtis D, Forti MD, Domenici E, Ehrenreich H, Escott-Price V, Esko
T, Fanous AH, Gareeva A, Gawlik M, Gejman PV, Gill M, Glatt SJ, Golimbet V, Hong KS, Hultman CM,
Hyman SE, Iwata N, Jönsson EG, Kahn RS, Kennedy JL, Khusnutdinova E, Kirov G, Knowles JA, Krebs
M, Laurent-Levinson C, Lee J, Lencz T, Levinson DF, Li QS, Liu J, Malhotra AK, Malhotra D, McIntosh A,
McQuillin A, Menezes PR, Morgan VA, Morris DW, Mowry BJ, Murray RM, Nimgaonkar V, Nöthen MM,
Ophoff RA, Paciga SA, Palotie A, Pato CN, Qin S, Rietschel M, Riley BP, Rivera M, Rujescu D, Saka MC,
Sanders AR, Schwab SG, Serretti A, Sham PC, Shi Y, St Clair D, Stefánsson H, Stefansson K, Tsuang MT,
van Os J, Vawter MP, Weinberger DR, Werge T, Wildenauer DB, Yu X, Yue W, Holmans PA, Pocklington AJ,
Roussos P, Vassos E, Verhage M, Visscher PM, Yang J, Posthuma D, Andreassen OA, Kendler KS, Owen
MJ, Wray NR, Daly MJ, Huang H, Neale BM, Sullivan PF, Ripke S, Walters JT, O’Donovan MC. Mapping
genomic loci implicates genes and synaptic biology in schizophrenia. Nature 604, 502-508 (2022)

276 Yaku A, Ishikawa Y, Iwasaki T, Hiwa R, Matsuo K, Saji H, Yurugi K, Miura Y, Furu M, Ito H, Fujii T, Maekawa T, Hashimoto M, Ohmura K, Mimori T, Terao C. Genetic architecture underlying IgG-RF production is
distinct from that of IgM-RF. Rheumatology (Oxford) 62, 2015-2020 (2022)
277 Yakushiji-Kaminatsui N, Kondo T, Ohinata Y, Takano J, Koseki H. Genetic, Genomic, and Imaging Approaches to Dissect the Role of Polycomb Group Epigenetic Regulators in Mice. Methods Mol Biol
2529, 207-228 (2022)
278 Yamaguchi K, Ishigaki K, Suzuki A, Tsuchida Y, Tsuchiya H, Sumitomo S, Nagafuchi Y, Miya F, Tsunoda
T, Shoda H, Fujio K, Yamamoto K, Kochi Y. Splicing QTL analysis focusing on coding sequences reveals
mechanisms for disease susceptibility loci. Nat Commun 13, 4659 (2022)
279 Yamaguchi Y, Kato Y, Edahiro R, Søndergaard JN, Murakami T, Amiya S, Nameki S, Yoshimine Y, Morita
T, Takeshima Y, Sakakibara S, Naito Y, Motooka D, Liu Y, Shirai Y, Okita Y, Fujimoto J, Hirata H, Takeda Y,
Wing JB, Okuzaki D, Okada Y, Kumanogoh A. Consecutive BNT162b2 mRNA vaccination induces shortterm epigenetic memory in innate immune cells. JCI Insight 7, e163347 (2022)
280 Yamamoto K, Sonehara K, Namba S, Konuma T, Masuko H, Miyawaki S, Kamatani Y, Hizawa N, Ozono
K, Yengo L, Okada Y. Genetic footprints of assortative mating in the Japanese population. Nat Hum
Behav 1-9 (2022)
281 Yamashita M, Taniuchi I. Fine-tuning Notch1 by the stage-specific enhancer. Nat Immunol 23, 15091511 (2022)
282 Yamazaki K, Miyauchi E, Kato T, Sato K, Suda W, Tsuzuno T, Yamada-Hara M, Sasaki N, Ohno H, Yamazaki K. Dysbiotic human oral microbiota alters systemic metabolism via modulation of gut microbiota ingerm-free mice. J Oral Microbiol 14, 2110194 (2022)
283 Yan M, Komatsu N, Muro R, Huynh NC, Tomofuji Y, Okada Y, Suzuki HI, Takaba H, Kitazawa R, Kitazawa
S, Pluemsakunthai W, Mitsui Y, Satoh T, Okamura T, Nitta T, Im S, Kim CJ, Kollias G, Tanaka S, Okamoto
K, Tsukasaki M, Takayanagi H. ETS1 governs pathological tissue-remodeling programs in diseaseassociated fibroblasts. Nat Immunol 23, 1330-1341 (2022)
284 Yang S, Ha K, Song W, Fujita M, Kübler K, Polak, Hiyama E, Nakagawa H, Kim H, Lee H. COOBoostR: anextreme gradient boosting-based tool for robust tissue or cell-of-origin prediction of tumors. Life 13,
71 (2022)
285 Yengo L, Vedantam S, Marouli E, Sidorenko J, Bartell E, Sakaue S, Graff M, Eliasen AU, Jiang Y, Raghavan S, Miao J, Arias JD, Graham SE, Mukamel RE, Spracklen CN, Yin X, Chen S, Ferreira T, Highland HH,
Ji Y, Karaderi T, Lin K, Lüll K, Malden DE, Medina-Gomez C, Machado M, Moore A, Rüeger S, Sim X,
Vrieze S, Ahluwalia TS, Akiyama M, Allison MA, Alvarez M, Andersen MK, Ani A, Appadurai V, Arbeeva
L, Bhaskar S, Bielak LF, Bollepalli S, Bonnycastle LL, Bork-Jensen J, Bradfield JP, Bradford Y, Braund PS,
Brody JA, Burgdorf KS, Cade BE, Cai H, Cai Q, Campbell A, Cañadas-Garre M, Catamo E, Chai J, Chai X,
Chang L, Chang Y, Chen C, Chesi A, Choi SH, Chung R, Cocca M, Concas MP, Couture C, Cuellar-Partida
G, Danning R, Daw EW, Degenhard F, Delgado GE, Delitala A, Demirkan A, Deng X, Devineni P, Dietl
A, Dimitriou M, Dimitrov L, Dorajoo R, Ekici AB, Engmann JE, Fairhurst-Hunter Z, Farmaki A, Faul JD,
Fernandez-Lopez J, Forer L, Francescatto M, Freitag-Wolf S, Fuchsberger C, Galesloot TE, Gao Y, Gao
Z, Geller F, Giannakopoulou O, Giulianini F, Gjesing AP, Goel A, Gordon SD, Gorski M, Grove J, Guo X,
Gustafsson S, Haessler J, Hansen TF, Havulinna AS, Haworth SJ, He J, Heard-Costa N, Hebbar P, Hindy
G, Ho YA, Hofer E, Holliday E, Horn K, Hornsby WE, Hottenga J, Huang H, Huang J, Huerta-Chagoya
A, Huffman JE, Hung Y, Huo S, Hwang MY, Iha H, Ikeda DD, Isono M, Jackson AU, Jäger S, Jansen IE,
Johansson I, Jonas JB, Jonsson A, Jørgensen T, Kalafati I, Kanai M, Kanoni S, Kårhus LL, Kasturiratne
A, Katsuya T, Kawaguchi T, Kember RL, Kentistou KA, Kim H, Kim YJ, Kleber ME, Knol MJ, Kurbasic A,
Lauzon M, Le P, Lea R, Lee J, Leonard HL, Li SA, Li X, Li X, Liang J, Lin H, Lin S, Liu J, Liu X, Lo KS, Long J,
Lores-Motta L, Luan J, Lyssenko V, Lyytikäinen L, Mahajan A, Mamakou V, Mangino M, Manichaikul A,
Marten J, Mattheisen M, Mavarani L, McDaid AF, Meidtner K, Melendez TL, Mercader JM, Milaneschi
Y, Miller JE, Millwood IY, Mishra PP, Mitchell RE, Møllehave LT, Morgan A, Mucha S, Munz M, Nakatochi
M, Nelson CP, Nethander M, Nho CW, Nielsen AA, Nolte IM, Nongmaithem SS, Noordam R, Ntalla I,
Nutile T, Pandit A, Christofidou P, Pärna K, Pauper M, Petersen ER, Petersen LV, Pitkänen N, Polašek O,
Poveda A, Preuss MH, Pyarajan S, Raffield LM, Rakugi H, Ramirez J, Rasheed A, Raven D, Rayner NW,
Riveros C, Rohde R, Ruggiero D, Ruotsalainen SE, Ryan KA, Sabater-Lleal M, Saxena R, Scholz M, Sendamarai A, Shen B, Shi J, Shin JH, Sidore C, Sitlani CM, Slieker RC, Smit RA, Smith AV, Smith JA, Smyth
LJ, Southam L, Steinthorsdottir V, Sun L, Takeuchi F, Tallapragada DS, Taylor KD, Tayo BO, Tcheandjieu
C, Terzikhan N, Tesolin P, Teumer A, Theusch E, Thompson DJ, Thorleifsson G, Timmers PR, Trompet
S, Turman C, Vaccargiu S, van der Laan SW, van der Most PJ, van Klinken JB, van Setten J, Verma SS,
Verweij N, Veturi Y, Wang CA, Wang C, Wang L, Wang Z, Warren HR, Bin Wei W, Wickremasinghe AR,
Wielscher M, Wiggins KL, Winsvold BS, Wong A, Wu Y, Wuttke M, Xia R, Xie T, Yamamoto K, Yang J,
Yao J, Young H, Yousri NA, Yu L, Zeng L, Zhang W, Zhang X, Zhao J, Zhao W, Zhou W, Zimmermann ME,
Zoledziewska M, Adair LS, Adams HH, Aguilar-Salinas CA, Al-Mulla F, Arnett DK, Asselbergs FW, Åsvold
BO, Attia J, Banas B, Bandinelli S, Bennett DA, Bergler T, Bharadwaj D, Biino G, Bisgaard H, Boerwinkle
E, Böger CA, Bønnelykke K, Boomsma DI, Børglum AD, Borja JB, Bouchard C, Bowden DW, Brandslund
I, Brumpton B, Buring JE, Caulfield MJ, Chambers JC, Chandak GR, Chanock SJ, Chaturvedi N, Chen YI,
Chen Z, Cheng C, Christophersen IE, Ciullo M, Cole JW, Collins FS, Cooper RS, Cruz M, Cucca F, Cupples
LA, Cutler MJ, Damrauer SM, Dantoft TM, de Borst GJ, de Groot LC, De Jager PL, de Kleijn DP, Janaka de
Silva H, Dedoussis GV, den Hollander AI, Du S, Easton DF, Elders PJ, Eliassen AH, Ellinor PT, Elmståhl S,
Erdmann J, Evans MK, Fatkin D, Feenstra B, Feitosa MF, Ferrucci L, Ford I, Fornage M, Franke A, Franks
PW, Freedman BI, Gasparini P, Gieger C, Girotto G, Goddard ME, Golightly YM, Gonzalez-Villalpando
C, Gordon-Larsen P, Grallert H, Grant SF, Grarup N, Griffiths L, Gudnason V, Haiman C, Hakonarson H,
Hansen T, Hartman CA, Hattersley AT, Hayward C, Heckbert SR, Heng C, Hengstenberg C, Hewitt AW,
Hishigaki H, Hoyng CB, Huang PL, Huang W, Hunt SC, Hveem K, Hyppönen E, Iacono WG, Ichihara S,
Ikram MA, Isasi CR, Jackson RD, Jarvelin M, Jin Z, Jöckel K, Joshi PK, Jousilahti P, Jukema JW, Kähönen
M, Kamatani Y, Kang KD, Kaprio J, Kardia SL, Karpe F, Kato N, Kee F, Kessler T, Khera AV, Khor CC,
Kiemeney LA, Kim B, Kim EK, Kim H, Kirchhof P, Kivimaki M, Koh W, Koistinen HA, Kolovou GD, Kooner
JS, Kooperberg C, Köttgen A, Kovacs P, Kraaijeveld A, Kraft P, Krauss RM, Kumari M, Kutalik Z, Laakso
M, Lange LA, Langenberg C, Launer LJ, Le Marchand L, Lee H, Lee NR, Lehtimäki T, Li H, Li L, Lieb W,
Lin X, Lind L, Linneberg A, Liu C, Liu J, Loeffler M, London B, Lubitz SA, Lye SJ, Mackey DA, Mägi R,
Magnusson PK, Marcus GM, Vidal PM, Martin NG, März W, Matsuda F, McGarrah RW, McGue M, McKnight AJ, Medland SE, Mellström D, Metspalu A, Mitchell BD, Mitchell P, Mook-Kanamori DO, Morris

96

AD, Mucci LA, Munroe PB, Nalls MA, Nazarian S, Nelson AE, Neville MJ, Newton-Cheh C, Nielsen CS,
Nöthen MM, Ohlsson C, Oldehinkel AJ, Orozco L, Pahkala K, Pajukanta P, Palmer CN, Parra EJ, Pattaro C,
Pedersen O, Pennell CE, Penninx BW, Perusse L, Peters A, Peyser PA, Porteous DJ, Posthuma D, PowerC, Pramstaller PP, Province MA, Qi Q, Qu J, Rader DJ, Raitakari OT, Ralhan S, Rallidis LS, Rao DC, Redline
S, Reilly DF, Reiner AP, Rhee SY, Ridker PM, Rienstra M, Ripatti S, Ritchie MD, Roden DM, Rosendaal FR,
Rotter JI, Rudan I, Rutters F, Sabanayagam C, Saleheen D, Salomaa V, Samani NJ, Sanghera DK, Sattar
N, Schmidt B, Schmidt H, Schmidt R, Schulze MB, Schunkert H, Scott LJ, Scott RJ, Sever P, Shiroma EJ,
Shoemaker MB, Shu X, Simonsick EM, Sims M, Singh JR, Singleton AB, Sinner MF, Smith JG, Snieder H,
Spector TD, Stampfer MJ, Stark KJ, Strachan DP, ’t Hart LM, Tabara Y, Tang H, Tardif J, Thanaraj TA, Timpson NJ, Tönjes A, Tremblay A, Tuomi T, Tuomilehto J, Tusié-Luna M, Uitterlinden AG, van Dam RM, vander Harst P, Van der Velde N, van Duijn CM, van Schoor NM, Vitart V, Völker U, Vollenweider P, Völzke H,
Wacher-Rodarte NH, Walker M, Wang YX, Wareham NJ, Watanabe RM, Watkins H, Weir DR, Werge TM,
Widen E, Wilkens LR, Willemsen G, Willett WC, Wilson JF, Wong T, Woo J, Wright AF, Wu J, Xu H, Yajnik
CS, Yokota M, Yuan J, Zeggini E, Zemel BS, Zheng W, Zhu X, Zmuda JM, Zonderman AB, Zwart J, Chasman DI, Cho YS, Heid IM, McCarthy MI, Ng MC, O’Donnell CJ, Rivadeneira F, Thorsteinsdottir U, Sun YV,
Tai ES, Boehnke M, Deloukas P, Justice AE, Lindgren CM, Loos RJ, Mohlke KL, North KE, Stefansson K,
Walters RG, Winkler TW, Young KL, Loh P, Yang J, Esko T, Assimes TL, Auton A, Abecasis GR, Willer CJ,
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map of common genetic variants associated with human height. Nature 610, 704-712 (2022)
286 Yin X, Kim K, Suetsugu H, Bang S, Wen L, Koido M, Ha E, Liu L, Sakamoto Y, Jo S, Leng R, Otomo N,
Kwon Y, Sheng Y, Sugano N, Hwang MY, Li W, Mukai M, Yoon K, Cai M, Ishigaki K, Chung WT, Huang H,
Takahashi D, Lee S, Wang M, Karino K, Shim S, Zheng X, Miyamura T, Kang YM, Ye D, Nakamura J, Suh
C, Tang Y, Motomura G, Park Y, Ding H, Kuroda T, Choe J, Li C, Niiro H, Park Y, Shen C, Miyamoto T, Ahn
G, Fei W, Takeuchi T, Shin J, Li K, Kawaguchi Y, Lee Y, Wang Y, Amano K, Park DJ, Yang W, Tada Y, Lau
YL, Yamaji K, Zhu Z, Shimizu M, Atsumi T, Suzuki A, Sumida T, Okada Y, Matsuda K, Matsuo K, Kochi Y,
Yamamoto K, Ohmura K, Kim T, Yang S, Yamamoto T, Kim B, Shen N, Ikegawa S, Lee H, Zhang X, Terao
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Budget, Personnel and Patents
Personnel FY2022

IMS Budget FY2022

JPY Million

Government funding for operations

2,953

External competitive funding

2,111

Total

5,064

There were 13 patents registered from January to December 2022.

2022

Total
13

International
patents
9

Domestic patents(Japan)4Category

Number

Deputy Director

3

Senior Advisor

1Team Leader

40

Coordinator3

Deputy Team Leader

8

Senior Scientist

15

Senior Research Scientist

4

Research Scientist

53

Postdoctoral Researcher

21

Special Postdoctoral Researcher

8

Research Fellow

8

Research Associate

7

Senior Technical Scientist

4Technical Scientist

13

Expert Technician

16

Technical Staff I

64

Technical Staff II

45

International Program Associate

3

Junior Research Associate

27

Student Trainee

158
5

Research Administrative Support Staff

5

Assistant

24

Part-time Staff

49

Senior Visiting Scientist

31

Visiting Scientist

216

Visiting Technicain

13

Visiting Researcher

9

Temporary Staffing

19

Research Consultant

5Consultant

3

Special Temporary Employee

3

Total

Data and Statistics

Research Administrator

Events1

Projects

Director

Lab Activities

Patents
Patents

Research Highlights

IMS Budget FY2022

884

97

Original Photos of the Cover and Front Pages

Cover

Front page of Part 1

A metabolic regulatory network generated by transomics2cytoscape,our software developed for automatic visualization of molecular networks that spans across multiple omic layers.

Single molecule fluorescent in-situ hybridization (smFISH) of MEG3long noncoding RNA in primary human fibroblasts, showing exclusive
localization in the nucleus. MEG3 (red); DAPI (blue).

Credit to Mr. Kozo Nishida and Dr. Katsuyuki Yugi

Credit to Dr. Youtaro Shibayama

Laboratory for Integrated Cellular Systems

Laboratory for Advanced Genomics Circuit

Front page of Part 2

Front page of Part 3

Vascular structure of mouse ovary. Endothelial cells of capillary vessels(green) and endothelial cells of large blood vessels (red).
Credit to Drs. Chisayo Kozuka & Masatsugu Ema

Xenopus laevis (albino) blastula microinjected with mRNA encoding
EmGFP localized to mitochondria. Mitochondria of mRNA injected area
are labeled with EmGFP as detected under fluorescent microscope.

Laboratory for Epigenome Inheritance & Shiga University of Medical Science

Credit to Dr. Yuuri Yasuoka

Front page of Part 4

Front page of Part 5

Serial imaging of a mouse blastocyst immunostained for Cdx2
(green), Nanog (red), Sox17 (yellow), and DAPI (blue).

A cross-section of a Xenopus tropicalis tadpole immunostained with
5D4 antibody followed by hematoxylin staining. 5D4 antibody detects
highly sulfated keratan sulfate (brown) which is enriched inside otic
vesicles (top-right and bottom-left) and outside notochord (bottomright), but not in brain (top-left).

Credit to Dr. Chisayo Kozuka

Laboratory for Epigenome InheritanceLaboratory for Comprehensive Genomic Analysis

Credit to Dr. Yuuri Yasuoka

98

Laboratory for Comprehensive Genomic Analysis

Access to RIKEN Yokohama Campus

Local Access
By BusTake the #08 bus from Platform 8 at the East Exit of
Tsurumi Station (also accessible from the West Exitof Keikyu Tsurumi Station) and get off at the RIKEN
Shidai Daigakuin Mae bus stop. The institute is acrossthe street. All buses from this platform are bound for
Fureyu.
Buses depart Tsurumi every 5–15 minutes. It takes
about 15 minutes to arrive at RIKEN Yokohama. The fareis 220 yen.
By Train

A 15-minute walk from JR Tsurumi-Ono Station (JRTsurumi Line), which is directly accessible by transferfrom JR Tsurumi Station.
Trains run about every 10 minutes during morning andevening rush hour, but less frequently at other times.
By Taxi

Use the taxi stand at the East Exit of JR Tsurumi Stationor the West Exit of Keikyu Tsurumi Station. The trip takes
about 10 minutes and costs around 1,200 yen.

From the Airport
From Haneda Airport

From Narita Airport

Route 1

From Narita Airport Station take the JR Sobu Line (Rapid
Express), Airport Limousine Bus or JR Narita Express* to
JR Shinagawa Station. (JR Sobu Line is the most inexpensive option and takes about 1 hour and 15 minutes).
From JR Shinagawa Station take the JR Keihin Tohoku
Line (Yokohama direction) to JR Tsurumi Station (18minutes). Next, follow the Local Access directions above
to get to RIKEN Yokohama.

Take the Keikyu Railways Airport Express* (blue kanjisign) for Yokohama and get off at Keikyu Tsurumi Station (27–29 minutes). Airport Express trains run every
10-15 minutes between 9:30 a.m. and 9:30 p.m. Next,
follow the Local Access directions above to get to RIKEN
Yokohama.
Route 2

Take any train marked with a green (express), red or
dark grey kanji sign to Keikyu Kamata Station. Transfer
to the Keikyu Main Line and take a local train* toward
Yokohama until Keikyu Tsurumi Station* (12 minutes).
*Only Airport Express (blue kanji sign) and local trains(dark grey kanji sign) stop at Keikyu Tsurumi Station.
Note that Keikyu Tsurumi Station and JR Tsurumi Station
are two different railway stations and are separated bya bus rotary (the stations are about 150 meters apart).

* A reserved seat express that requires payment of asurcharge in addition to train fare.

99

RIKEN Center for
Integrative Medical Sciences
http://www.ims.riken.jp/english/
RIKEN Yokohama Campus
1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City,
Kanagawa, 230-0045, Japan
Tel : 045-503-9121
Fax : 045-503-9113
Email : ims-web@riken.jp

RIKEN IMS
Annual Report 2022

RIKEN 2023-032