http://www.ims.riken.jp/english/
RIKEN Yokohama Campus
1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City,
Kanagawa, 230-0045, Japan
Tel : 045-503-9111
Fax : 045-503-9113
Email : yokohama@riken.jp

RIKEN IMS
Annual Report 2017

RIKEN IMS Annual Report 2017 RIKEN Center for Integrative Medical Sciences

RIKEN Center for
Integrative Medical Sciences

RIKEN IMS
Annual Report 2017
RIKEN Center for Integrative Medical Sciences

RIKEN 2017-059

RIKEN Center for Integrative Medical Sciences
Organization Chart

Access to RIKEN Yokohama Campus

Local Access

RIKEN President
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.

Hiroshi Matsumoto

Director

Buses depart Tsurumi every 5–15 minutes. It takes
about 15 minutes to arrive at RIKEN Yokohama. The
fare is 220 yen.

Tadashi Yamamoto

Integrative
Medical Sciences
Planning Office

By Train
A 15-minute walk from JR Tsurumi-Ono Station (JRTsurumi Line), which is directly accessible by transferfrom JR Tsurumi Station.

Senior Advisor

rains run about every 10 minutes during morning andevening rush hour, but less frequently at other times.

Masaru Taniguchi
Shizuo Akira

Searchable train timetables in English are available at
http://www.hyperdia.com/en/

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.

RIKEN Center for
Integrative
Medical Sciences
Advisory Council
Deputy Director
Michiaki Kubo
Haruhiko Koseki
Kazuhiko Yamamoto

Max Cooper (chair)Mark Lathrop (vice chair)
Hiroyuki Aburatani
Rudi Balling
Riccardo Dalla-Favera
Michel Georges
Ronald N. Germain
Hajime Karasuyama
Yutaka Kawakami
Paul W. Kincade
Bernard MalissenJohn O’Shea
Fiona Powrie
Peter Sorger
Kiyoshi Takatsu
Katsushi Tokunaga
Dale Umetsu
Arthur Weiss

From the Airport
From Haneda Airport

From Narita Airport

Route 1
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.

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 themost 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(18 minutes). 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).

* A reserved seat express that requires payment of asurcharge in addition to train fare.
Searchable train timetables in English are available at
http://www.hyperdia.com/en/*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).

85

Core for Homeostatic Regulation
Lab. for Cell Signaling: Takashi Saito

Lab. for Immune Homeostasis: Taishin Akiyama

Lab. for Lymphocyte Differentiation: Tomohiro Kurosaki

Lab. for Skin Homeostasis: Masayuki Amagai

Lab. for Transcriptional Regulation: Ichiro Taniuchi

Lab. for Metabolic Homeostasis: Naoto Kubota

Lab. for Immune Cell Systems: Shigeo Koyasu

Lab. for Immune Crosstalk: Hilde Cheroutre

Lab. for Human Disease Models: Fumihiko Ishikawa

Lab. for Inflammatory Regulation: Takashi Tanaka

Lab. for Intestinal Ecosystem: Hiroshi Ohno

Lab. for Cytokine Regulation: Masato Kubo

Lab. for Mucosal Immunity: Sidonia FagarasanLab. for Innate Immune Systems: Kazuyo MoroLab. for Gut Homeostasis: Kenya Honda

Core for Precise Measuring and ModelingLab. for Developmental Genetics: Haruhiko KosekiLab. for Integrated Bioinformatics: Todd Duane Taylor

Lab. for Integrative Genomics: Osamu Ohara

Lab. for Tissue Dynamics: Takaharu Okada

Lab. for Disease Systems Modeling: Hiroaki KitanoLab. for Integrated Cellular Systems: Mariko Okada

Lab. for Medical Science Mathematics: Tatsuhiko Tsunoda

Lab. for Metabolomics: Makoto Arita

Lab. for Immunogenetics: Tadashi Yamamoto

Lab. for Microbiome Sciences: Masahira HattoriCore for Genomic Medicine
Lab. for Genotyping Development: Yukihide Momozawa

Lab. for Autoimmune Diseases: Kazuhiko Yamamoto

Lab. for Genome Sequencing Analysis: Hidewaki Nakagawa

Lab. for Digestive Diseases: Kazuaki Chayama

Lab. for Statistical Analysis: Yoichiro Kamatani

Lab. for Bone and Joint Diseases: Shiro Ikegawa

Lab. for Pharmacogenomics: Taisei Mushiroda

Lab. for Endocrinology, Metabolism and Kidney Diseases:

Lab. for International Alliance on Genomic Research:

Taisei Mushiroda

Momoko Horikoshi
Lab. for Respiratory and Allergic Diseases: Mayumi Tamari

Lab. for Cardiovascular Diseases: Kaoru Ito

Program for Medical Innovations
Lab. for Immune Regulation: Masaru Taniguchi

Drug Discovery Antibody Platform Unit: Toshitada TakemoriLab. for Immunotherapy: Shin-ichiro Fujii

Young Chief Investigator Program
YCI Laboratory for Immune Regeneration: Tomokatsu Ikawa

YCI Laboratory for Trans-omics: Katsuyuki Yugi

YCI Laboratory for Cellular Bioenergetic Network:

YCI Laboratory for Immunological Transcriptomics:

Toshimori Kitami

Hideyuki Yoshida

YCI Laboratory for Next-Generation Proteomics: Yibo WuiContents

Organization .......................................................................... iContents ................................................................................. ii

Director’s Report ................................................................... iv

Part 1
Research Highlights
Alternative pathway for NKT cell development ................ 2
Six new genetic loci associated with atrial fibrillation
are identified in the Japanese population .....................
Mast cells are crucial for induction of group 2
innate lymphoid cells and clearance of helminth
infections .........................................................................
Mapping disease genes to immune cells ............................
New link between Polycomb and Xist RNA for X
chromosome inactivation ..............................................
BATF is a critical regulator of regulatory T cells
in peripheral tissues ........................................................

3

4
5
6

Genome-wide association study reveals theinvolvement of B lymphocytes in obesity .................... 8
Ectopically colonized oral bacteria may induce
inflammatory bowel disease. ......................................... 9
Activation of immune T cells leads to behavioral
changes ............................................................................. 10
Blocking key pathways is a way to defeat cancer cells ..... 11
New asthma risk loci have been identified andfound to colocalize with immune cell cis-acting
regulatory elements ........................................................ 127Part 2Lab Activities
Core for Homeostatic Regulation ........................... 14
Laboratory for Cell Signaling ........................................ 15
Laboratory for Lymphocyte Differentiation ................ 16
Laboratory for Transcriptional Regulation .................. 17

Laboratory for Medical Science Mathematics ............. 34
Laboratory for Immunogenetics ................................... 35
Laboratory for Integrated Bioinformatics .................... 36
Laboratory for Tissue Dynamics .................................. 37

Laboratory for Immune Cell Systems .......................... 18
Laboratory for Human Disease Models ....................... 19

Laboratory for Integrated Cellular Systems ................. 38
Laboratory for Metabolomics ....................................... 39

Laboratory for Intestinal Ecosystem ............................ 20
Laboratory for Mucosal Immunity ............................... 21
Laboratory for Gut Homeostasis .................................. 22
Laboratory for Immune Homeostasis .......................... 23

Core for Genomic Medicine ....................................... 40
Laboratory for Genotyping Development ................... 41
Laboratory for Genome Sequencing Analysis ............. 42
Laboratory for Statistical Analysis ................................ 43

Laboratory for Skin Homeostasis ................................. 24
Laboratory for Metabolic Homeostasis ........................ 25

Laboratory for Pharmacogenomics .............................. 44
Laboratory for Cardiovascular Diseases ...................... 45

Laboratory for Immune Crosstalk ................................ 26
Laboratory for Inflammatory Regulation .................... 27
Laboratory for Cytokine Regulation ............................ 28
Laboratory for Innate Immune Systems ...................... 29

Laboratory for Autoimmune Diseases ......................... 46
Laboratory for Digestive Diseases ................................ 47
Laboratory for Bone and Joint Diseases ....................... 48
Laboratory for Endocrinology, Metabolism andCore for Precise Measuring and Modeling ......... 30
Laboratory for Developmental Genetics ...................... 31

Kidney Diseases ........................................................ 49
Laboratory for Respiratory and Allergic Diseases ...... 50

Laboratory for Integrative Genomics ........................... 32
Laboratory for Disease Systems Modeling .................. 33

Program for Medical Innovations .......................... 51
Laboratory for Immune Regulation ............................. 52ii

Laboratory for Immunotherapy .................................... 53

Confocal Laboratory ...................................................... 60

Drug Discovery Antibody Platform Unit .................... 54
Young Chief Investigator Program
YCI Laboratory for Immune Regeneration ................. 55

Genomics Laboratory ..................................................... 61
Animal Facility ................................................................ 61
Other Programs

YCI Laboratory for Cellular Bioenergetic Network ... 56
YCI Laboratory for Trans-omics ................................... 57
YCI Laboratory for Immunological

RIKEN International Program Associate (IPA) .......... 62
RIKEN Foreign Postdoctoral Researcher (FPR)
Program ..................................................................... 62

Transcriptomics ........................................................ 58
YCI Laboratory for Next-Generation Proteomics ...... 59
Central Facilities

RIKEN Junior Research Associate (JRA) Program .... 62
RIKEN Special Postdoctoral Researcher (SPDR)
Program ..................................................................... 62

FACS Laboratory ............................................................ 60

Part 3
Research Projects
Projects
iPS project ........................................................................ 64
Medical Sciences Innovation Hub Program(MIH) ......................................................................... 64
Integrated omics approach to elucidate
the impact of the gut microbiomeon the pathogenesis of type 2 diabetes ................... 65
NKT cell projects ............................................................ 65

Linkage to RIKEN Program for Drug Discovery
and Medical Technology Platforms (DMP) .......... 66
PGRN-RIKEN IMS Project ........................................... 66
Collaboration with Asian institutes and SEAPharm ... 67
International Cancer Genome Consortium (ICGC)
and PCAWG .............................................................. 67
Humanized mouse .......................................................... 68
Award Winners 2017 .................................................... 68

Part 4
EventsRIKEN IMS Summer Program (RISP) 2017 ..................... 70
The IMS-JSI International Symposium on
Immunology 2017 .......................................................... 70
14th/15th PGRN-RIKEN Strategic Alliance Meetings ..... 71

Tsinghua-RIKEN Joint Symposium on Immunology
and Immunotherapy ....................................................... 72
RIKEN IMS-McGill Symposium ........................................ 72
Harvard Summer School 2017 ............................................ 73

RIKEN IMS-Luxembourg FNR Joint Symposium ............ 71

Adjunct Professorship Programs ........................................ 73
Guest lectures 2017 ............................................................... 74

Part 5
Data and Statistics
Publications 2017 .................................................................. 76

Access to RIKEN Yokohama Campus ................................ 85

Budget, personnel and patents ............................................ 84iii

Director’s ReportJ

ust over two years have passed since I became Director of the
RIKEN Center for Integrative Medical Sciences (IMS) in October 2015.
2017 was the last year of our center’s five-year mid-term plan.
RIKEN IMS was established in 2013 through the merging of twoformer centers, the Research Center for Allergy and Immunology
and the Center for Genomic Medicine. The aim of the new center
was to contribute to future medical care through establishmentof innovative medical science by clarifying the mechanisms of
disease development through a combination of genomic, immunological and omics analysis approaches. Looking back, I believethat we have achieved this aim but it is only the first of many steps
to come as we strive towards our long-term goal of contributing to
the next generation of medical science leading to a healthy longlived society.
Examples of how IMS researchers are driving innovative multidisciplinary science and laying the foundation for the next IMS
mid-term plan include Kazuhiko Yamamoto’s work on rheumatoid arthritis, a complex multi-genetic autoimmune disease, andShin-ichiro Fujii’s work on cell therapeutics. By using the resultsfrom genome-wide association studies (GWAS), Dr. Yamamoto’s
team studied how the associated genes in human were involved indisease pathogenesis by combing molecular biology approaches
and animal disease models, essentially transforming one type of
research (GWAS) to another (mechanistic). Dr. Fujii’s laboratory
launched a clinical trial study on NKT cell therapy for early stagelung cancer patients in collaboration with the National Hospital
Organization. In addition, his group is investigating novel drugdelivery systems that have the potential to enhance antitumor immunity, and efforts are currently underway for preclinical studies
that could ultimately lead to clinical trials. Such translational research, or application of basic immunology research towards disease therapy, is an area that IMS plans to strengthen in the coming
years, especially in the treatment of cancer and development ofiv

the field of cancer immunology.
From the feedback we received at the IMS Advisory Council
Meeting held in September 2016, and the RIKEN Advisory Council meeting held in December 2016, we began to plan for the second five-year center term that starts in April 2018. While bothadvisory councils agreed that IMS has made many important scientific contributions in the areas of immunology and genomics,
they felt our center could make even more significant advances
through the addition of a translational regulation division, specifically the Division of Genomic Technologies (DGT) led by Piero Carninci. We agreed that the inclusion of DGT would have astrong synergistic effect on our center’s original goal to establish
innovative medical research through multidisciplinary approaches, and I am happy to announce that, as of April 1, 2018, they
will become part of the new IMS center. New collaborations andpartnerships are already forming, and I look forward to seeing theunfolding of new research fields, platforms and technologies that
result from this merger of complimentary expertises.
One program I am quite proud of is the IMS Young Chief Investigator (YCI) program. This program was established in 2011
with the hopes of nurturing young scientists who will become future leaders in multidisciplinary research. This year we welcomed
two new scientists, Katsuyuki Yugi who heads the YCI Laboratory
for Trans-omics, and Yibo Wu who heads the YCI Laboratory for
Next-Generation Proteomics. Moreover, as demonstration of thisprogram’s success, Tomokatsu Ikawa, former head of the YCI Laboratory for Immune Regeneration, became an Associate Professor
in Immunobiology at Tokyo University of Science.
Our researchers continued to perform outstanding researchand publish papers in significant journals in 2017. Kenya Honda reported that TH1 cell induction and inflammation is driven
by ectopic colonization of oral bacteria in the intestine (Science,2017). Sidonia Fagarasan reported that brain monoamines andemotional behavior is perturbed in PD-1-deficient mice throughmetabolic shift induced by systemic activation of T cells (Nature
Immunology, 2017). Fumihiko Ishikawa reported that inhibitionof critical pathways overcomes mutational complexity in acute
myeloid leukemia (Science Translational Medicine, 2017). There
were 312 papers published from IMS in 2017.
With the approaching expansion of our center in 2018, I believe that IMS will have an even greater impact on the scientificcommunity in the years ahead.

Tadashi Yamamoto
Director,
RIKEN Center for Integrative Medical Sciences

Part 1
Research
Highlights

Alternative pathway for NKT cell
development

Research highlights

Figure: Novel alternative developmental pathway for
NKT cells
In the genetic fate-mapping experiment, yellow fluorescentprotein (shown in light green) is turned on starting at the
CD4+CD8+ double-positive (DP) stage, thus making it possible
to mark mature T and NKT cells that developed from DP stage
thymocyte precursors. However, cells before the DP stage, i.e.,at the CD4–CD8 – double-negative stage as well as mature
NKT cells that developed directly from DN stage precursors
without passing through the DP stage, would not express theyellow fluorescent protein (shown in red).

T

he Natural killer T (NKT) cell is called the fourth type oflymphocyte, following the three major types known as T
and B lymphocytes as well as natural killer (NK) cells. NKT cells
are different from other lymphocytes because they function to activate various types of immune cells in the innate and acquired
immune systems, resulting in establishing long-term memory responses against pathogens and tumors.
NKT cells have a single invariant T cell receptor (TCR) recognizing only glycolipid antigens, whereas the TCR repertoireof conventional T cells recognizes an almost unlimited numberof peptide antigens. The NKT cell receptor gene is conserved
among species by Darwinian-positive selection, thus, NKT cells
are thought to be important for protection against pathogens andessential for the species survival. However, the question of how
these cells develop remains a puzzle for researchers.
T-lineage cells generally pass through three developmental stages (Figure) as they differentiate in the thymus. The mostimmature thymic precursor cells, known as the double-negative
stage, express neither CD4 nor CD8 surface markers. As theseprecursors differentiate further, they express both surface markers, called the double-positive stage, before finally maturing intoeither CD4 or CD8 single-positive T cells.
It has long been believed that NKT cells develop in the thymus through the double-positive stage along with conventional
T cells. However as this conventional theory did not provide an
explanation for functional differences between NKT and T cells,
Nyambayar Dashtsoodol, Masaru Taniguchi and their colleagues
Original Paper:
Dashtsoodol N, Shigeura T, Aihara M, Ozawa R, Kojo S,
Harada M, Endo TA, Watanabe T, Ohara O, Taniguchi M.
Alternative pathway for the development of Vα14+ NKT
cells directly from CD4–CD8 – thymocytes that bypasses
the CD4+CD8+ stage. Nat Immun 18, 274–282 (2017)2

in IMS sought to resolve this dilemma by using genetically modified mice that completely lack gene rearrangement at the double-positive stage. If the conventional theory was correct, neither
T cells nor NKT cells should exist in this mouse. Surprisingly, they
could detect NKT cells, although their number was relatively reduced. “This result suggested the existence of an alternative NKT
cell developmental pathway,” commented Nyambayar.
To confirm this unexpected finding, they used a techniquecalled genetic fate-mapping. They employed another geneticallymodified mouse expressing a yellow fluorescent protein (YFP)
that turns on during the double-positive stage. While CD4+ andCD8+ T cells from the mice expressed the YFP, some NKT cells
did not, indicating that they developed without passing throughthe double-positive stage. “Our findings demonstrated that someNKT cells can bypass the double-positive stage and differentiate
directly from the double-negative stage, which means these cells
were differentiated earlier than it was thought” remarked Nyambayar. They also demonstrated that NKT cells generated by thisalternative pathway were mainly found in the liver and highly
expressed IFN-γ, a cytokine active against pathogens and tumor
cells, and perforin and granzyme, proteins that are important forcytotoxic activity.
“NKT cells that develop via this alternative pathway have higher cytotoxic activity and are essential for body defenses. We hopeto elucidate their function and contribute to cancer immune therapy in the future,” says Masaru Taniguchi.

Six new genetic loci associatedwith atrial fibrillation are
identified in the Japanese
population

Research highlights

Figure: Atrial fibrillation associated withirregular and rapid heart rate
©The Japan Stroke Association and Japanese Heart
Rhythm SocietyA

trial fibrillation (A-fib) is the most common cardiac arrhythmia. It is associated with abnormal cardiac rhythm
characterized by irregular and often rapid fibrillation of theatria, the upper chambers where blood enters the heart (Figure). Untreated, A-fib increases the risk of stroke, heart failure
and other heart-related complications. In Japan and elsewhere, the prevalence of A-fib increases with age, reaching
3.2% among Japanese who are 80 years old. Several studies
have indicated a relationship between genetic backgroundand the prevalence of A-fib. For example, individuals who
have at least one parent with A-fib have approximately threetimes greater risk of developing the disease than people without parents with A-fib. In addition, a large-scale cohort study
has shown an increased risk of A-fib in populations of European ancestry compared to Africans, Hispanics or Asians.
These observations suggested different A-fib pathogenesis
and risk factors, especially genetic factors among different
ancestry groups. Given the increasing aging population in Japan, the identification of predictive risk markers for A-fib isurgently needed.
To investigate the genetic loci associated with A-fib in theJapanese population, a research team at the RIKEN Center for
Integrative Medicine conducted a genome-wide associatedstudy (GWAS) with 8,180 A-fib patients and 28,612 controls,
followed by an additional study with 3,120 patients and125,064 controls from the Japanese population. Combining
these two studies into a meta-analysis, the team successfully

identified six new loci near the KCND3, PPFIA4, SLC1A4CEP68, HAND2, NEBL and SH3PXD2A genes. Five of the six
newly discovered loci were specific to the Japanese population, suggesting that there might be different genetic factors
affecting susceptibility across ancestry groups.
Surprisingly, further expression quantitative trait locus(eQTL) analysis showed that PPFIA4 and SH3PXD2A are involved in neural development processes, especially axon
guidance and neural crest cell development. When the investigators analyzed these pathways, they discovered that several
genes involved in these neural processes are significantly associated with A-fib. Further study is required to understandthe molecular basis of the involvement of axon guidance aswell as neural crest cells in A-fib pathogenesis.
The team also evaluated the risk of cumulative effects froma total of 15 associated genetic variants (the newly discovered
6 variants and 9 previously reported variants). In the group ofpatients who carried the most risk alleles, they predicted an
approximately 7.0 times greater risk compared to individuals
in the group with the fewest risk alleles. The implementationof a genetic risk score for A-fib could aid in identifying individuals who are at risk for cardiac arrhythmia.
The genotype data of the Japanese population used in thisstudy is publicly available in an anonymous format at the National Bioscience Database Center, Japan Science and Technology Agency (NBDC, JST).

Original paper:
Low SK, Takahashi A, Ebana Y, Ozaki K, Christophersen
IE, Ellinor PT, AFGen Consortium, Ogishima S,
Yamamoto M, Satoh M, Sasaki M, Yamaji T, Iwasaki
M, Tsugane S, Tanaka K, Naito M, Wakai K, Tanaka
H, Furukawa T, Kubo M, Ito K, Kamatani Y, Tanaka T.
Identification of six new genetic loci associated withatrial fibrillation in the Japanese population. Nat
Genet 49, 953–958 (2017)

3

Mast cells are crucial for
induction of group 2 innate
lymphoid cells and clearanceof helminth infections

Research highlights

Figure: Mechanism by which mast cells activate
ILC2s for worm expulsion
Upon helminth infection, ATP is released from injured/dying epithelial cells (top left) and activates mast cells
through the P2X7 receptor (bottom left). Activated mast
cells release IL-33 which in turn stimulates ILC2s leading to the production of IL-13 (bottom center). Finally,
IL-13 promotes mucin secretion by goblet cells (topright) to expel worms.

T

he World Health Organization (WHO) reported that
more than 1.5 billion people, or 24% of the world’s
population, suffer from helminth infections and that such
infections are widely distributed in tropical and subtropicalareas. Infections with intestinal helminths can cause anemia
and malnutrition and are major socioeconomic problems indeveloping countries. There is thus an urgent need to elucidate the mechanism of protective immune responses against
helminths.
Our body activates type 1 immune responses against
pathogens such as bacteria and viruses, while type 2 immune
responses are induced by helminths. A research group led by
Hiroshi Ohno of the RIKEN Center for Integrative Medical
Sciences demonstrated that mast cells play a critical role foractivation of group 2 innate lymphoid cells (ILC2s), which
are responsible for parasite expulsion in the early phase of
infection.
The researchers examined Spi-B-deficient (Spib-/-) mice,
which exhibit mast cell hyperplasia due to altered myeloid
cell differentiation. To analyze the role of Spi-B in intestinal helminth infection, they orally infected Spib-/- mice with
Heligmosomoides polygyrus (Hp), an intestinal helminth,and found that the Spib-/- mice were better protected thanwild-type (WT) mice. There were far fewer Hp eggs in thefeces of Spib-/- mice compared to WT mice, and also fewer
adult worms. In addition, the number of mucus-producing
goblet cells was increased in Spib-/- mice. These findings reOriginal paper:
Shimokawa C, Kanaya T, Hachisuka M, Ishiwata K,
Hisaeda H, Kurashima Y, Kiyono H, Yoshimoto T, Kaisho
T, Ohno H. Mast cells are crucial for induction of group 2
innate lymphoid cells and clearance of helminth infections. Immunity 46, 863–874 (2017)

4

vealed an unexpected resistance of Spib-/- mice to Hp infection. Since the depletion of mast cells in Spib-/- mice before
the infection completely eliminated their Hp resistance, thisresistance was dependent on mast cells.
They further found that ILC2s and IL-33, a cytokine that
activates ILC2s, were increased in Spib-/- mice after Hp infection. It had been thought that intestinal epithelial cells
release IL-33 to activate ILC2s; however, surprisingly, Ohno
and colleagues found that mast cells are crucial for IL-33
production and ILC2 activation (Figure). “We found a new
function of mast cells in innate immune responses against
nematode infection. When the nematode invades the intestinal tissue, adenosine triphosphate (ATP) is released fromthe injured epithelial cells and stimulates mast cells. Activated mast cells secrete IL-33 and thereby stimulate ILC2s.
Then, activated ILC2s produce IL-13, which promotes mucin secretion by goblet cells in the intestinal epithelia, leading to worm expulsion,” says Ohno.
Increasing or activating mast cells can be an attractive
and effective strategy for controlling helminth infections.
However, at the same time, type 2 immune responses, despite the benefit of protection against helminth infections,can be a cause of allergy and inflammatory diseases. “Regulation of mast cell-derived type 2 immune responses could
be a new preventive measure and therapy for these diseases,”concludes Ohno.

Mapping disease genes toimmune cells

Research highlights

Figure: Researchers demonstrate a new way toidentify gene variants associated with complex
diseasesG

ene variants tied to rheumatoid arthritis and other diseases can now be traced to particular faulty immune

cells.
A valuable analytical tool developed by RIKEN researchers could help to reveal when multiple genes are all working through a common pathway in specific immune cells
that underpin complex diseases such as diabetes or heartdisease.
To demonstrate the tool’s effectiveness, the scientists
applied it to DNA datasets from rheumatoid arthritis sufferers and confirmed the importance of immune dysregulation through a cell-signaling protein called tumor necrosis
factor (TNF). Anti-TNF drugs are some of the best-selling
medicines in the world—a fact that Kazuyoshi Ishigaki of
the RIKEN Center for Integrative Medical Sciences says
confirms the “robustness of our pipeline.” As such, he adds,“It’s reasonable to expect that our pipeline can be applied toother diseases.”
To identify the genes and biological pathways involved incomplex immune-related diseases, Ishigaki and his team—led by Kazuhiko Yamamoto and Yuta Kochi, also from the
RIKEN Center for Integrative Medical Sciences—first looked
for DNA sequences that explained gene activity levels in fivekinds of immune cells as well as unfractionated peripheral
blood (Figure). They used blood samples from 105 healthy
Japanese individuals to build their ‘expression quantitative
trait loci’ (eQTL) database for each of these cell types.
This article was reproduced from RIKEN Research
http://www.riken.jp/en/research/rikenresearch/highlights/20170017/

The researchers then cross-referenced their databaseagainst a catalogue of published gene-sleuthing studies andshowed that even some non-autoimmune diseases, such as
Parkinson’s disease and schizophrenia, have a large immune
component. “By investigating critical immune pathways inthese diseases, we might be able to develop novel immunologic treatments for them,” Ishigaki says.
The RIKEN investigators next applied their cell-sorting
model to genetics datasets from thousands of Japanese individuals with rheumatoid arthritis. They found that the
combined action of 176 genes altered TNF signaling in aparticular subset of immune cells known as helper T cells,
which express a surface protein called CD4, but not in othertypes of immune cells.
According to Ishigaki, drug developers can use this finding to build a new generation of TNF-targeted drugs thattarget both TNF and CD4 receptors. This will give the drugs
a more anti-inflammatory effect as they will act only in thosecells that have gone awry in the autoimmune disease. “Ourfindings suggest that we can improve the efficiency of current anti-TNF therapy,” he says.
Kochi hopes the research community will embrace his
team’s eQTL database for identifying genes implicated inparticular cells in any disease of interest—and since “theprediction models are provided as supplemental data in thearticle,” he says, “anyone can use them.”

Original paper:
Ishigaki K, Kochi Y, Suzuki A, Tsuchida Y, Tsuchiya H, Sumitomo S, Yamaguchi K, Nagafuchi Y, Nakachi S, Kato
R, et al. Polygenic burdens on cell-specific pathways
underlie the risk of rheumatoid arthritis. Nat Genet 49,
1120–1125 (2017)

5

New link between Polycomb
and Xist RNA for X chromosome
inactivation

Research highlights

Figure: New model of Polycomb-mediated genesilencing by Xist RNA
The classical model proposed a direct interaction between
Xist RNA and PRC2, followed by the recruitment of the
PCGF2/4-PRC1 complex through its chromobox-containing CBXprotein subunit. Results of the present study have led to a newmodel in which Xist RNA instead recruits another PRC1 subcomplex, PCGF3/5-PRC1. Subsequent recruitment of PRC2 on theinactive X chromosome is dependent on monoubiquitylationof histone H2A catalyzed by PCGF3/5-PRC1. (Known subunitsof the PRC1 and PRC2 complexes are indicated on the figure by
their acronyms. Unlabeled subunits are accessory proteins.)M

ammalian females have two X sex chromosomes (XX)but males are XY, so females have twice as many X-linked
genes as males. To balance X-linked gene dosage, females randomly silence one of the X chromosomes in individual cells earlyin development. This epigenetic process, called X chromosome
inactivation, involves a noncoding RNA known as Xist and the
Polycomb repressive complexes PRC1 and PRC2. Haruhiko
Koseki and colleagues of the RIKEN Center for Integrative Medical Sciences, in collaboration with Oxford University and theKazusa DNA Institute, elucidated a key role of a specific PRC1
complex in initiating Polycomb recruitment by Xist RNA andshowed that PRC recruitment is critical for Xist-mediated chromosome silencing and female embryogenesis.
Xist RNA recruits PRC1 and PRC2 to the future inactive X
chromosome to deposit suppressive histone modifications, suchas the ubiquitination of histone H2A lysine 119 (H2AK119ub1)
and the methylation of histone H3 lysine 27 (H3K27me3). These
histone modifications are thought to be important for the chromosome-wide gene silencing that occurs with X chromosome
inactivation.
Previous studies revealed that Xist RNA directly binds to PRC2and catalyzes the methylation of H3 Lysine 27. Following this epigenetic modification, the PRC1 complex was proposed to bindto H3K27me3 through its chromobox-containing CBX protein
subunit, which has a high affinity for H3K27me3. Although thismodel is attractive for explaining how Xist RNA establishes Polycomb-mediated suppressive chromatin, experimental evidence toOriginal paper:
Almeida M, Pintacuda G, Masui O, Koseki Y, Gdula M,
Cerase A, Brown D, Mould A, Innocent C, Nakayama
M, Schermelleh L, Nesterova TB, Koseki H, Brockdorff
N. PCGF3/5-PRC1 initiates Polycomb recruitment in X
chromosome inactivation. Science 356, 1081–1084(2017)

6

validate it was lacking. In addition, PRC1 was recently shown
to exist as four different subcomplexes, making the story lessstraightforward.
In this study, by using Polycomb group ring finger (Pcgf3/5)
conditional knockout mice, the collaborative research group
showed that one of these four PRC1 subcomplexes, PCGF3/5PRC1, is necessary for female embryogenesis and for both
PRC1-mediated H2AK119 ubiquitylation and PRC2-mediatedH3K27 methylation of the inactive X chromosome. Moreover,in this situation the recruitment of PRC2/H3K27me3 was dependent on the initial ubiquitylation of Histone H2A catalyzed
by PCGF3/5-PRC1. They also demonstrated that the initiationof Xist-mediated gene silencing is greatly impaired in the absence of PCGF3/5-PRC1, indicating that PCGF3/5-PRC1 initiates
Xist-mediated gene silencing by recruiting PRC1 and PRC2. Thus,
the authors proposed a new model for the relationship between
Xist RNA and Polycomb, in which Xist RNA first recruits
PCGF3/5-PRC1 on the future inactive X chromosome to ubiquitylate underlying nucleosomes. PRC2 then binds to this epigenetic histone mark through recognition by the DNA-binding protein
JARID2 or by an alternative but currently unknown mechanism(Figure).
“Next, we would like to determine whether other noncoding
RNAs use the same mechanism to recruit Polycomb to their target
chromatin loci. We hope that future research will reveal the whole
picture of X chromosome inactivation” says Koseki.

Research highlights

BATF is a critical regulator of
regulatory T cells in peripheral
tissues
Foxp3WT
Foxp3WTGTAAACAGTCAACA

Dysregulationof Batf, etc.

GTAAACAGTCAACAtarget genes

WT
?
Batf

A384T

cTreg cells

Batf
emTreg cells

ToleranceR

Foxp3A384T

target genes

Figure: The A384T mutation impairs effector
Treg (eTreg) cell homeostasis by repressing Batf
expression.

egulatory T cells (Tregs) establish and maintain immune tolerance by restraining excessive immune responses that lead
to autoimmunity, inflammation and allergy, whereas excessive
Treg activity suppresses immune responses against pathogens
and tumors. Thus, it is important to regulate the delicate balanceof Treg activity to maintain immune homeostasis.
Shohei Hori, Team Leader of RIKEN Center for Integrative
Medical Sciences (IMS), and Shimon Sakaguchi, Professor of Osaka University, previously reported that the transcription factor
Foxp3 acts as a master regulator for the development and immunosuppressive function of Tregs. However, Foxp3 binds to thousands of genomic sites and interacts with hundreds of other proteins. Because of this complex transcriptional network, the molecular mechanisms of Foxp3 function in Tregs remained a mystery.
Mutations in Foxp3 cause a devastating multi-organ humanautoimmune disease called IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome. To determine
the molecular functions of Foxp3 in Tregs, Shohei Hori and hiscolleagues established mouse models harboring Foxp3 mutations(I363V, R397W, and A384T) that had been identified in IPEX patients and predicted to affect Foxp3 DNA binding. Mice harboring
either I363V or R397W mutations developed systemic multi-organ inflammation, similar to Foxp3-deficient mice, because of
their impaired DNA binding activity. In contrast, A384T mice exhibited an autoimmune phenotype only in certain non-lymphoidtissues, such as skin, lung and colon. Although thymic Treg development was normal, the frequency of Tregs was reduced in those

Foxp3A384T

cTreg cells

emTreg cells

Autoimmunity

tissues, while inflammatory helper T cells were increased. “A384T
mutation does not impair in vitro function of Tregs but results ina distinctive autoimmune disease. So, we decided to focus on thismutation,” says Hori.
Tregs can be classified into two groups, “central” Treg (cTreg)
cells enriched in lymphoid tissues, and “effector” or “memory”
Treg (emTreg) cells localized in non-lymphoid tissues. Because
cTregs differentiate into emTregs, they thought that the A384T
mutation impairs differentiation and expansion of emTregs.
To study how the mutation impairs emTreg differentiation,
they analyzed gene expression in A384T Tregs as well as A384T
Foxp3 DNA binding. They combined results from these analyses
and found that A384T is a gain-of-function mutation that enables
Foxp3 binding to the promoter of a transcription factor gene,
Batf. This binding suppressed BATF expression in Tregs, leading
to the impaired differentiation of emTregs (Figure).
To further study the function of BATF, they analyzed Tregs in
BATF-deficient mice. Indeed, BATF-deficient and A384T Tregs
showed similar functional defects in that both were unable toprevent inflammation in vivo. When BATF was retrovirally transduced into A384T Tregs, differentiation to emTregs and their accumulation in peripheral tissues were rescued and immunosuppressive function was recovered.
“BATF has a fundamental function to coordinate the differentiation and accumulation of emTregs. Regulation of BATF expression
or function will have a therapeutic possibility as a novel treatmentof autoimmunity, inflammation, allergy and cancer,” says Hori.

Original paper:
Hayatsu N, Miyao T, Tachibana M, Murakami R, Kimura
A, Kato T, Kawakami E, Endo TA, Setoguchi R, Watarai
H, Nishikawa T, Yasuda T, Yoshida H, Hori S. Analysesof a mutant Foxp3 allele reveal BATF as a critical transcription factor in the differentiation and accumulationof tissue regulatory T cells. Immunity 47, 268–283(2017)

7

Genome-wide association study
reveals the involvement of B
lymphocytes in obesity

Research highlights

Figure: Enrichment of identified variants in active enhancers
Enrichment of the variants in the active enhancers in
10 cell groups (a) and in immune-related cells (red) andthe central nervous system (blue) (b). PMA-I: phorbol
12-myristate 13-acetate plus ionomycin.

Obesity is a risk factor for a wide variety of health problems. Behavior, environment and genetic factors arethought to interact in causing obesity. However, the mechanisms of body weight regulation and potential differencesamong individuals remain unknown.
Yoichiro Kamatani and his colleagues at the RIKEN
Center for Integrative Medical Sciences (IMS), in collaboration with researchers in the Tohoku Medical Megabank
Organization, the Iwate Tohoku Medical Megabank Organization and National Cancer Center Japan, identified 112 newloci associated with obesity. Their findings of the genetic
links between body mass index (BMI) and diseases provided
surprising evidence that B lymphocytes have a role in thepathogenesis of obesity.
To identify genetic loci associated with obesity, researchers conducted a genome-wide association study (GWAS) of
170 thousand Japanese people using roughly 6 million genetic variants followed by a study of an additional 15 thousand Japanese. By combining these studies, they successfully identified 85 loci including 51 newly discovered lociassociated with BMI. They further conducted trans-ethnic
meta-analysis using publicly available GWAS data of 350
thousand Europeans. Using a method called MANTRA(Meta-ANalysis of Transethnic Association studies), they
identified 61 additional new loci associated with BMI. Thus,
a total of 112 new loci were successfully identified in thislarge-scale GWAS of BMI.

Original paper:
Akiyama M, Okada Y, Kanai M, Takahashi A, Momozawa Y, Ikeda M, Iwata N, Ikegawa S, Hirata M,
Matsuda K, Iwasaki M, Yamaji T, Sawada N, Hachiya T,
Tanno K, Shimizu A, Hozawa A, Minegishi N, Tsugane
S, Yamamoto M, Kubo M, Kamatani Y. Genome-wide
association study identifies 112 new loci for bodymass index in the Japanese population. Nat Genet 49,
1458–1467 (2017)8

They next investigated biological functions of these newly
identified genetic variants. They evaluated enrichment of theidentified variants in cell-type-specific epigenetic regulatorssuch as enhancers and promoters. “Unexpectedly, we foundsignificant enrichment of the identified genetic variants inthe active enhancers of immune cells, B cells specifically, in
addition to cells in the central nervous system and in adipose tissues” said Kamatani. “Significant enrichment wasalso found in active promoters of B cells, pancreatic islets
and brain cells (Figure). Our cell-type-specific analyses suggested a surprising involvement of lymphocytes in the regulation of body weight.”
Lastly, they investigated genetic correlations between BMI
and other traits. By evaluating the genetic correlations between this study and other previous GWAS studies conducted at RIKEN IMS, they found positive correlations of BMI
with type 2 diabetes, cardiovascular diseases, asthma andossification of posterior longitudinal ligament of the spine(OPLL). Significant negative correlations were observed inadolescent idiopathic scoliosis (AIS), schizophrenia andrheumatoid arthritis (RA). The results indicated that obese
people have more risks for type 2 diabetes, cardiovasculardiseases, asthma and OPLL, while thin people have moregenetic risks for RA, AIS and schizophrenia. “Our findings
provide insight into the links between BMI and complex diseases and provide genetic evidence that lymphocytes have arole in the pathogenesis of obesity” noted Kamatani.

Ectopically colonizedoral bacteria may induce
inflammatory bowel disease.

Research highlights

Figure:The normal gut microbiota suppresses colonization by
Klebsiella species, but imbalances in the gut microbiota
will allow Klebsiella species to colonize and proliferate
in the gut. This induces the accumulation of TH1 cells
and could elicit pathological inflammation in a genetically susceptible host.

Avariety of bacteria reside in the gut and oral cavity andthey play important roles in maintaining our healthby potently affecting our immune system and physiological
functions. Intestinal colonization by bacteria of oral origin
has been correlated with several negative health outcomes,
including inflammatory bowel disease (IBD). However, acausal role of oral bacteria ectopically colonizing the intestine remains unclear. A research group led by Kenya Hondaof the RIKEN Center for Integrative Medical Sciences and
Keio University, and Masahira Hattori of RIKEN Integrative
Medical Sciences and Waseda University showed that oral
bacteria called Klebsiella species are strong inducers of T
helper 1 (Th1) cells when they colonize in the gut. Excessive
activation of Th1 cells may contribute to the development ofinflammatory bowel diseases, such as Crohn’s disease (CD)and ulcerative colitis (UC).
First, these investigators transplanted saliva samples fromtwo patients with CD into germ-free mice. In mice receiving a saliva sample from one of the patients, they noticed amarked accumulation of interferon γ (INF-γ)+ Th1 cells in
the intestinal lamina propria. From the feces of these mice
they isolated and cultured many oral bacterial strains andinoculated them into other germ-free mice. These experiments identified Klebsiella pneumoniae 2H7 (Kp-2H7) as astrong inducer of Th1 cells.
Kp-2H7 was resistant to multiple antibiotics and tended
to colonize when the intestinal microbiota was dysbiotic in

specific-pathogen-free (SPF) mice. To test the influence of
Kp-2H7 colonization on the development and exacerbationof CD, they orally administered Kp-2H7 into both wild-type
and colitis-prone Il10-/- mice. In the intestine of wild-type
hosts, despite induction of Th1 cells, Kp-2H7 colonization
did not induce any inflammatory changes, whereas Kp-2H7
colonization in colitis-prone Il10-/- mice induced severe gut
inflammation. These experiments suggested that Kp-2H7
acts as a gut pathobiont in the context of a genetically susceptible host (Figure).
In addition, they orally administered saliva samples fromtwo healthy donors into germ-free wild-type mice. Unexpectedly, the sample from one healthy donor also induced
a substantial increase in Th1 cells, suggesting that Klebsiellaspecies with Th1 cell induction capability may exist in theoral cavity of not only IBD patients but also healthy individuals. This result suggests that taking excessive antibiotics
over a long period would allow Klebsiella species to colonizein the gut of even a healthy person. Furthermore, persistenceof Klebsiella species is also observed in several other diseases.
“Developing antibiotics to specifically target Klebsiellaspecies, or inhibitors of their colonization in the gut could
provide a novel therapeutic strategy for IBD. Also, identifying members of the normal gut microbiota that can provide
colonization resistance against Klebsiella species could leadto new treatments for patients with infections from multidrug-resistant Klebsiella species,” says Honda.

Original paper:
Atarashi K, Suda W, Luo C, Kawaguchi, Motoo, Narushima S, Kiguchi Y, Yasuma K, Watanabe E, Tanoue T,
Thaiss CA, Sato M, Toyooka K, Said HS, Yamagami H,
Rice SA, Gevers D, Johnson RC, Segre JA, Chen K, Kolls
JK, Elinav E, Morita H, Xavier RJ, Hattori M, Honda
K. Ectopic colonization of oral bacteria in the intestine
drives TH1 cell induction and inflammation. Science
358, 359–365 (2017)9

Activation of immune T cells leads
to behavioral changes

Research highlights

Figure: Reduced levels of monoamine neurotransmitters in the brain of PD-1-deficient miceMicroscopy of coronal brain sections of wild-type andPD-1 deficient mice (left), stained for tryptophan hydroxylase (TPH), serotonin (5-HT) and the DNA-binding
dye DAPI; raphe nuclei (white insets) are enlarged in
the panels on the right (single-color and overlay images). Scale bars, 1 mm.

Scientists from the RIKEN Center for Integrative Medical Sciences in Japan and collaborators have found that
prolonged activation of immune cells changes the body’s metabolism, and that this activation actually leads to changes
in behavior.
It is currently known that individual T cells change their
metabolism to meet their energy needs after being activated, but the systemic metabolic effect of sustained activation of the immune system has remained unexplored. To
understand the systemic effects, the group looked at T cell
activation in mice designed to lack a surface receptor called
PD-1, which is necessary for inhibiting the activity of T cells.
T cells remain activated in mice without the receptor, similar to those in the immune systems of people with certain
types of autoimmune disease. In these mice, they found thatamino acids were depleted in the blood, and that they wereincreased in T cells themselves, implicating the T cells in thechange.
The team tracked and imaged amino acids in many organs, and found that the depletion of amino acids from theblood was taking place due to the accumulation of aminoacids in activated T cells in the lymph nodes, showing thatstrong or long-lasting immune responses can cause metabolic changes elsewhere in the body.
The remaining question was whether this depletion ofamino acids was actually having any systemic effect. By ana-This article was redacted from RIKEN Press Release
http://www.riken.jp/en/pr/press/2017/20171024_1/

10lyzing the biochemistry of the brain, they found that the systemic decrease in the amino acids tryptophan and tyrosinein blood led to lower amounts available in the brain, limiting
production of the neurotransmitters serotonin and dopamine (Figure). These neurotransmitters affect emotions, motivation and fear—for example, serotonin is often a target ofdrugs that combat depression. The researchers found that
their depletion in mice without PD-1 resulted in behavioral
changes dominated by anxiety and exacerbated fear responses, which could be remedied by providing a diet rich in an
essential amino acid. “Together these data indicate that excessive activation of T cells causes a systemic metabolomic shift with consequences that extend beyond the immune
system,” says Michio Miyajima, one of the four first co-authors of this study.
According to Sidonia Fagarasan, the leader of the group,“We were fascinated to see that this happens, as it revealed
the power of the immune system to influence many aspectsof the body’s physiology besides infection and immunity. It
will be interesting in the future to investigate whether thetrigger of fear and anxiety by T cell activation is merely aside effect of the process, or whether there is an evolutionary benefit of this adaptation. We would also like to further
investigate these changes, as the blockade of PD-1 is being
investigated as an anti-cancer therapy.”

Original paper:
Miyajima M, Zhang B, Sugiura Y, Sonomura K, Guerrini
MM, Tsutsui Y, Maruya M, Vogelzang A, Chamoto K,
Honda K, Hikida K, Ito S, Qin H, Sanuki R, Suzuki K,
Furukawa T, Ishihama Y, Matsuda F, Suematsu M, Honjo
T, Fagarasan S. Metabolic shift induced by systemic T
cell activation in PD-1-deficient mice perturbs brain
monoamines and emotional behavior. Nat Immunol
18, 1342–1352 (2017)

Blocking key pathways is a way
to defeat cancer cells

Research highlights

Figure: Eradication of FLT3-ITD+ AML cells in vivo
through combined inhibition of a leukemia-initiating mutation and an anti-apoptotic pathway
Mice engrafted with AML derived from 12 patients received four different treatments (no treatment, ABT-199(BCL-2 inhibitor) alone, RK-20449 alone, andcombination). Frequencies of human AML cells in therecipient blood are shown over time.

S

cientists from the RIKEN Center for Integrative Medical
Sciences and international collaborators have found that inhumanized mice, a cocktail of drugs blocking certain key pathways is effective in eliminating acute myeloid leukemia (AML), a
disease which is estimated to kill more than 250,000 people a year
around the world.
The most difficult problem with AML is disease relapse, which
occurs in a majority of patients being treated with chemotherapy.
During the last decade or so, it has become recognized that cells
called leukemia stem cells (LSCs) can cause relapse because theysurvive the onslaught of chemotherapy drugs and proliferate.
The group began to investigate compounds that could target
these stem cells and in 2013 announced that they had discovered
one—now known as RK-20449. This compound targets a certainclass of tyrosine kinases—receptors that play an important role insignaling for cells in the bone marrow and blood, such as the ones
that cause leukemia.
Now, in research published in Science Translational Medicine,the group has shown that targeting two important pathways simultaneously is a promising route for eliminating cancer.
One of the difficulties of developing targeted therapies against
AML and other tumors is that the cancers can be very geneticallydiverse—cells in different patients and even cells in a single patient may harbor different mutations, making it hard to determine
which are truly important for tumor growth or survival. Many ofthe mutations found in cancerous AML cells, for example, are also
found in the cells of people—especially aged people—without
This article was redacted from RIKEN Press Release
http://www.riken.jp/en/pr/press/2017/20171026_1/

leukemia.
To elucidate which mutations are truly relevant, the group
took cells from AML patients in various stages of the disease andtransplanted them into immune-deficient mice engineered to accept human cells. They then examined how the cells behaved—in
either a normal or leukemic way—in organs such as bone marrowor spleen. “What we did,” says Fumihiko Ishikawa, the leader ofthe group, “is to connect the genomic information and biological
functions of the cells.”
Using this method, they were able to discover that a mutation
in a gene coding FLT3, an important tyrosine kinase, is critical fortransforming normal bone marrow cells into AML cells and that
another gene, BCL2, functions to promote therapeutic resistancein FLT3-mutated AML. This mutation, called FLT3-ITD, is one of
the most common mutations found in AML patients. The group
showed that by using RK-20449 to block abnormal signaling
caused by FLT3-ITD, AML cells with multiple mutations could
be effectively eliminated. In addition, by simultaneously targeting BCL-2 with a second drug called venetoclax (ABT-199), they
could achieve the complete elimination of AML in the transplanted mice in most of the AML cases tested (Figure).
“This shows,” says Fumihiko Ishikawa, “that determining
which of the mutations in a diverse landscape are critical in leukemia onset and which of the pathways are critical for therapeutic resistance in leukemia, and simultaneously targeting thosepathways is an encouraging way to treat difficult cancers suchas AML.”

Original paper:
Saito Y, Mochizuki Y, Ogahara I, Watanabe T, Hogdal L,
Takagi S, Sato K, Kaneko A, Kajita H, Uchida N, Fukami
T, Shultz LD, Taniguchi S, Ohara O, Letai AG, Ishikawa
F. Overcoming mutational complexity in acute myeloid
leukemia by inhibition of critical pathways. Sci Transl
Med 9, eaao1214 (2017)11

New asthma risk loci have been
identified and found to colocalize
with immune cell cis -acting
regulatory elements

Research highlights

Figure: The results of multi-ancestry GWAS
meta-analysis of asthma risk.
The analysis included a total of 23,948 cases and118,538 controls. Black, previously known loci; red, newloci identified in the European-ancestry meta-analysis;
blue, additional new loci identified in the multi-ancestry meta-analysis. The dashed horizontal line denotes P=5×10−8.

An international study by the Trans-National Asthma
Genetics Consortium (TAGC) has discovered five new
regions of the genome that are associated with an increased
risk of asthma. As TAGC members, Tatsuhiko Tsunoda andhis colleagues at the RIKEN Center for Integrative Medical
Sciences contributed to this effort, the world’s largest meta-analysis.
Asthma is a chronic inflammatory disease that affects
more than 300 million people worldwide. The prevalence
rate of asthma varies from 5–8% in Japan, 3.9% in Mexican
Americans and 12.5% in African Americans. The genetic effect on the risk of asthma is estimated to vary from 25–80%.
Such high variability reflects the complex nature of the disease, influenced not only by genetics but also by environmental factors such as air pollution and allergens. Moreover,asthma is not a single disease and has heterogeneous symptomatic features. Thus, more than 45 worldwide groups ofinvestigators established TAGC to construct a comprehensive catalog of genetic asthma risk regions that are robust
across populations and environmental conditions.
TAGC conducted genome-wide association studies(GWAS) on a total of 142,486 individuals (19,954 asthma
cases and 107,715 controls of European ancestry, 2,149 casesand 6,055 controls of African ancestry, 1,239 cases and 3,976

Original paper:
Demenais F, Kubo M, Takahashi A, Tsunoda T, et al.
Multiancestry association study identifies new asthma
risk loci that colocalize with immune-cell enhancer
marks. Nat Genet 50, 42–53 (2018)12

controls of Japanese ancestry, and 606 cases and 792 controlsof Latino ancestry.)
As a result, they discovered 18 genetic loci associated withasthma, including five novel loci (Figure). Among them, thestrongest correlation with asthma was found in the BACH2
genomic region, a gene known to be important in the immune response against infections. The second strongest signal was located near the GNGT2 genomic region, a gene that
promotes NF-κB activation. Further study revealed sharedoverlaps of asthma risk variants with risk alleles for autoimmune diseases and other diseases featuring chronic inflammation, including cardiovascular diseases, cancers, and neuropsychiatric diseases, which strengthens the concept that
asthma is a multifactorial disease.
The study also showed that genetic risk variants associated with asthma are often located near epigenetic markers inimmune cells of cis-acting regulatory elements such as enhancers and promoters. These results suggest a role of asthma risk variants in the epigenetic regulation of immune-related processes.
These discoveries highlight the importance of integrating genomic and epigenomic data to better understand thepathogenesis of complex diseases like asthma and for the development of effective new therapies.

Part 2Lab Activities

Core for
Homeostatic
RegulationT

he ultimate goal of the Core for Homeostatic Regulation is to elucidate
the mechanisms of onset of human diseases and to create new scientificparadigms. This Core clarifies the regulation of homeostasis in individuals, focusing on their immune, metabolic and environmental response systems. In
addition, the Core for Homeostatic Regulation will validate the disease models established by the Core for Precise Measuring and Modeling in a multitiertimeframe from before to after the onset of diseases.
The Core for Homeostatic Regulation is composed of 15 laboratories,
which are divided into four areas;[1] Immune homeostasis
Cell signaling (T. Saito), Lymphocyte differentiation (T. Kurosaki), Immune homeostasis (T. Akiyama), Metabolic homeostasis (N. Kubota)[2] Lymphocyte development
Transcriptional regulation (I. Taniuchi), Human disease models (F. Ishikawa)[3] Mucosal immunity
Intestinal ecosystem (H. Ohno), Mucosal immunity (S. Fagarasan), Immune cellsystems (S. Koyasu), Gut homeostasis (K. Honda), Immune crosstalk (H. Cheroutre)[4] Allergy and inflammation
Skin homeostasis (M. Amagai), Inflammatory regulation (T. Tanaka), Cytokine
regulation (M. Kubo), Innate immune systems (K. Moro)
All of these areas elucidate the basic mechanisms of immune regulation at
cellular, tissue and systemic levels. We ultimately aim to analyze the onset of
autoimmune diseases, metabolic disorders [1], primary immunodeficiency [2],inflammatory bowel disease and colitis [3], and atopic dermatitis and allergic
diseases [4].

14

Laboratory for

Lab activities

Cell Signaling
Group Director: Takashi Saito

Figure: STING stimulation induces growth arrest
and type I-IFN production in T cells.
Stimulation of T cells through TCR (antigen) and STING(STING ligand) induced T cell growth arrest by inhibiting mTORC1 and simultaneously induced productionof type-I IFN by T cells. Effector T cells such as Th1 andactivated CD8 T cells produce high levels of type-I IFN,
which may contribute to anti-tumor immunity and protection from viral infection.

Recent Major Publications
Takeuchi A, Saito T. CD4+ CTL, a Cytotoxic Subset of
CD4+ T cells, Their Differentiation and Function. Front
Immunol 8, 194 (2017)
Hayashi M, Aoshi T, Haseda Y, Kobiyama K, Wijaya E,
Nakatsu N, Igarashi Y, Standley DM, Yamada H, Honda-Okubo Y, Hara H, Saito T, Takai T, Coban C, Petrovsky
N, Ishii KJ. Advax, a delta inulin microparticle, potentiates in-built adjuvant property of co-administeredvaccines. EBioMedicine 15, 127–136 (2017)
Hashimoto-Tane A, Sakuma M, Ike H, Yokosuka T,
Kimura Y, Ohara O, Saito T. The Micro adhesion-ringsurrounding each TCR microclusters forms synapse-likestructure essential for T cell activation. J Exp Med 213,
1609–1625 (2016)

Invited Presentations
Saito T. “Regulation of T cell activation and function by
innate signals” Hokkaido University Seminar (Sapporo,
Japan) December, 2017
Saito T. “Regulation of T cell activation and function by
innate signals” IFReC Colloquium, August, 2017
Saito T. “STING activation in T cells induces growtharrest and IFN production” FASEB Summer Conference(Snowmass, USA) June, 2017
Saito T. “Dynamic regulation of T cell activation andco-stimulation” MSD special seminar (Boston, USA)
June, 2017
Saito T. “Initiation of immune response for protectionof our body” RIKEN Wako open campus seminar (Wako,
Japan) April, 2017T

cells play central roles in immune regulation. They initiate immune responses, andupon activation generate various effector T cells that protect against infection andoncogenesis. Aberrant T cell function results in infectious and autoimmune diseases andcancer. Our group aims to determine the molecular mechanism of T cell activation, differentiation and homeostasis, particularly from a signaling perspective.
T cell activation is induced through TCR-microclusters (MC), the signaling clusters generated by recruiting TCR and proximal signaling molecules. We have analyzed function and dynamics of TCR-MC and downstream signal molecules such as thedownstream adaptor molecule CIN85. Analysis of T cell-specific CIN85-deficient mice
revealed that CIN85 functions in negatively regulating TCR signals by recruiting several
negative regulators such as Sts-2 phosphatase as a feedback regulation of activation.
We also investigated the regulation of T cell activation by innate signals. We have already analyzed the function of TLRs and nucleic acid recognition in T cells. Since STING,
a major intracellular DNA sensor in innate cells, is highly expressed in T cells, its function in T cell activation was analyzed. STING activation in T cells induced growth arrestand production of type I-IFN, in an mTORC1 dependent manner. The level of type 1-IFN
produced by effector T cells was much higher than by innate cells (Figure). Together
with our observation that STING in T cells contributes to anti-tumor immune responses,
STING activation in T cells can be utilized for modulating both T cell proliferation andanti-tumor immunity.
The ultimate aim of our diverse approaches is to elucidate the mechanisms of induction of autoimmune diseases through aberrant T cell function in order to be able tomodulate them and inhibit/prevent autoimmunity and allergic inflammation. We haveanalyzed the regulation of T cell function by phosphatases (PTPN22 and PTPN2), whose
deficiency is related to the induction of autoimmune diseases. We generated and analyzed mice with a T cell-specific deficiency in these phosphatases and the function of these
phosphatases in T cell activation by identifying associated proteins and performing imaging analysis. The onset of autoimmunity will be then analyzed in these mouse models.
15

Laboratory for

Lab activities

Lymphocyte
Differentiation
Group Director: Tomohiro Kurosaki

Figure: Development of plasma cell precursors in
the germinal center(Left) A population of Bcl6loCD69hi light zone (LZ) GC
cells with IRF4 and higher affinity BCR favors the plasma cell fate. In contrast, Bcl6hiCD69hi cells with lower affinity BCRs favors GC recycling. CD40 acts as a dose-dependent regulator for plasma cell precursor formation.
(Right) CD40 signaling up-regulates adhesion molecules, such as ICAM-1 or SLAM, thereby affording morestable GC B-TFH contacts. The consequence of strong interaction with TFH is the formation of IRF4+Bcl6lo plasmacell-prone GC B cells.

H

Recent Major Publications
Ise W, Fujii K, Shiroguchi K, Ito A, Kometani K, Takeda K,
Kawakami E, Yamashita K, Suzuki K, Okada T, Kurosaki T. T Follicular Helper Cell-Germinal Center B Cell
Interaction Strength Regulates Entry into Plasma Cellor Recycling Germinal Center Cell Fate. Immunity 48,
702–715 (2018)
Inoue T, Shinnakasu R, Ise W, Kawai C, Egawa T, Kurosaki T. The transcription factor Foxo1 controls germinal
center B cell proliferation in response to T cell help. J
Exp Med 214, 1181–1198 (2017)
Shinnakasu R, Kurosaki T. Regulation of memory B andplasma cell differentiation. Curr Opin Immunol 45,
126–131 (2017)

Invited Presentations
Kurosaki T. “Molecular mechanisms of generating
human immune memory responses” Consortium of Biological Sciences 2017 (Kobe, Japan) December, 2017
Kurosaki T. “Selection of Germinal Center B Cells into
the Memory B Cell or Plasma Cell Compartment” KAIInternationl Meeting 2017 (Seoul, South Korea) November, 2017
Kurosaki T. “Selection mechanism of germinal center
cells into plasma fate” The 19th Germinal Centre Conference (Venice, Italy) September, 2017
Kurosaki T. “Molecular mechanisms of generating human immune memory responses” The 19th JSI Immunology Summer School (Hayama, Japan) July, 2017
Kurosaki T. “Selection of germinal-center B cells intomemory B cell or plasma cell Compartment” The 6th NIF
Winter School on Advanced Immunology (Singapore,
Singapore) January, 201716

umoral memory relies on the development of memory B cells and long-lived
plasma cells, and the vast majority of these cells are derived from germinal center (GC) B cells. Therefore, our lab has been focusing on characterizing ofthese three cell types and clarifying how memory B and plasma cells are generated
through GC reactions.
For plasma cell differentiation, BCRs in post-GC plasma cells were heavily
dominated by somatic mutations that result in high affinity antibodies, even ata time when such mutations were present in only a small fraction of GC cells.
Hence, higher-affinity B cells are directed to the plasma cell fate, whereas lower-affinity cells enter into the recycling GC cell pool.
Regarding the selection mechanism, it has been postulated that precursor cells
selected towards recycling GC or plasma cell fates already become committed in
the GC, thereafter entering the recycling dark zone (DZ) or plasmablast pool, respectively. Indeed, it was already reported that IRF4, a key factor for initiatingplasma cell differentiation, is expressed in a small subset of mouse light zone (LZ)
GC B cells. However, these IRF4+ cells did not express the GC transcription factor
Bcl6, therefore the observed IRF4+ cells are not GC cells, but early plasmablasts.
Thus, this “already committed” GC precursor model still remains speculative.
To rigorously test the GC precursor model, we first identified a small population of Bcl6loCD69hi LZ GC cells with higher-affinity BCRs and that express IRF4,
which favors the plasma cell fate over GC recycling. In contrast, Bcl6hiCD69hi LZ
GC cells with lower-affinity BCRs favored GC recycling. The Bcl6loCD69hi population has begun to down-regulate Bcl6 and S1pr2 and to upregulate EBI2, which
likely represent the process of restraining the GC program and of exiting the GC.
Mechanistically, the generation of Bcl6loCD69hi cells relied on CD40 in a dose-dependent manner. Moreover, we found that ICAMI and SLAM levels on LZ GC
cells were up-regulated by CD40 stimulation. Consequently, Bcl6loCD69hi cells expressed higher levels of these adhesion molecules than Bcl6hiCD69hi cells, thereby
affording more stable GC B-TFH contacts; attenuating this interaction decreased
expression of IRF4. Therefore, we propose a precursor model in which the duration of the TFH-GC B interaction is a key decisive factor for formation of plasma
cell precursor versus GC recycling precursor cells.

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Transcriptional
Regulation
Group Director: Ichiro Taniuchi

Figure: Lineage scrambling by loss of Bcl11b inhelper vs cytotoxic lineage choice.
(A) Predicted structure of wild type and mutant Bcl11b
protein lacking the last zinc finger motif at the C-terminal end because of a frameshift mutation. Numbers
above the diagrams indicate amino acid positionsof the five Bcl11b zinc fingers in the mature protein.
Loss of Bcl11b function results in (B) redirection of
MHC class-I selected cells into CD4+CD8− cells and (C)emergence of CD4+CD8− T cells expressing both ThPOKand Runx3.

Recent Major Publications
Tenno M, Kojo S, Lawir D-F, Hess I, Shiroguchi K, Ebihara T, Endo T, Muroi S, Satoh R, Kawamoto H, Boehm
T and Taniuchi I. Cbfβ2 controls differentiation of andconfers homing capacity to pre-thymic progenitors. J
Exp Med 215, 595–610 (2018)
Kojo S, Tanaka H, Endo TA, Muroi S, Liu Y, Seo W, Tenno
M, Kakugawa K, Naoe Y, Nair K, Moro K, Katsuragi Y,
Kanai A, Inaba T, Egawa T, Venkatesh B, Minoda A,
Kominami R, Taniuchi I. Priming of lineage-specifying
genes by Bcl11b is required for lineage choice inpost-selection thymocytes. Nat Commun 8, 702 (2017)
Kakugawa K, Kojo S, Tanaka H, Seo W, Endo T, Kitagawa Y, Muroi S, Tenno M, Yasmin N, Kohwi Y, Sakaguchi
S, Kohwi-Shigematsu, T, Taniuchi I. Essential roles of
SATB1 in specifying T lymphocyte subsets. Cell Rep 19,
1176–1188 (2017)

Invited Presentations
Taniuchi I. “Roles of Runx Transcription Factors in Immune Cell Development” The 46th Annual Meeting of
the Japanese Society for Immunology (Sendai, Japan)
December, 2017
Taniuchi I. “Unique roles of the C-terminal end sequences in Runx and Cbfb proteins” The 21st International
RUNX Conference (Pennsylvania, USA) October, 2017
Taniuchi I. “Roles of Runx Transcription Factors in
Immune System Development” IMS-JSI International
Symposium on Immunology 2017 - Decoding Immune
Complexity from Cell to System - (Tokyo, Japan) June,
2017.
Taniuchi I. “T cell development and Runx transcription
factors” Seminar at the University of Massachusetts(Amherst, USA) May, 2017.
Taniuchi I. “Regulation of T cell development in thethymus by transcription factors” Symposium in Honor of
Ellen Rothenberg, The Molecular Developmental Biology of Lymphocytes (Los Angeles, USA) April, 2017.

T

he vertebrate immune system consists of two components, innate and acquired. The acquired immune system, as defined by the acquisition of a system for generating pools of lymphocytes with a broad variety of antigen-specificities, appeared latter during evolution. Thus, a primary developmental programof T lymphocytes that occurs in a primary lymphoid organ, the thymus, has been
shaped to select useful and non-self-reactive immune soldiers by using a sophisticated nuclear program that integrates environmental cues sensed by T cell antigen
receptors (TCR).
My laboratory has been addressing how TCR signals are integrated into cellfate determination in the cell nucleus by using helper- versus cytotoxic-lineage
choice as a model, in which expression of ThPOK transcription factors serves asa key determinant. Our previous studies identified a transcriptional silencer, referred to as the Thpok silencer, in the Thpok locus as a switch to turn off Thpok
expression and direct MHC class I-selected thymocytes to become cytotoxic-lineage cells. Our recent studies have identified Bcl11b and Satb1 as novel Thpok silencer-binding proteins. Interestingly, both positive and negative regulation of theThpok gene are impaired by loss of either Bcl1b or Satb1, suggesting that these
proteins regulate higher-ordered chromatin structures at the Thpok locus. In linewith this assumption, a site-specific chromatin-immune precipitation technology
revealed that the Thpok silencer is assembled in close proximity to enhancer/promoter regions specifically in cytotoxic-lineage T cells. We also found that the last
Zn-finger domain in the Bcl11b protein is crucial for regulation of not only Thpok
but also Runx3 and Foxp3, another lineage-specifying gene essential for cytotoxic
and regulatory T cell differentiation, respectively. Thus, dysregulated expression of
ThPOK and Runx3 by loss of Bcl11b function led to lineage scrambling, in which asignificant proportion of both MHC class I- and class II-selected cells are redirected into the opposite lineage.

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Laboratory for

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Immune Cell Systems
Group Director : Shigeo Koyasu

Figure: IL-33-ILC2 axis plays an important role inanti-melanoma immunity.
B16 melanoma cells grow in the recipient mice but
intraperitoneal administration of IL-33 significantly
suppresses tumor growth. IL-33 administration induces
infiltration of ILC2 and eosinophils, which likely haveanti-tumor activity, into the tumor tissue.

Recent Major Publications
Ealey KN, Moro K, Koyasu S. Are ILC2s Jekyll and Hydein airway inflammation? Immunol Rev 278, 207–218(2017)
Wagner M, Moro K, Koyasu S. Plastic heterogeneityof innate lymphoid cells in cancer. Trends Cancer 5,326–335 (2017)

Invited Presentations
Koyasu S. “Innate lymphoid cells in helminth infection”
The 10th Federation of African Immunological Societies(FAIS) Congress (Hammamet, Tunisia) December, 201718

W

e have been studying the role of group 2 innate lymphoid cells (ILC2).
ILC2 are capable of producing large amounts of type 2 cytokines such as
IL-5 and IL-13. We examined the role of the IL-33-ILC2 axis in tumor immunity
using the transplantable B16 melanoma model system. We found that intraperitoneal administration of IL-33 significantly reduced melanoma growth in the recipient mice. The protective effect of IL-33 was not observed when we used IL-33
receptor (T1/ST2)-deficient mice as a B16 melanoma cell recipient, indicating that
IL-33 signals are critical for the anti-tumor effect. When we examined the tumor
tissues, we found an infiltration of ILC2 as well as eosinophils, implying that infiltration and proliferation of eosinophils by ILC2-derived eotaxin and IL-5 plays
a role in anti-tumor immunity. We have also found that lactic acid produced bytumor cells suppressed ILC2 expansion in the tumor tissues and that B16 melanoma cells lacking lactate dehydrogenase failed to suppress ILC2 expansion, resulting in a slower melanoma growth rate in the recipient mice compared to micetransplanted with lactate dehydrogenase-sufficient melanoma cells. The effect of
IL-33 treatment was stronger against lactate dehydrogenase-deficient melanoma
cells compared to lactate dehydrogenase-sufficient melanoma cells. These results
suggest that the balance between the IL-33-ILC2 axis and lactate production bytumor cells affects melanoma growth in vivo.

Laboratory for

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Human Disease Models
Group Director: Fumihiko Ishikawa

Figure: Creating new therapeutic strategies
targeting poor prognosis leukemia through amultifaceted approach(Upper) Mutations acquired as early as at the hematopoietic stem cell (HSC) level accumulate over timecreating clonal, but non-malignant, hematopoiesis. In
acute myeloid leukemia (AML) patients, pre-malignant
HSCs continue to generate multilineage hematopoietic
cells as permissive mutations accumulate. With acquisition of a critical mutation, occurring at various levelsof human hematopoietic development, non-malignant
clonal hematopoiesis is converted to malignant hematopoiesis. This creates a state in which non-malignant
multilineage hematopoiesis and leukemic hematopoiesis co-exist. (Lower left) In FLT3-mutated AML
cells, the balance between cell survival and cell death
is disturbed by strong BCL2 function (Lower right) By
targeting a mutation with high malignant potential anda molecule related to therapeutic resistance, leukemia
cells harboring multiple co-existing somatic mutations
are eliminated.

Recent Major Publications
Saito Y, Mochizuki Y, Ogahara I, Watanabe T, Hogdal L,
Takagi S, Sato K, Kaneko A, Kajita H, Uchida N, Fukami
T, Shultz LD, Taniguchi S, Ohara O, Letai AG, Ishikawa
F. Overcoming mutational complexity in acute myeloid
leukemia by inhibition of critical pathways. Sci TransMed 9, eaao1214 (2017)
Najima Y, Tomizawa-Murasawa M, Saito Y, Watanabe
T, Ono R, Ochi T, Suzuki N, Fujiwara H, Ohara O, Shultz
LD, Yasukawa M, Ishikawa F. Induction of WT1-specifichuman CD8+ T cells from human HSCs in HLA class I Tg
NOD/SCID/IL2rgKO mice. Blood 127, 722–734 (2016)

Invited Presentations
Ishikawa F. “Understanding normal and malignant
human hematopoiesis with humanized mice” The 76th
Annual Meeting for Japan Cancer Association (Yokohama, Japan) October, 2017
Ishikawa F. “Functional single cell genomics for leukemia” Stanford ISCBRM-RIKEN IMS Joint Symposium(Stanford, USA) May, 2017T

he specific aim of our laboratory has been to understand the dynamics ofhuman hematopoiesis, immunity, and diseases, and to apply our researchfindings to clinical medicine. By transplanting human normal and malignant stem
cells into immune-compromised NOD/SCID/Il2rgKO (NSG) newborns, we havesucceeded in reconstituting multiple organs of the recipients with human normal
or malignant hematopoiesis. We further aim to create next generation humanized
mice expressing human proteins, such as cytokines and adhesion molecules, thatserve essential roles in mediating signaling in the hematopoietic microenvironment.
In malignant stem cell research, we previously discovered how acute myeloid
leukemia (AML) development and relapse occurs using the humanized mousemodel. Since whole genome sequencing has revealed the presence of multiple
mutations in individual patients’ leukemia cells, we have sought to identify critical mutations that need to be targeted to destroy genetically complex human leukemia. To this end, we are currently approaching the disease by integrating single
cell genomics and the humanized mouse system.

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Intestinal Ecosystem
Group Director: Hiroshi Ohno

Figure: Schematic representation of the mechanism for the role of mast cells in activation of
ILC2s upon helminth infection
Upon helminth infection, ATP is released from injured
epithelial cells (top left) and activates mast cells (bottom left). Activated mast cells release IL-33 which inturn stimulates ILC2s leading to the production of IL-13(bottom center). Finally, IL-13 promotes mucin secretionby goblet cells (top right) to eradicate helminths.

Recent Major Publications
Date Y, Ebisawa M, Fukuda S, Shima H, Obata Y,
Takahashi D, Kato T, Hanazato M, Nakato G, Williams
IR, Hase K, Ohno H. NALT M cells are important for
immune induction for the common mucosal immune
system. Potential Role of the Formation of Tunneling
Nanotubes in HIV-1 Spread in Macrophages. Int Immunol 29, 471–478 (2017)
Jinnohara T, Kanaya T, Hase K, Sakakibara S, Kato T,
Tachibana N, Sasaki T, Hashimoto Y, Sato T, Watarai
H, Kunisawa J, Shibata N, Williams IR, Kiyono H, Ohno
H. IL-22BP dictates characteristics of Peyer's patch
follicle-associated epithelium for antigen uptake. J Exp
Med 214, 1607–1618 (2017)
Shimokawa C, Kanaya T, Hachisuka M, Ishiwata K,
Hisaeda H, Kurashima Y, Kiyono H, Yoshimoto T, Kaisho
T, Ohno H. Mast Cells Are Crucial for Induction of Group
2 Innate Lymphoid Cells and Clearance of Helminth
Infections. Immunity 46, 863–874 (2017)

Invited Presentations
Ohno H. “Small Intestinal Microbes Accelerate Autoimmune Inflammation in the Central Nerve System”
CIMI-PARIS SYMPOSIUM “Microbiota and Medicine”(Paris, France) December, 2017
Ohno H. “Crucial roles of mast cells for induction ofgroup 2 innate lymphoid cells and clearance of helminth infections” 2017 International Conference, Korean Society for Molecular and Cellular Biology (Seoul,
Korea) September, 2017
Ohno H. “The function of M cells in host-microbe
interaction” Falk Foundation Symposium 207 Gut
Microbiome and Mucosal or Systemic Dysfunction:
Mechanisms, Clinical Manifestations and Interventions(Brisbane, Australia) May, 2017
Ohno H. “Integrated multi-omics approach for understanding the gut ecosystem” Institut Necker Enfants
Malades 2nd International Symposium. Immunology
2017: New Horizons (Paris, France) April, 2017
Ohno H. “The impact of gut microbiome on the pathogenesis of experimental autoimmune encephalomyelitis in mice, a model of multiple sclerosis” The 3rd
Microbiome R&D and Business Collaboration Congress:
Asia (Hong Kong, China) March, 201720

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normous numbers of commensal bacteria, called the gut microbiota, residein our intestines; nevertheless, we do not unconditionally accept those microorganisms. The intestinal immune system somehow senses the type and quantityof bacteria in the gut lumen and tries to contain them. Reciprocally, the gut microbiota shape the host immune system, and the host-gut microbiota interaction
profoundly impacts our physiology and pathology.
Gut-associated lymphoid tissue (GALT) such as Peyer’s patches is crucial forintestinal immune responses. GALT are covered by a specialized epithelium calledfollicle-associated epithelium (FAE). The intestinal epithelium is protected fromthe gut microbiota in several ways, e.g., the epithelial cells secrete antimicrobial
proteins such as Reg3γ and are covered by mucus secreted from goblet cells. Fucosylation of the epithelium has also been shown to protect from infection by pathogens such as Salmonella. IL-22 signaling induces all these epithelial phenotypes.
Interestingly, these features are suppressed in FAE by unknown mechanisms. Recently, we have shown that IL-22BP, an endogenous inhibitor of IL-22 signaling, isstrongly expressed only under the FAE and confers the characteristic FAE phenotypes.
We have also reported that mast cells are crucial for induction of group 2 innate lymphoid cells (ILC2s) during the clearance of helminth infection. We foundthat Spi-B-KO mice, which exhibit mast cell hyperplasia, rapidly expelled theHeligmosomoides polygyrus (Hp) nematode. This was accompanied by inductionof ILC2s and goblet cell hyperplasia. Upon Hp infection, mast cells were rapidly
activated to produce IL-33, a potent ILC2 activator, in response to ATP released
from Hp-damaged intestinal epithelium. Inhibition of the ATP receptor on mast
cells rendered the Spi-B-KO mice susceptible to Hp, concomitant with elimination of mast-cell activation and ILC2 induction. These results reveal a previously
unknown role for mast cells in innate immunity in that activation of mast cells by
ATP results in secretion of IL-33 crucial for ILC2 activation (Figure).

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Mucosal Immunity
Team Leader: Sidonia Fagarasan

Figure: Reduced levels of monoamine neurotransmitters in the brain of Pdcd1-/- mice
Imaging mass spectrometry showing the distribution
and relative level of dopamine (DA) and serotonin (5HT) in sagittal brain sections from WT and Pdcd1-/-, thegene encoding PD-1, mice.

Recent Major Publications
Miyajima M, Zhang B, Sugiura Y., Sonomura K., Guerrini
MM, Tsutsui Y, Maruya M, Vogelzang A, Chamoto K,
Honda K, Hikida T, Qin H, Sanuki R, Suzuki K, Furukawa
T, Ishihama Y, Matsuda F, Suematsu M, Honjo T, Fagarasan S. Metabolic shift induced by systemic activationof T cells in PD-1 deficient mice perturbs brain monoamines and emotional behavior. Nat Immunol 18,
1342–1352 (2017)
Chamoto K, Chowdhury PS, Kumar A, Fagarasan S,
Honjo T. Mitochondria activation chemicals synergize
with PD-1 checkpoint blockade for T cell-dependentanti-tumor activity. Proc Natl Acad Sci U S A 114,
E761–E770 (2017)
Zhang B, Chikuma S, Hori S, Fagarasan S, Honjo T.
Nonoverlapping roles of PD-1 and FoxP3 in maintaining
immune tolerance in a novel autoimmune pancreatitis mouse model. Proc Natl Acad Sci U S A 113,
8490–8495 (2016)

Invited Presentations
Fagarasan S. “Excessive T cell activation in the absenceof PD-1 affects behavior” The 1st Cold Spring Harbor
Asia conference on inflammation: Basic Mechanisms
and Relevant Diseases (Shuzou, China) December, 2017
Fagarasan S. “Involvement of PD-1 in antibody diversification and body homeostasis” 19th International
Conference on Lymphatic Tissues and Germinal Centersin Immune Reactions (Venice, Italy) September, 2017
Organizer
Fagarasan S. “Involvement of PD-1 in antibody diversification and systemic homeostasis” 2017 NHRI/IBMS
Joint International Conference on inflammation and
Disease (Taipei, Taiwan) February, 2017

T cell activation has far-reaching effects on other major physiologicalsystems
We have discovered a novel impact of T cell activation on systemic metabolic homeostasis. We demonstrate that besides boosting immunity, the activation of theimmune system has far-reaching effects on other major physiological systems of
the body.
We found that persistent T cell activation resulted in drastic systemic metabolic changes, including significant reduction of almost all proteinogenic amino acids(AA) levels from the serum. Remarkably the reduction of aromatic AA like tryptophan, tyrosine and phenylalanine was evident from a relatively young age (twomonths old) and seems to precede all other aminome changes. Furthermore, we
linked the depletion of tyrosine and tryptophan in the periphery to reduced synthesis of brain monoamine neurotransmitters such as dopamine and serotonin.
We further demonstrated that such biochemical alterations caused abnormal behavior in mice, dominated by anxiety and enhanced fear responses. Dietary tryptophan supplementation aimed at increasing serotonin in PD-1-deficient mice
restored neurotransmitter homeostasis and normal behavior phenotypes.
Mechanistic insights into the T cell-mediated systemic metabolomic shift
We found in vitro and in vivo that activated T cells increased expression of AA
transporters and, as a result, accumulated high concentrations of intracellular AA.
Thus, the observed systemic AA depletion is the result of accumulation of AA inside the activated immune cells, particularly effector/memory T cells.
A remarkable and unexpected finding was that the increase of intracellular
AA cargo occurred despite the concurrent increase in anabolic activity following activation. This finding illustrates a novel and counterintuitive direct rather
than inverse relationship between certain intracellular metabolite concentrations
and their downstream catabolism rates. Our results challenge the dogma that increased protein synthesis and catabolism reduce the levels of free AA within cells,
a notion strongly held in the field of metabolomics.

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Gut Homeostasis
Team Leader: Kenya Honda

Figure: Th1 cell induction and inflammation byectopic colonization of oral microbiota
Scanning electron micrograph of the proximal colonsof Klebsiella pneumoniae strain 2H7 mono-associatedwild-type or colitis-prone IL-10 deficient mice. K. pneumoniae strain 2H7 induced severe inflammation only
in IL-10 deficient mice, suggesting that it acts as a gut
pathobiont in the context of a genetically susceptible
host.

T

Recent Major Publications
Atarashi K, Suda W, Luo C, Kawaguchi, Motoo, Narushima S, Kiguchi Y, Yasuma K, Watanabe E, Tanoue T,
Thaiss CA, Sato M, Toyooka K, Said HS, Yamagami H,
Rice SA, Gevers D, Johnson RC, Segre JA, Chen K, Kolls
JK, Elinav E, Morita H, Xavier RJ, Hattori M, Honda
K. Ectopic colonization of oral bacteria in the intestine
drives TH1 cell induction and inflammation. Science
358, 359–365 (2017)
Honda K, Littman DR. The microbiota in adaptive immune homeostasis and disease. Nature 535, 75–84(2016)
Tanoue T, Atarashi K, Honda K. Development andmaintenance of intestinal regulatory T cells. Nat Rev
Immunol 16, 295–309 (2016)

Invited Presentations
Honda K. “Activation of CD8 T cells by the gut microbiota” CSH ASIA CONFERENCES Microbiota, Metagenomics& Health (Suzhou, China) September, 2017
Honda K. “Intestinal Colonization Resistance Against
Oral Resident Bacteria” 18th International Congress of
Mucosal Immunology (ICMI 2017) (Washington D.C.
USA) July, 2017
Honda K. “Modulation of the immune system by the gut
microbiota” CSHL Fundamental Immunology & Its Therapeutic Potential (Cold Spring Harbor, USA) April, 2017
Honda K. “Immune modulation by the gut microbiota”
CSH ASIA CONFERENCES Bacterial Infection & Host Defense (Suzhou, China) April, 2017
Honda K. “Regulation of the immune system by the gut
microbiota” Alberta-Japan Agency for Medical Researchand Development (AMED) Workshop for Medical Innovation (Calgary, Canada) February, 201722

he Laboratory for Gut Homeostasis has been trying to identify specific membersof the gut microbiota that regulate specific branches of the host mucosal immune
system. Our long-term goal is to develop new strategies to treat pathological conditions
such as inflammatory bowel disease (IBD), allergy, cancer, and obesity by well-informed
manipulation of the gut microbiota.
Previously, we succeeded in isolation of 17 human gut-derived clostridial strains thatare potent inducers of intestinal CD4+Foxp3+ regulatory T (Treg) cells. These strains areable to trigger the accumulation of colonic Treg cells with strong suppressive activity for
effector T cells. Oral introduction of these 17 strains resulted in reduced GVHD severity
and this was mediated through production of short chain fatty acids by the 17 strains. We
also isolated 20 strains of TH17-inducing bacteria strains consisting of various genera
from an ulcerative colitis patient fecal sample. The 20 strains induce TH17 cells throughadhesion to colonic epithelial cells.
This year, we searched for immune stimulatory bacteria in the human saliva microbiota, because it has been reported that intestinal colonization by bacteria of oral origin
correlates with several negative health outcomes, such as IBD. Moreover, oral bacteria
are often resistant to multiple antibiotics and can cause healthcare-associated intestinal
infections. However, the precise influence exerted by ectopically colonized oral bacteria in the gut still remains unclear. To identify immune stimulatory bacteria of humanoral origin, saliva samples were obtained from healthy human donors and patients with
Crohn’s disease (CD) and inoculated into germ-free (GF) mice. A saliva sample from one
CD patient induced a marked accumulation of TH1 cells in the colonic lamina propria of
the inoculated mice. We cultured cecal contents from the mice inoculated with the CDpatient saliva and succeeded in isolation of 8 individual bacterial strains. A significant
increase in Th1 cells was observed in GF mice inoculated with a mixture of the isolated 8
strains. Among the 8 strains, a Klebsiella pneumoniae strain was found to be responsible
for TH1 cell induction. The isolated Klebsiella strain was resistant to multiple antibiotics,
tended to colonize in dysbiotic microbiota and elicited a severe gut inflammation in mice
genetically prone to colitis (Fig). These bacteria appeared to produce innate immune ligands, most likely packaged in outer membrane vesicles, to induce TH1 cells. Our worksuggests that there is a subtype of IBD in which bacteria of oral origin contribute to thepathogenesis.

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Immune Homeostasis
Team Leader: Taishin Akiyama

Figure: A hypothetical model of mTEC differentiation
Aire-expressing mature mTECs differentiate from
common progenitor cells through pro-pMEC and pMEC
stages. Mechanisms underlying commitment to mTEC
lineage remain to be determined. We are trying to
identify critical regulators for mTEC commitment (referred to as “X”).

Recent Major Publications
Inuki S, Aiba T, Kawakami S, Akiyama T, Inoue JI, Fujimoto Y. Chemical Synthesis of d-glycero-d-manno-Heptose 1,7-Bisphosphate and Evaluation of Its Ability to
Modulate NF-κB Activation. Org Lett 19, 3079–3082(2017)
Kawasaki M, Kawasaki K, Oommen S, Blackburn J,
Watanabe M, Nagai T, Kitamura A, Maeda T, Liu B,
Schmidt-Ullrich R, Akiyama T, Inoue J, Hammond NL,
Sharpe PT, Ohazama A. Regional regulation of Filiform
tongue papillae development by Ikkα/Irf6. Dev Dyn
245, 937–946 (2016)
Akiyama N, Takizawa N, Miyauchi M, Yanai H, Tateishi
R, Shinzawa M, Yoshinaga R, Kurihara M, Demizu Y,
Yasuda H, Yagi S, Wu G, Matsumoto M, Sakamoto
R, Yoshida N, Penninger JM, Kobayashi Y, Inoue J,
Akiyama T. Identification of embryonic precursor cells
that differentiate into thymic epithelial cells expressing
autoimmune regulator. J Exp Med 213, 1441-1458(2016)

M

edullary thymic epithelial cells (mTECs) play an essential role in self-tolerance induction. mTECs have the unique ability to express many kindsof self-antigens, including proteins that are expressed in a tissue-specific manner(tissue specific antigens; TSAs). TSAs are presented to developing T cells in thethymic medulla either directly by mTECs or indirectly by thymic dendritic cells.
As result, developing T cells recognizing TSA peptide-MHC complexes undergo
apoptosis or conversion into regulatory T cells, which suppress immune reactions.
The transcription factor autoimmune regulator (Aire) promotes expression ofsome TSAs and controls self-tolerance induction mediated by mTECs.
Several studies showed that mTEC development is dependent on signalingfrom tumor necrosis factor (TNF) receptor family, receptor activator of NF-κB(RANK), CD40, and lymphotoxin β-receptor (LtβR). It was reported that signaling through these receptors activates the NF-κB transcription factor via two distinct intracellular signaling pathways, classical and non-classical NF-κB pathways.
These two modes of NF-κB activation have non-redundant roles in developmentof Aire-expressing mTECs (Aire+ mTECs). However, it remained to be determinedwhich mTEC differentiation stages are regulated by these signaling pathways.
We recently identified embryonic precursor cells of Aire+ mTECs (pMECs).
The pMECs expresses both the mTEC maker UEA-1 ligand and cortical TEC molecules and differentiate into mTECs that are capable of suppressing autoimmune
disease onset caused by mTEC dysfunction. Classical NF-κB activation by RANK
signaling promotes differentiation of pMEC into Aire+ mTECs. Non-classical NFκB activation triggered by RANK and LtβR signaling promotes pMEC induction
from their progenitors Thus, cytokine-dependent differentiation of embryonic
Aire+ mTECs is divided into two stages regulated by distinct intracellular signaling pathways. We are currently investigating gene expression profiles of pMECs
and their precursor pro-pMECs to identify molecules critical for commitment to
mTEC differentiation.
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Skin Homeostasis
Team Leader: Masayuki Amagai

Figure: Comprehensive analysis of skin barrier
homeostasis
Our team is trying to clarify the mechanisms of skinbarrier homeostasis by focusing on stratum corneum(SC), tight junction (TJ), and SG1 cells. We establisheda live imaging system to study the cornification process
in mice. We also focus on the study of host-microbe
interactions on skin.

Recent Major Publications
Miyamoto A, Lee S, Cooray NF, Lee S, Mori M, Matsuhisa N, Jin H, Yoda L, Yokota T, Itoh A, Sekino M,
Kawasaki H, Ebihara T, Amagai M, Someya T. Inflammation-free, gas-permeable, lightweight, stretchable
on-skin electronics with nanomeshes. Nat Nanotechnol 12, 907–913 (2017)
Amagai M. Modulating immunity to treat autoimmune
disease. New Eng J Med 375, 1487–1489 (2016)
Yokouchi M, Atsugi T, Logtestijn MV, Tanaka RJ, Kajimura M, Suematsu M, Furuse M, Amagai M, Kubo A.
Epidermal cell turnover across tight junctions based on
Kelvin's tetrakaidecahedron cell shape. eLife 5, e19593(2016)

Invited Presentations
Amagai M. “Stratum corneum as niche to control skinmicrobiota” The 6th Global Network Forum on Infection
and Immunity (Chiba, Japan) October, 2017
Amagai M. “Cracking the codes of autoimmune andallergic skin diseases” Rudi Cormane Lecture at 47th
Annual Meeting of the European Society of Dermatological Research (Salzburg, Austria) September, 2017
Matsui T. “Regulation of skin epidermal barrier formation by Ca2+ and pH” The Leibniz-AMED Workshop,
Chronic Inflammation, Infection and Healthy Aging(Ettal, Germany) September, 2017
Matsui T. “Involvement of endogenous retrovirus in theadaptive evolution of skin” The 2nd Japan-Korea International Symposium for Transposable Elements (Tokyo,
Japan) June, 2017
Amagai M. “Skin barrier homeostasis and its failure”
2017 NHRI/IBMS Joint International Conference on Inflammation & Diseases (Taipei, Taiwan) February, 201724

S

kin is the site where immunity meets external antigens. Cutaneous sensitization is now thought to be the initial key step for many allergic disorders, notonly atopic dermatitis (AD), but also asthma, food allergy and anaphylaxis. Skin
harbors several barriers to prevent easy penetration of external antigens into thebody; however, the exact molecular mechanisms by which the skin barriers form
and are maintained are largely unknown. The epidermis is keratinized stratified
squamous epithelia and is the outermost component of the skin. From bottom totop, the epidermis is composed of the stratum basale, stratum spinosum, stratum
granulosum (SG) and stratum corneum (SC). Our group has been focusing on the
SC barrier as an air-liquid barrier, and on tight junctions (TJ) as a liquid-liquidbarrier formed between SG2 cells, among many other skin barriers. There is afundamental biophysical paradox regarding the function of the epidermis, namely, how it can maintain the barrier but still constantly replace and shed cells. Ourgroup is trying to clarify how epidermal barrier homeostasis in maintained under normal conditions and how impaired barrier function occurs and affects microenvironments of the skin in various disease conditions. We use comprehensive
approaches combining molecular biology, biochemistry, ultrastructural anatomy,
live cell imaging, microbiology, and systems biology. For example, we have recently succeeded in isolating and characterizing SG1 cells and also in visualizing
SC-pH in living mice, which enables us to perform several unique experiments tounderstand SC homeostasis. Another of our strengths is to be able to go back andforth between the findings in basic science in mice and those in clinical science inhumans with various skin diseases. Our goal is to understand skin barrier homeostasis in health and diseases, and to provide patients suffering from severe allergic
diseases with more targeted, ideal therapeutic approaches with fewer side effects.

Laboratory for

Lab activities

Metabolic Homeostasis
Team Leader: Naoto Kubota

Figure: Pathology arising from failure of insulin
homeostasis
In chronic energy excessive conditions, e.g., sustained
hyperinsulinemia observed in obesity, there is aconsistent reduction in the expression levels of Irs2, but
not of Irs1, in endothelial cells, liver cells andmacrophages. This results in impaired insulin-induced
glucose uptake and suppression of gluconeogenesis. On
the other hand, since the expression level of Irs1 is notdecreased, excessive insulin activity is observed in liver,smooth muscle cells, cancer cells and adipose tissue,
where Irs1 plays pivotal role in insulin signaling. This
results in increased hepatic lipogenesis, progression ofatherosclerosis, cancer, and obesity under conditions ofsustained hyperinsulinemia.

Recent Major Publications
Sasaki M, Sasako T, Kubota N, Sakurai Y, Takamoto I,
Kubota T, Inagi R, Seki G, Goto M, Ueki K, Nangaku M,
Jomori T, Kadowaki T. Dual Regulation of Gluconeogenesis by Insulin and Glucose in the Proximal Tubules of
the Kidney. Diabetes 66, 2339–2350 (2017)
Sakurai Y, Kubota N, Takamoto I, Obata A, Iwamoto M,
Hayashi T, Aihara M, Kubota T, Nishihara H, Kadowaki
T. Role of insulin receptor substrates in the progressionof hepatocellular carcinoma. Sci Rep 7, 5387 (2017)
Kubota T, Kubota N, Kadowaki T. Imbalanced Insulin
Actions in Obesity and Type 2 Diabetes: Key Mouse
Models of Insulin Signaling Pathway. Cell Metab 25,
797–810 (2017)

Invited Presentations
Kubota T. “Molecular mechanisms of impairment of
M2-type macrophage activation in obesity” 22th Adiposcience Symposium (Osaka, Japan) Aug, 2017
Kubota N, Kubota N, Kadowaki T. “Insulin resistanceand atherosclerosis” The 60th Annual Meeting of theJapan Diabetes Society (Nagoya, Japan) May, 2017
Kubota N, Kubota N, Kadowaki T. “New concept of
insulin resistance-Metabolic zonation in liver-” The 60th
Annual Meeting of the Japan Diabetes Society (Nagoya, Japan) May, 2017I

n recent years, there has been a rapid increase in the incidence of type 2 diabetes
in both Western and Asian countries. However, the precise molecular mechanisms
underlying the progression of type 2 diabetes remain poorly understand. The goal of ourteam is to identify molecular mechanisms of insulin secretion and insulin resistance.
1) Molecular mechanism of insulin secretion
Impaired insulin secretion leads to the development of type 2 diabetes. This impaired
insulin secretion is thought to be partially caused by genetic factors. Most of the common variant single-nucleotide polymorphisms (SNPs) identified by genome-wide association study (GWAS) have been reported to be associated with defective pancreatic islet
function. However, the functional role of genes identified by GWAS remains unclear. To
elucidate the physiology and pathophysiological role of such genes in vivo, we have generated genetically engineered mice (Diabetologia 2014). Specifically, we are investigating
common variants in potassium voltage-gated channel subfamily Q member 1 (KCNQ1)
and ubiquitin-conjugating enzyme E2 E2 (UBE2E2), which confer the largest effect on
the risk of type 2 diabetes in Asians.
2) Molecular mechanism of insulin resistanceObesity-induced insulin resistance plays a crucial role as the pathogenesis of lifestyle-related diseases, including metabolic syndrome, nonalcoholic fatty liver disease (NAFLD),
and type 2 diabetes. Insulin resistance is defined as a condition in which physiologicalinsulin signals are impaired for some reason, such as chronic inflammation. Once insulinbinds to the insulin receptor, insulin receptor substrate (IRS)-1 and IRS-2 are activated,and mediate intracellular insulin signaling. Until now, we have been studying the role of
IRS-1 and IRS-2, which show ubiquitous expression patterns (Diabetes 2000, Circulation 2003, J Clin Invest 2004, Cell Metab 2008, Cell Metab 2011, Cell 2012, Nat Commun
2016, Sci Rep 2017, Cell Metab 2017). We will continue to clarify the underlying mechanisms of insulin resistance by studying new aspects of these two molecules.

25

Laboratory for

Lab activities

Immune Crosstalk
Team Leader: Hilde Cheroutre

Figure: Our major interest is to understand thelink between T cell receptor (TCR) signals at theplasma membrane and nuclear gene expression
in developing thymocytes and activated T cells
We identified a novel RARα isoform that localizes
preferentially in the cytoplasm (cRARα). This isoform
is distinct from the nuclear RARα (nRARα) and is
involved in proximal TCR signaling and TCR-induced
Notch and c-myc activation, which promote initial T cellproliferation. In another project we examine Themis.
Cytoplasmic Themis resides proximal to the TCR and isconstitutively associated with Grb2, which binds both
LAT and SHP1 and negatively affects TCR signaling. We
found that Themis also localizes to the nucleus and thatits translocation to the nucleus is critical for its function
in developing thymocytes. We are now aiming toelucidate the nuclear function of Themis and evaluate
the importance of its genomic function in thymocyte
development and T cell activation.

Recent Major Publications
Nieke S, Yasmin N, Kakugawa K, Yokomizo T, Muroi S,
Taniuchi I. Unique N-terminal sequences in two Runx1
isoforms are dispensable for Runx1 function. BMC Dev
Biol 17, 14 (2017)
Kakugawa K, Kojo S, Tanaka H, Seo W, Endo TA, Kitagawa Y, Muroi S, Tenno M, Yasmin N, Kohwi Y, Sakaguchi
S, Kowhi-Shigematsu T, Taniuchi I. Essential Roles of
SATB1 in Specifying T Lymphocyte Subsets. Cell Rep
19, 1176–1188 (2017)
Larange A, Cheroutre H. Retinoic Acid and Retinoic Acid
Receptors as Pleiotropic Modulators of the Immune
System. Annu Rev Immunol 34, 369–394 (2016)
Verstichel G, Vermijlen D, Martens L, Goetgeluk G,
Brouwer M, Thiault N, Van Caeneghem Y, De Munter S,
Weening K, Bonte S, Leclerq G, Taghon T, Kerre T, Saevs
Y, Van Dorpe J, Cheroutre H, Vandekerckhove B. The
checkpoint for agonist selection precedes conventional
selection in human thymus. Sci Immunol 2, eaah4232(2017)

Invited Presentations
Cheroutre H. “Control of the Functional Fate of CD4
T Cells by LncRNA” National Institute of Health MIST
meeting (Bethesda, USA) June, 2017
Cheroutre H. “Non-genomic function of RARalpha in T
cells” Institute for Research in Biomedicine (Bellinzona,
Switzerland) April, 2017
Cheroutre H. “CD4 CTL at the mucosal barrier” The
Chiba-UCSD Mucosal Immunology and Vaccine Symposium, UCSD (La Jolla, USA) March, 2017
Cheroutre H. “A Give-and-Take Relation between TGFbeta and the Gut Environment Drives the CD4 CTL Fate.”
Keystone Symposia: TGF-β in Immunity, Inflammation
and Cancer (Taos, USA) January, 201726

W

e discovered cytoplasmic retinoic acid receptor alpha (cRARα) as a newmember of the TCR signalosome and an interacting partner with ZAP70.
We found that cRARα plays a critical non-genomic role in the proximal TCR signaling complex as well as in TCR-induced NOTCH activation and c-Myc expression
and early activation-induced proliferation. Furthermore, we characterized cRARαat the molecular level and identified it as an alternative splice form of the nuclear
RARα1 and -2, with a shared conserved C-terminal region containing the ligand
binding domain (LBD). Cytoplasmic RARα is expressed by mature T cells as wellas immature thymocytes, indicating that RARα might also serve non-genomicroles during thymic development and selection. We are now designing various in
vitro and in vivo strategies to fully characterize the non-genomic function of RARαat the molecular and cellular level and under physiological and disease settings. In
another study, we newly identified Themis as an essential gene for T cell development by phenotype screening of ENU-induced mutant mice. Themis functions
by interacting with Grb2 and SHP1, thus down-modulating TCR signal strengthand allowing positive selection of thymocytes that further mature to conventionalnaïve T cells. By generating specific nuclear localization signal deletion mutants,
we now find that the nuclear localization of Themis is critical and essential for
its function. Therefore, in addition to its function in proximal TCR signaling, we
speculate that Themis also plays a role in the nucleus to control TCR-induced gene
expression. We are now aiming to elucidate the genomic function of Themis. We
generated a Themis-ERT2 fusion protein, which tethers Themis protein in thecytoplasm and induces nuclear translocation upon tamoxifen administration. In
addition, we are also generating ChIP-seq data using a newly generated x3FLAG
tagged Themis knock-in mouse.

Laboratory for

Lab activities

Inflammatory Regulation
Team Leader: Takashi Tanaka

Figure: Microbiota-dependent development of
NASH in PDLIM2-deficient mice
Representative Hematoxylin and Eosin (HE)-stained
liver histopathology in wild-type and PDLIM2-deficientmice. PDLIM2-deficient liver showed massive accumulation of lipid droplets in the hepatocytes and theinfiltration of inflammatory cells.

Recent Major Publications
Shin C, Ito Y, Ichikawa S, Tokunaga M, Sakata-Sogawa
K, Tanaka T. MKRN2 is a novel ubiquitin E3 ligase forthe p65 subunit of NF-κβ and negatively regulates inflammatory responses. Sci Rep 7, 46097 (2017)
Tanaka T. Clarification of the molecular mechanismsthat negatively regulate inflammatory responses. In:
Miyasaka M, Takatsu K. (eds.), Chronic Inflammation:
Mechanisms and Regulation, 1st edition, Tokyo,
Japan: Springer Japan KK, pp109–118 (2016)

Invited Presentations
Tanaka T. “Microbiota-dependent development of
non-alcoholic steatohepatitis (NASH) in PDLIM2-deficient mice” Luxembourg FNR-RIKEN Joint Symposium,
Understanding Inflammatory Diseases beyond Complexity (Yokohama, Japan) October, 2017
Tanaka T. “Molecular mechanism how Nahlsgen controls biological function of the skin” NAHLS Research
Symposium (Osaka, Japan) October, 2017
Tanaka T. “Negative regulation of inflammatory responses by LIM proteins” The 1st RIKEN-McGill Symposium, Excellence in Immunology & Genetics (Montreal,
Canada) May, 2017T

he inflammatory response is an important host defense mechanism to sense
and eliminate invading microbial pathogens. However, these inflammatory
responses must be terminated at the appropriate time point, otherwise excessive
and uncontrolled responses can damage normal tissue and lead to chronic inflammatory diseases. Our research goal is to identify a series of key negative regulatorsof inflammation and clarify the complete picture of the molecular mechanisms forregulating inflammatory responses.
Non-alcoholic steatohepatitis (NASH) is a chronic hepatic inflammation associated with immune cell infiltration and fibrosis. In recent years, NASH has
become clinically important, since 10–20% of NASH cases may progress to livercirrhosis and hepatocellular carcinoma. However, the molecular mechanisms underlying the development of NASH remain unclear. PDLIM2 is a nuclear ubiquitin E3 ligase containing PDZ and LIM domains. In our previous study, we demonstrated that PDLIM2 functions as a ubiquitin E3 ligase for NF-κB and STAT3/4
transcription factors, negatively regulating inflammatory responses. We recently
found that PDLIM2-deficient mice spontaneously develop NASH-like pathology.
Notably, the onset of NASH in these mice completely depends on their environment. PDLIM2-deficient mice develop NASH in the animal facility of Harvard
University but not in the RIKEN Yokohama facility. It is well known that systemic inflammation can be modified by gut microbiota. We therefore colonized gut
microbiota from Taconic Farms mice into germ-free PDLIM2-deficient mice andfound that PDLIM2-deficient mice with Taconic microbiota environment could
develop NASH even in the RIKEN facility when fed a higher fat diet. Microarray
analysis of PDLIM2-deficient liver showed the upregulation of several inflammation and metabolism-related genes. These data suggest that the Taconic microbiota environment is essential for the development of NASH in combination withPDLIM2-deficiency. We are now trying to identify the specific microbes or microbiota-derived metabolites that contribute to the NASH phenotype.
27

Laboratory for

Lab activities

Cytokine Regulation
Team Leader: Masato Kubo

Figure: Innate and adaptive immunity crosstalkduring the sensitization and challenge phase oflung inflammation
In the sensitization phase (solid lines), pulmonary
epithelial cells can be activated directly by proteaseallergens. In response, lung epithelial cells release IL33 that directly or indirectly activates ILC2 to produce
IL-13. In some cases, lung eosinophils could be analternative source of IL-13. IL-13 drives the maturationof CD11b+ cDCs, which depend on the transcription
factor IRF4 for their maturation from pre-cDCs. After
activation, the CD11b+ cDCs migrate into the draining
mediastinal lymph nodes, where naïve T cells differentiate into Th2 cells. During the challenge phase(dashed lines), DCs again have a predominant role inTh2 effector function. A high dose of protease allergenactivates monocytic DCs (moDCs) and recruits effector
Th2 cells through the production of CCL17 and CCL22.
In this case, moDCs need to express pattern-recognition
receptors, such as TLRs, to stimulate release of thesechemokines. The pulmonary epithelial cell-derived IL33 directly activates effector Th2 cells to produce IL-5
and IL-13, while the allergen-bearing DCs activate theproduction of all Th2 cytokines, including IL-4, IL-5, andIL-13, in the response to allergen.
Recent Major Publications
Wang Y, Kuang Z, Yu X, Ruhn KA, Kubo M, Hooper LV.
The intestinal microbiota regulates body composition
through NFIL3 and the circadian clock. Science 357,
912–916 (2017)
Kubo M. Innate and adaptive type 2 immunity inlung allergic inflammation. Immunol Review, 278,
162–172 (2017)
Kubo M. T follicular helper and TH2 cells in allergic responses. Allergol Int 66,377–381 (2017)
Invited Presentations
Kubo M. “Role of T follicular helper (TFH) and TH1 in flu
specific humoral immunity” Cytokine 2017 (Kanazawa,
Japan) October-November, 2017
Kubo M. “A Role of STAT3 in Barrier Integrity and Microbiota Composition of the Skin” Annual Conference ofthe Wide River Institute of Immunology International
Symposium (Soul, Korea) October, 2017
Kubo M. “Role of cytokine in skin homeostasis andatopic dermatitis” The 4th Japan-Lithuania Natural andLife Sciences Joint Symposium (Tokyo, Japan) October,
2017
Kubo M. “Cytokine signaling in allergic responses” The
3rd Tsinghua-RIKEN Joint Workshop (Beijing, China)
September, 2017
Kubo M. “New therapeutic approach for atopic dermatitis (AD) using comprehensive analysis and system
biology” International Biomedical Interface Symposium(Taipei, Taiwan) March, 201728

T

cells play a central role in the effector and regulatory functions of the immunological surveillance system, and aberrations in these functions can lead tovarious immunological disorders. IL-4 is a cytokine commonly secreted by TH2
and follicular helper T (TFH) cells after antigenic sensitization. TFH-derived IL-4
is the major contributor to class switch recombination to Immunoglobulin G1(IgG1) and E (IgE). We have summarized in a review article in Allergology International (2017) how TH2 and TFH cells contribute to asthma, a pulmonary allergic inflammatory disease, resulting in bronchial hyper reactivity. Atopic asthma
is defined by IgE antibody-mediated mast cell degranulation, while in non-atopic
asthma there is no allergen specific IgE and more involvement of innate immune
cells, such as basophils, group 2 innate lymphoid cells (ILC2), and eosinophils. An
innate cell network (IL-33/TSLP - basophil - ILC2 - IL-5/IL-13 axis) can facilitate
the sensitization phase of a type 2 inflammatory responses, and this innate network further contributes to the adaptive Th2 cell response in the chronic state. We
have discussed the interface and cross-talk between innate and adaptive immune
cells in asthma in a review article in Immunological Reviews (2017).
We have accumulated evidence that NFIL3/E4BP4 is a CLOCK regulatingtranscription factor that also has a critical role in the pulmonary allergic inflammatory response via controlling development of ILC2s and IL-10 and IL-13 production. Recently, in collaboration with our group, Lora Hooper found a novelrole for NFIL-3 as a CLOCK regulator of circadian oscillation-controlled lipid
absorption and export in intestinal epithelial cells thorough a DC-ILC3 innate immune cell network (Science, 2017).

Laboratory for

Lab activities

Innate Immune Systems
Team Leader: Kazuyo Moro

Figure: Development of ILC2 occur in the peripheral tissues.
Step 1 (Lineage commitment): Strength and durationof Notch signals and IL-7 concentrations coordinately
regulate the cell fate decision to T cell, B cell, or ILCs
from CLP. Step 2 (Terminal differentiation): After commitment to the ILC lineage, CHILP or ILCP migrate to theperipheral tissues during the fetal stage. CCR9+ ILC2
committed progenitors (CCR9+ ILCP) predominantly
differentiate to immature ILC2 in situ with the supportof CD45-CD31- PDGFRα+gp38+ mesenchymal cells in
the mesentery. STAT5 activators are essential for theirmaturation after birth.

Recent Major Publications
Koga S, Hozumi K, Hirano K, Yazawa M, Terooatea T,
Minoda A, Koyasu S, Moro K. Peripheral PDGFRα+gp38+
mesenchymal cells support the differentiation of fetalliver-derived ILC2. J. Exp. Med. in press
Kamatani T, Fukunaga K, Miyata K, Shirasaki Y, Tanaka
J, Baba R, Matsusaka M, Kamatani N, Moro K, Betsuyaku T, Uemura S. Construction of a system using a deeplearning algorithm to count cell numbers in nanoliter
wells for viable single-cell experiments. Sci Rep 7,16831 (2017)
Moro K, Kabata H, Tanabe M, Koga S, Takeno N, Mochizuki M, Fukunaga K, Asano K, Betsuyaku T, Koyasu S.
Interferon and IL-27 antagonize the function of group
2 innate lymphoid cells and type 2 innate immune responses. Nat Immunol 17, 76–86. (2016)

Invited Presentations
Moro K. “Role of fetal liver and peripheral tissues indevelopment and maturation of ILC2” The 46th Annual
Meeting of The Japanese Society for Immunology (Sendai, Japan) December, 2017
Moro K. “Current topics in the innate immune system”
The 5th Annual Meeting of the International Cytokine
and Interferon Society (Kanazawa, Japan) November,
2017
Moro K. “Regulation of lipid metabolite-mediated IL-4
production in group 2 innate lymphoid cells.” The 65th
Annual Meeting of Japanese Society of Allergology(Tokyo, Japan) June, 2017
Moro K. “Discovery of group 2 innate lymphoid cells”
The American Association of Immunologists Annual
Meeting (Washington D.C., USA) May, 2017
Moro K. “Group 2 innate lymphoid cell and allergic
inflammation” Advances in Targeted Therapies Meeting2017 (Mandelieu, France) March, 2017O

ur research group focuses on group 2 innate lymphoid cells (ILC2), an innate lymphocyte lineage that we identified in 2010. ILC2 localize to a variety of tissues such as fat, lung, intestine, liver and skin, and mediate immunity tohelminth and fungal infections via strong type 2 cytokine production. Infection
with helminths or fungi induces IL-25 and IL-33 production by epithelial cells or
endothelial cells and activates ILC2, leading to eosinophilia and goblet cell hyperplasia resulting from the activity of IL-5 and IL-13, respectively.
ILC2 are thought to derive from common lymphoid progenitors (CLP) in thebone marrow (BM). The transcription factors essential for ILC2 differentiation
have been extensively studied. However, the external factors regulating commitment of CLP to the ILC lineage, as well as the sites and stromal cells that constitute the optimal microenvironment for ILC2-specific differentiation, are not fully
defined. To this end, we focused on the development of ILC2 in the peripheral
tissues. First, we found that concentration of IL-7, strength and duration of Notch
signaling are three key external factors important in the process of CLP to common helper-like ILC progenitor (CHILP) differentiation in the fetal liver. Next,
we identified three different stages of ILC2 in the fetal mesentery: ILC progenitors
lacking the developmental potential to become T or B cells; CCR9+ ILC2 progenitors that differentiate predominantly into ILC2; and KLRG1- immature ILC2 that
require STAT5 signals for maturation. We further demonstrated that ILC2 differentiation from ILC progenitors, but not from CLP, is supported by mesenteric PDGFRα+gp38+ mesenchymal cells. Collectively, our results suggest that early
differentiation of ILC2 up until the ILC-committed progenitor stage occurs in the
fetal liver via IL-7 and Notch signals, while final differentiation after the CHILP/
ILCP stage occurs in the peripheral tissues with the aid of PDGFRα+gp38+ stromalcells.

29

Core for
Precise Measuringand ModelingToward the ultimate goal of obtaining a comprehensive understanding of
the pathogenesis of human diseases, the functions of the Core for Precise
Measuring and Modeling are three pronged: production of mouse models,
multiomics measurements and quantitative bioimaging, and bioinformatics/modeling of human disease processes. Through close interactions among
these three branches of the core, we aim to collect a wide variety of quantitative data in order to build a computational and predictive network of the disease process. As for the production of genetically engineered mice that will be
used as models of human diseases, the laboratory for Developmental Genetics has begun to apply recent advances in genome engineering technology,e.g., CRISPR/Cas9-based genome editing, and thereby considerably enhance
the production capacity and power of the disease models. Regarding the
precise quantitative measurements branch, we have recently enhanced thepower of metabolite analysis by the Laboratory for Metabolomics. Together
with mRNA/protein profiling by the Laboratory for Integrative Genomics, theenhanced multiomics measurements and bio-imaging (Laboratory for Tissue
Dynamics) will greatly contribute to exploration of the etiology of humandiseases. After being processed by bioinformatics (Laboratory for Integrated
Bioinformatics), the datasets are used for modeling (Laboratories for Disease
Systems Modeling and Integrated Cellular Systems). The laboratory for Medical Science Mathematics is working to fill the gap between humans and mice.
As a leading IMS project, an atopic dermatitis model mouse, provided by the
Laboratory for Immunogenetics, has been extensively analyzed from several
different angles, fully exploiting the analysis powers of this core. These efforts
should enable us to identify new biomarkers for early diagnosis and prevention of atopic dermatitis in the very near future.

30

Laboratory for

Lab activities

Developmental Genetics
Group Director: Haruhiko Koseki

Figure: RNF20-mediated H2BK120ub1 facilitates
initiation of early replication
RNF20-mediated H2B monoubiquitination demarcatesvery early replicating regions and contributes to maintain precise replicating timing.

Recent Major Publications
Dong Y, Isono KI, Ohbo K, Endo TA, Ohara O, Maekawa
M, Toyama Y, Ito C, Toshimori K, Helin K, Ogonuki N,
Inoue K, Ogura A, Yamagata K, Kitabayashi I, Koseki
H. EPC1/TIP60-mediated histone acetylation facilitates
spermiogenesis in mice. Mol Cell Biol 37, e00082–17(2017)
Almeida M, Pintacuda G, Masui O, Koseki Y, Gdula M,
Cerase A, Brown D, Mould A, Innocent C, Nakayama
M, Schermelleh L, Nesterova TB, Koseki H, Brockdorff
N. PCGF3/5-PRC1 initiates Polycomb recruitment in X
chromosome inactivation. Science 356, 1081–1084(2017)
Endoh M, Endo TA, Shinga J, Hayashi K, Farcas A,
Ma KW, Ito S, Sharif J, Endoh T, Onaga N, Nakayama
M, Ishikura T, Masui O, Kessler BM, Suda T, Ohara O,
Okuda A, Klose RJ, Koseki H. PCGF6-PRC1 suppresses
premature differentiation of mouse embryonic stem
cells by regulating germ cell-related genes. Elife 6,
e21064 (2017)

Invited Presentations
Koseki H. “Activating Polycomb-repressed genes inmammals” France-Japan Epigenetics Workshop (Paris,
France) November, 2017
Koseki H. “Development of adoptive immunotherapy
for cancer using iPS-derived NKT cells” The 21st Annual
Meeting of Japanese Association of Cancer Immunology (Chiba, Japan) June, 2017
Koseki H. “Polycomb-mediated regulation of transitionof transcriptional status” The 69th Annual Meeting of
the Japan Society for Cell Biology (Sendai, Japan) June,
2017
Koseki H. “Clinical potential of iPS cell-derived invariant
NKT cells” Stanford ISCBRM-RIKEN IMS Joint Symposium (Stanford, USA) May, 2017
Koseki H. “Gene regulation by Polycomb variants” RIKEN-McGill Symposium (Montreal, Canada) May, 2017T

he Developmental Genetics Research Group is pursuing a research program
to elucidate the molecular mechanisms underlying organ development andstem cell functions. Particular emphasis has been put on epigenetic regulation
mediated by the combinatorial actions of Polycomb group (PcG) gene products,
DNA methylation mechanisms and cell cycle regulation.
DNA replication timing – a term coined to describe the temporal order of
DNA segments being replicated in S phase – is recently considered a new epigenetic mark. Like its epigenetic counterparts, DNA replication timing is also cell
type-specific and highly correlated with gene transcription status. However, it remains unclear how DNA replication timing is established and whether it is a regulator of gene transcription, or vice versa. To answer these questions, we exploited
H2B ubiquitination (H2BK120ub1), a histone modification required for efficient
DNA replication and gene transcription, as our study model. By comparing the
global distribution of H2BK120ub1 with the DNA replication timing profile, we
found that H2BK120ub1 is mostly enriched at the earliest replicating regions.
To ask whether H2BK120ub1 was responsible for initiating early replication, we
tethered Rnf20, the E3 ubiquitination ligase of H2B ubiquitination, at a particular genomic region and observed earlier replication. Nevertheless, domains according to our genome wide scale analysis, not only the H2BK120ub1 enriched
early regions, but also the entire genome rely on this mark, at least partially, todefine the replication timing. But interestingly, a shift in DNA replication timingin Rnf20 knockout cells was not accompanied by significant changes in gene expression, suggesting that gene transcription does not depend on DNA replication
timing for regulation. By using a series of DNA replication assays, we found thatH2B ubiquitination regulates DNA replication timing by modulating the time ofreplication origin initiation.

31

Laboratory for

Lab activities

Integrative Genomics
Group Director: Osamu Ohara

Figure: Comparison of columns packed with
non-porous and porous reverse-phase particles
for shotgun proteomics(A) Schematic representations of the flow path in a
non-porous and a porous particle. (B) A scatter plot ofPeak intensities of common peptides identified in tryptic digests of proteins of HEK293-F cells using columns
packed with non-porous and porous reverse-phaseparticles. (C) Comparison of the number of proteins
identified in 200 ng, 100 ng and 20ng of protein digests of HEK293-F cells by chromatographic separation
on non-porous and porous reverse-phase particles. We
observed that the use of non-porous reverse-phaseparticles considerably enhances protein identification ina small amount of sample.

Recent Major Publications
Kadowaki T, Ohnishi H, Kawamoto N, Hori T, Nishimura
K, Kobayashi C, Shigemura T, Ogata S, Inoue Y, Kawai
T, Hiejima E, Takagi M, Imai K, Nishikomori R, Ito S,
Heike T, Ohara O, Morio T, Fukao T, Kanegane H. Haploinsufficiency of A20 causes autoinflammatory andautoimmune disorders. J Allergy Clin Immunol, 141,1485–1488 (2018)
Saito Y, Mochizuki Y, Ogahara I, Watanabe T, Hogdal L,
Takagi S, Sato K, Kaneko A, Kajita H, Uchida N, Fukami
T, Shultz LD, Taniguchi S, Ohara O, Letai AG, Ishikawa
F. Overcoming mutational complexity in acute myeloid
leukemia by inhibition of critical pathways. Sci Transl
Med 9, eaao1214 (2017)
Fujiki R, Hijikata A, Shirai T, Okada S, Kobayashi M,
Ohara O. Molecular mechanism and structural basis ofgain-of-function of STAT1 caused by pathogenic R274Q
mutation. J Biol Chem 292, 6240-6254 (2017)

Invited Presentations
Ohara O. “Dissection of the immune cell society bysingle-cell technologies: Sequencing, production, andcharacterization of B-cell immunorepertoires retrieved
from single cells” Single Cell Science Symposium:
TECHNOLOGY MEETS BIOLOGY (Yokohama, Japan)
July, 2017
Ohara O. “Applications and future perspectives ofadvanced genomics for clinical diagnosis” The 27th
Annual Meeting of Pediatric Rheumatology Associationof Japan (Kyoto, Japan) October, 201732

B

ecause genomics is now an approach of choice when we tackle complex problems in medical sciences, our laboratory is currently involved in many intramural and extramural collaborations and various strategic projects organizedby the center, in addition to providing our colleagues in the center with technicalsupport as a central function. While we spend a considerable amount of time andeffort on these activities, a part of effort is also dedicated to continuously updating
our approaches with the least delay, but only after new technologies become mature and robust enough for applications in medical sciences.
In addition to this basic mission, we certainly keep it in mind that technology
development has had a significant impact on the design of biological experiments
and greatly deepens our understanding of biological systems. As we have experienced it first hand by the recent emergence of next-generation DNA sequencing
technology, we believe that newly emerging technology frequently changes the experimental approaches in biology. In this context, the most critical issue for ourlaboratory is to correctly decide on the direction of technology development. We
have recently taken advantage of single-cell analysis platforms, but our approaches so far have mainly been based on next-generation DNA sequencing and antibody-assisted imaging technologies. However, we believe that high-sensitivity
proteome analysis will play a key role in the very near future. To begin to address
this, we recently developed a liquid-chromatography (LC) system to improve thedetection sensitivity of mass-spectrometry equipped with LC (Figure). While thisis just an example, our laboratory will continue pursuing development of new
measurement techniques in genomics for medical science researches at the center.

Laboratory for

Lab activities

Disease Systems
Modeling
Group Director: Hiroaki Kitano

Figure: Transcription regulator network analysis
revealed that several regulators of AP-1 arealtered in Socs3 cKO.
(A) Upstream analysis was performed using IPA software to identify highly regulated transcription factors
at 2 and 10 weeks in Socs3 cKO. Activator protein-1(AP-1)-related transcription factors were differentiallyregulated at both time points. (B) Predicted mechanistic network of AP-1 regulation; numbers represent
log2(fold change) of AP-1–related genes. Different
structures of nodes represent different functionalclasses of gene products. Red indicates DEGs selected
for validation. The nature of the relationship between
nodes (direct or indirect) is indicated by a solid or dotted line, respectively.

Recent Major Publications
Bajpai A, Ishii T, Miyauchi K, Gupta V, Nishio-Masaike
Y, Shimizu-Yoshida Y, Kubo M, Kitano H. Insights into
gene expression profiles induced by Socs3 depletion in
keratinocytes. Sci Rep 7, 15830 (2017)
Kawakami E, Nakaoka S, Tazro Ohta T, Kitano H.
Weighted enrichment method for prediction of transcription regulators from transcriptome and global
chromatin immunoprecipitation data. Nucleic Acids
Res 44, 5010–5021 (2016)
Kawakami E, Singh VK, Matsubara K, Ishii T, Matsuoka
Y, Hase T, Kulkarni P, Siddiqui K, Kodilkar J, Danve N,
Subramanian I, Katoh M, Shimizu-Yoshida Y, Ghosh
S, Jere A, Kitano H. Network analyses based on comprehensive molecular interaction maps reveal robust
control structures in yeast stress response pathways.
NPJ Syst Biol Appl 2, 15018 (2016)

Invited Presentations
Kitano H. “Nobel Turing Challenge: The Day AI win The
Nobel Prize and Future of Civilization” Luxembourg
Centre for Systems Biomedicine seminar (Luxembourg,
Luxembourg) May, 2017
Kitano H. “AI-driven Life Science Innovation and Grand
Challenge” AI x Life Science Symposium (Tokyo, Japan)
May, 2017
Kitano H. “Impacts of Artificial Intelligence for Pharmaceutical Industry: Disruptive Innovations in Scientific
Discovery and Biomedical Sciences” The FIP 6th Pharmaceutical Sciences World Congress 2017(PSWC 2017)(Stockholm, Sweden) May, 2017
Kitano H. “Systems Toxicology by artificial intelligence”
The 44th Annual Meeting of the Japanese Society of
Toxicology (Yokohama, Japan) July, 2017
Kitano H. “Systems Biology: Tools and Integrated
Platforms for the 3Rs” The 10th World Congress on
Alternatives and Animals in the Life Sciences (Seattle,USA) Aug, 2017T

he Laboratory for Disease Systems Modeling (LDSM) is focusing on an in-depth
understanding of several biological processes relevant to disease systems, with possible applications to clinical practice. We carried out two major projects, one is to uncover the functions of Socs3 in keratinocytes and the other is study effects of the NAD+
biosynthesis pathway and Sirtuins in aging.
A) Socs3 ProjectSpecific in vivo deletion of suppressor of cytokine signaling 3 (Socs3) in keratinocytes
causes severe skin inflammation with infiltration of immune cells. To investigate the roleof Socs3 in keratinocytes, we studied global RNA-Seq profiles from Socs3 conditional
knockout (cKO) mice at two different ages (2 and 10 weeks). Over 400 genes were differentially expressed at both time points. In samples from 2-week-old mice, there wasdown-regulation of genes involved in keratin-related functions and up-regulation ofgenes involved in lipid metabolism. At week 10, multiple chemokine and cytokine genes
were up-regulated. Functional annotation revealed that the genes differentially expressedin the 2-week-old mice play roles in keratinization, keratinocyte differentiation, and epidermal cell differentiation. By contrast, differentially expressed genes in the 10-week-old
animals are involved in acute immune-related functions. A group of Activator Protein-1–
related genes was highly up-regulated in Socs3 cKO mice at both ages. This observation
was validated using qRT-PCR in SOCS3-depleted human keratinocyte–derived HaCaT
cells. Our results suggest that, in addition to participating in immune-mediated pathways, SOCS3 also plays important roles in skin barrier homeostasis.
B) Aging Project
The effect of SIRT1 (mammalian) and Sir2 (budding yeast), and nicotinamide mononucleotide as a chemical substance to affect these genes via the NAD+ biosynthesis circuit
has been investigated. Precision systems biology using budding yeast strengthens our understanding of key biological processes by providing deeper insights into detailed molecular processes with our original gTOW genome-wide assay system. Quantitative analyses
using the gTOW assay revealed that a high level of SIR2 expression was permissive instrains with low NAD levels and that SIR2 expression increased NAD levels and growth
speed, but SIR2 cannot be highly expressed in strains with normal NAD levels. This implies that SIR2 expression may be precisely regulated with NAD levels.
33

Laboratory for

Lab activities

Medical Science
Mathematics
Group Director: Tatsuhiko Tsunoda

Figure: Medical Big Data Analysis for Precision
Medicine(a) Common analysis steps and methodologies. (b) Application to omics data from 300 hepatocellular carcinoma cases revealed six clusters, which showed significantly different disease-free survival rates (Nat Genet
48, 500–509 (2016)). (c) Multi-ancestry meta-GWAS
revealed novel asthma-related loci (Nat Genet 50,
42–53 (2018)). The known asthma loci are in black. The
seven novel loci detected in the European-ancestry meta-analysis are in red. The two additional loci detectedin the multi-ancestry meta-analysis are in blue.

Recent Major Publications
Demenais F, et al. Multiancestry association study
identifies new asthma risk loci that colocalize withimmune-cell enhancer marks. Nat Genet 50, 42–53(2018)
Shigemizu D, Iwase T, Yoshimoto M, Suzuki Y, Miya F,
Boroevich KA, Katagiri T, Zembutsu H, Tatsuhiko Tsunoda. The prediction models for postoperative overall survival and disease-free survival in patients with breast
cancer. Cancer Med 6, 1627–1638 (2017).
Fujimoto A+, Furuta M+, Totoki Y+, Tsunoda T+, Kato M+(+: co-first), ..., Nakagawa H. Whole genome mutationallandscape and characterization of non-coding andstructural mutations in liver cancer. Nat Genet 48,
500–509 (2016)

Invited Presentations
Tsunoda T. “Exploring etiologies, sub-classification, andrisk prediction of diseases based on big-data analysisof clinical and whole omics data in medicine” CREST
Big Data Fields Joint Meeting (Tokyo, Japan) December,
2017
Tsunoda T. “Trans-omic analysis drives precision medicine” The 1st International Symposium for Trans-Omics(Tokyo, Japan) November, 2017
Tsunoda T. “Multi-omic analysis for precision cancer
medicine” DNA sequencing technologies and theirapplication in practice WS (Yerevan, Armenia) October,
2017
Tsunoda T. “Omic analysis drives precision medicine”
International Conference for Precision Cancer Medicine(Tokyo, Japan) June, 2017
Tsunoda T. “Multiomics and clinical analysis of cancer”
CREST International Symposium on Big Data Application (Tokyo, Japan) January, 201734

T

he application of rapidly progressing omic profiling technologies and, in particular,
the promotion of personalized/precision/preventive medicine have recently become
major goals of medical research. Traditional therapies do not adequately take into account the individuality of each patient. Our laboratory develops strategies to overcome
such medical science limitations through a combination of mathematics and computational sciences. Nowadays, biomedical big data, consisting of both clinical and omic
profiles, are collected from hospitals and medical institutions. First, driven by need for
integrative analysis of clinical and omic data, we explore etiologies of intractable diseases,
e.g., cancer, common diseases, and neurodegenerative diseases. Next, we classify eachdisease into finer categories through molecular profiles, and clarify disease causing mechanisms through a systems approach. Last, we apply mathematical methods, e.g., machinelearning techniques, to optimize therapy prediction for each patient when she/he visitsa hospital or medical institute. We can also apply these methods to disease prevention
based on an individual’s medical history. Recently, we developed statistical and computational methodologies for analyzing up-to-date omics data, as well as for understanding
and predicting cancer progression based on genomic data, with a final aim of establishing
precision medicine and applying it to real data [Nat Genet 48, 500–509 (2016); Cancer
Med 6, 1627–1638 (2017); IEEE Trans Biomed Eng 64, 112–122 (2016); J Theor Biol
393, 67–74 (2016); BMC Bioinformatics 17, 319 (2016); BMC Med Genomics 9 (Suppl3), 74 (2016)]. On the basis of these methodologies, we succeeded in observing a significant correlation between the molecular clustering of omic data and clinical information,e.g. survival time, based on liver and breast cancer omic analysis, and have recently published these results [Nat Genet 48, 500–509 (2016); Cancer Med 6, 1627–1638 (2017)].
Another success in medical big data analysis that we have achieved is multi-ancestry
GWAS, which revealed five novel asthma-related loci [Nat Genet 50, 42–53 (2018)].

Laboratory for

Lab activities

Immunogenetics
Team Leader: Tadashi Yamamoto

Figures: Research projects in the laboratory
A. mRNA deadenylation in tissue development
Cnot complex-mediated mRNA deadenylation promotes liver development by decreasing undifferentiated cell-specific genes.
B. The responses of Ag-specific CD8 T cells following Ag encounter
IL-7, IL-15, and CD4 help are required for memory CD8
T cell maintenance. Long-lived memory CD8 T cells
expand and exert their function quickly when they
reencounter Ag.
C. The transcription factor “X” determines themTEC fate from a common progenitor expressing
Foxn1
Cortical thymic epithelial cells (cTECs) and mTECs share
a common endodermal origin. We hypothesize thattranscription factor “X” determine the development andfunction from progenitors to mTECs.

Recent Major Publications
Hayatsu N, Miyao T, Tachibana M, Murakami R, Kimura A, Kato T, Kawakami E, Endo TA, Setoguchi R,
Watarai H, Nishikawa T, Yasuda T, Yoshida H and Hori
S. Analyses of a mutant FoxP3 allele reveal BATF as a
critical transcription factor in the differentiation andaccumulation of tissue regulatory T cells. Immunity 47,
268–283 (2017)
Li T, Amari T, Semba K, Yamamoto T and Takeoka S.
Construction and evaluation of pH-sensitive immunoliposomes for enhanced delivery of anticancer drug to
ErbB2 over-expressing breast cancer cells. Nanomedicine 13, 1219–1227(2017)
Akiyama N, Takizawa N, Miyauchi M, Yanai H, Tateishi
R, Shinzawa M, Yoshinaga R, Kurihara M, Demizu Y,
Yasuda H, Yagi S, Wu G, Matsumoto M, Sakamoto R,
Yoshida N, Penninger JM, Inoue J and Akiyama T. Identification of embryonic precursor cells that differentiate
into thymic epithelial cells. J Exp Med 213, 1441–1458(2016)

Invited Presentations
Yamamoto T. “Post-transcriptional regulation by mRNApoly(A) tail” OIST & University of the Ryukyus Joint Symposium 2017 (Naha, Japan) October, 2017
Setoguchi R. “The mechanisms for memory CD8 T cellmaintenance” The 7th Awaodori Symposium for Life
Science (Tokushima, Japan) August, 2017
Yamamoto T. “Physiology of mRNA poly(A) tail andCCR4-NOT” Department of Biochemistry, McGill University (Montreal, Canada) May, 2017O

ur team is carrying out three projects to understand the molecular basis oftissue development and function.
1) Tissue development involves dramatic gene expression changes, which are
mediated by regulation of mRNA transcription and degradation. Suppression ofmRNA deadenylase activity leads to abnormal tissue development concomitantwith loss of the ability to eliminate unnecessary mRNAs. We are investigating how
the deadenylase regulates tissue development and function in a developmental
stage-specific manner and how it is deregulated in diseases.
2) Memory CD8 T cells are long-lived antigen (Ag)-specific cells that proliferate
and exert effector functions more robustly than naïve CD8 T cells upon reencounter with their cognate Ag. Memory CD8 T cells are maintained at a stable population over a long period. One of the objectives of our study is to new discovermechanisms by which memory CD8 T cells are maintained in vivo. These researchfindings should lead to innovative vaccination strategies for induction of protective immunity against tumor cells and chronic infections.
3) Medullary thymic epithelial cells (mTECs) expressing autoimmune regulator(Aire) are critical for induction of immune tolerance. However, the differentiation
program of Aire-expressing mTECs (Aire+ mTECs) is not fully understood. We
have recently identified the precursors of Aire+mTECs (pMECs) by monitoring
the expression of RANK, which is required for Aire+ mTEC differentiation. We
are now investigating what molecules define cell fates from progenitors to pMECs,
and how these molecules regulate the development and functions of mTECs.

Yamamoto T. “The CCR4-NOT deadenylase: its rolein controlling cells’ survival and differentiation invarious biological systems” The 6th Symposium of the
RIKEN-Max Planck Joint Research Center for Systems
Chemical Biology (Naha, Japan) April, 201735

Laboratory for

Lab activities

Integrated Bioinformatics
Team Leader: Todd D. Taylor

Figure: iCLiKVAL Overview
iCLiKVAL is a web-based tool that uses the power ofcrowdsourcing to accumulate annotation information
for all scientific media found online. Annotations in
the form of key-relationship-value tuples are added byusers through a variety of methods. Users can createor join common interest groups to work as part of acommunity. Controlled vocabulary lists can be created, edited and shared. Media can be bookmarked,
followed, reviewed and searched. Annotations can besorted, filtered and edited. The database is completely
searchable, without registration, and all of the data arefreely available to registered users via our application
programming interface.

Recent Major Publications
Ong SY, Kho H-P, Riedel SL, Kim S-W, Gan C-Y, Taylor TD,
Sudesh K. An integrative study on biologically recovered polyhydroxyalkanoates (PHAs) and simultaneousassessment of gut microbiome in yellow mealworm. J
Biotechnol 265, 31–39 (2018)
Chin KCJ, Taylor TD, Hebrard M, Anbalagan K, Dashti
MG, Phua KK. Transcriptomic study of Salmonella enterica subspecies enterica serovar Typhi biofilm. BMC
Genomics 18, 836–844 (2017)
Lye HS, Kato T, Low W-Y, Taylor TD, Prakash T, Lew LC,
Ohno H, Liong MT. Lactobacillus fermentum FTDC 8312
combats hypercholesterolemia via alteration of gut
microbiota. J Biotechnol 262, 75–83 (2017)

Invited Presentations
Taylor TD. “Turning big data into small data throughcrowdsourced curation: integrating all types of medical and scientific knowledge” Malaysia International
Genetics Conference (Selangor, Malaysia) September,
2017

36

W

e are developing an integrated database and sample-tracking system tohandle both small- and large-scale datasets of various types of experimental outputs. The system brings together an array of wet-lab experimental types being generated by various labs. Our goal is to develop a flexible system that makes
it easy for users to manage, access, analyze, integrate, and visualize their own data
as per their requirements.
We also develop general-purpose bioinformatic tools capable of efficiently processing and analyzing data from a variety of sources, with an emphasis on metagenomic data (e.g., taxonomic classification, phylogenic tree visualization, 16S rRNA
curation), host-microbiome interactions and scientific discovery through big data
curation. We have constructed a highly-curated genomic-based 16S ribosomal
RNA gene database, which is continually being updated as new sequences appear
in the public databases. Because metagenomic samples can contain hundreds or
thousands of different species and are not easy to visualize or quantify, we developed an alternative visualization method for displaying phylogenic trees thatallows users to, at a glance, comprehend the distribution of the species within theirsamples. Big data in the form of scientific media comes in many languages andformats: journal articles, books, images, videos, etc. While there are many resources for browsing, searching and annotating some of this media, there is no single
place to search them all at once, and generalized search engines do not allow for
the comprehensive and precise searches researchers require. To address these issues, we have developed a web-based tool that uses the power of crowdsourcing toaccumulate annotation information for all scientific media found online. This willallow for richer data searches and discovery of novel connections by integrating all
forms of scientific knowledge through a common terminology.

Laboratory for

Lab activities

Tissue Dynamics
Team Leader: Takaharu Okada

Figure: 3D imaging of skin nerves and dendritic
cell subsets
A whole-mount confocal fluorescence image of the earskin from an Xcr1gfp/+ CD11c-YFP mouse. PGP9.5+ nerve
fibers (red) are visualized together with XCR1+ dendritic
cells (light blue) and other dendritic cells (green).

Recent Major Publications
Herndler-Brandstetter D, Ishigame H, Shinnakasu R,
Plajer V, Stecher C, Zhao J, Lietzenmayer M, Kroehling
L, Takumi A, Kometani K, Inoue T, Kluger Y, Kaech SM,
Kurosaki T, Okada T, Flavell RA. Developmental Plasticity of KLRG1+ Effector CD8+ T Cells Promotes Protective
Immunity. Immunity in press
Okada T, Takahashi S, Ishida A, Ishigame H. In vivo multiphoton imaging of immune cell dynamics. Pflugers
Arch 468, 1793–1801 (2016)
Kitano M, Yamazaki C, Takumi A, Ikeno T, Hemmi H,
Takahashi N, Shimizu K, Fraser SE, Hoshino K, Kaisho
T, Okada T. Imaging of the cross-presenting dendritic
cell subsets in the skin-draining lymph node. Proc Natl
Acad Sci U S A 113, 1044–1049 (2016)

Invited Presentations
Okada T. “Imaging of peripheral nerves involved in the
inflammatory diseases.” The 3rd Annual Meeting ofJapanese Society of Osteoimmunology (Ishigaki, Japan)
June, 2017
Okada T. “Dynamic imaging of immune cells andsensory nerves.” RIKEN-McGill Symposium (Montreal,
Canada) May, 2017T

he goal of the laboratory is to mechanistically understand the in vivo cellular
dynamics that shape immune responses and inflammation. For this purpose,
we generate and analyze various fate-mapping reporter mice to analyze differentiation plasticity of immune cells and other cells. Using this approach, for example,
we have analyzed differentiation of cytotoxic T cells to identify developmental
pathways of highly protective memory CD8+ T cells. Our new data establish thatdevelopmental plasticity of KLRG1+ effector CD8+ T cells plays a crucial role inpromoting functionally versatile memory cells that mount highly protective responses against infections and cancer.
In addition, we are studying the roles for the peripheral nervous system inmodulation of inflammation. Through this study, we aim to find strategies to suppress chronic inflammation based on the modulation of neuronal activities. Particularly, we are interested in structural and functional changes in sensory neurons in dermatitis, and their interactions with immune cells and other cells suchas keratinocytes. In this study, multi-dimensional fluorescent imaging analysis isvery powerful for deciphering the diversity and dynamics of cellular activities.
Our imaging data have started to reveal that previously-unknown interactions between sensory neurons and keratinocytes may play an important role in preventing pruritic dermatitis.

37

Laboratory for

Lab activities

Integrated Cellular
Systems
Team Leader: Mariko Okada

Figure: Super-enhancer(SE)-based analysis ofhematopoietic development
Flow chart of the data analysis (left). Specific transcription factors in hematopoietic cells (right).

Recent Major Publications
Magi S, Iwamoto K, Yumoto N, Hiroshima M, Nagashima T, Ohki R, Garcia-Munoz A, Volinsky N, vonKriegsheim A, Sako Y, Takahashi K, Kimura S, Kholodenko BN. and Okada-Hatakeyama M. Transcriptionallyinducible Pleckstrin homology-like domain family
A member 1 attenuates ErbB receptor activity byinhibiting receptor oligomerization. J Biol Chem jbc.
M117.778399 (2017)
Magi S, Iwamoto K and Okada-Hatakeyama, M. Current
Status of Mathematical Modeling of Cancer – From theViewpoint of Cancer Hallmarks. Curr Opin Syst Biol 2,
38–47 (2017)
Inoue K, Shinohara H, Behar M, Yumoto N, Tanaka
G, Hoffmann A, Aihara K and Okada-Hatakeyama M.
Oscillation dynamics underlies functional switching of
NF-κB for B cell activation. NPJ Syst Biol Appl 2, 16024(2016)

Invited Presentations
Okada M. “Trans-Omics analysis of NF-κB regulation”
CREST & Scientific Research on Innovative Areas
Symposium. The 1st International Symposium forTrans-Omics (Tokyo, Japan) November, 2017
Okada M. “Classic yet unique dynamic properties of NFB gene regulation” OIST-JST Joint Seminar (Okinawa,
Japan) November, 2017
Okada M. “Cell shape and metabolism” The 11th Metabolome Symposium (Osaka, Japan) November, 2017
Okada M. “Systems Biology and Database” NBDC Workshop (Tokyo, Japan) November, 2017
Okada M. “Mathematical modeling of cancer signaling
network” The Third Trilateral Workshop for FrontierProtein Studies 2017 (Shanghai, China). August–September, 201738

T

he aims of the laboratory are to define the general regulatory rules in signal transduction-transcriptional networks in cell determination processes and to apply
this knowledge of regulatory principles to the understanding and treatment of humandiseases. We are currently pursuing three projects; (1) dynamics of nuclear NF-κB andgene regulation, (2) mathematical modeling of cancer hallmarks and (3) cell adhesion
regulated metabolism.
To understand the regulation of NF-κB-mediated gene expression, we are performing
integrative transcriptome and epigenetics analyses. Our analyses using H3K27Ac-ChIP,
RelA-ChIP and ATAC-seq revealed super-enhancer (SE)-regulated gene expression
mechanisms at the single-cell level. The results indicated that a cooperative mechanism
for DNA-protein binding mediated by SEs results in threshold responses in mRNA expression in individual B cells. The computational methods are also being applied to understanding hematopoietic development (Figure).
Signaling network is highly complex and exibits dynamic behavior to control cellfunctions. To understand the complex regulatory mechanism of the cancer cell signaling network, we are attempting to integrate all mathematical models developed in ourlaboratory that cover 60 % of the pathways in cancer hallmarks. The model parameters
can also be integrated with clinical gene expression data and thus can form the basis for
personalized simulation analysis.
Cell shapes regulated by cell adhesion are an important visible output of cell systems.
We used a mouse model, lacking Crk and Crkl genes, of which gene products control celladhesion and performed multi-omics analysis together with quantitative cell shape analysis on mouse embryo fibroblasts (MEF). The MEF obtained from the double-knockout
mice were smaller and had a round shape compared with spindle-shaped normal MEFs
and this morphology was associated with lower central metabolic activity. This phenotype was rescued by overexpression of an adhesion signaling molecule. Our study reveals
a novel mechanism for cell adhesion-dependent activation of metabolism.

Laboratory for

Lab activities

Metabolomics
Team Leader: Makoto Arita

Figure: Comprehensive analysis of oxidized
phospholipids (OxPLs) using a measured MS/MS
spectra library

Recent Major Publications
Aoyagi R, Ikeda K, Isobe Y, Arita M. Comprehensive
analyses of oxidized phospholipids using a measured
MS/MS spectra library. J Lipid Res 58, 2229–2237(2017)
Tsugawa H, Ikeda K, Arita M. The importance of
bioinformatics for connecting data-driven lipidomics
and biological insights. Biochim Biophys Acta 1862,
762–765 (2017)
Tsugawa H, Ikeda K, Tanaka W, Senoo Y, Arita M, Arita
M. Comprehensive identification of sphingolipid species
by in silico retention time and tandem mass spectral
library. J Cheminform 9, 19 (2017)

Invited Presentations
Arita M. “Omega-3 fatty acid metabolism in controllinginflammation and related diseases” The 7th Mind-Body
Interface International Symposium (Taichung, Taiwan)
November, 2017
Arita M. “Eosinophil polyunsaturated fatty acid metabolism and its potential control of inflammation andallergy” The 15th International Conference on Bioactive
Lipids in Cancer, Inflammation, and Related Diseases(Puerto Vallarta, Mexico) October, 2017
Arita M. “The importance of lipoquality in biologicalsystems” The 1st International Conference on Lipoquality (Tokyo, Japan) September, 2017
Arita M. “Lipidomics and discovery of novel bioactive
omega-3 fatty acid metabolites” The 1st International Symposium on Lipid Science and Biotechnology(ISLSB2017) (Guangzou, China) April, 2017
Arita M. “Omega-3 fatty acid metabolism in controllinginflammation and related diseases” The 4th International Forum on Omega-3 and Human Health (Chongqing, China) March, 2017

L

ipids are recognized as extremely diverse molecules. The precise determination of each molecular species of lipid, namely Lipo-Quality (Quality of Lipids), becomes a prerequisite not only to understand their biological functions inphysiology and disease, but also to discover novel bioactive lipids that may link lipid metabolism and biological phenotypes. A powerful method for the analysis oflipid metabolites is liquid chromatography tandem mass spectrometry (LC-MS/
MS). Our research is aimed at elucidating the structure and function of endogenous lipid metabolites that regulate inflammation and tissue homeostasis.
Recently we successfully developed a comprehensive analytical method for oxidized phospholipids (OxPLs) (Figure). OxPLs are widely thought to be associatedwith various diseases such as arteriosclerosis, diabetes and cancer. Biogenic OxPLs
were prepared by the addition of specific oxidized fatty acids to cultured cells,
where they were incorporated into cellular phospholipids. Untargeted lipidomics
by LC-quadrupole/time-of-flight (QTOF) MS was then applied to collect MS/MS
spectra for the OxPLs. Based on the measured MS/MS spectra of the biogenic
OxPLs, we developed a broad-targeted lipidomics system using triple quadrupole(tripleQ) MS. This advanced method will enable us to elucidate the structure-specific behavior of OxPLs and their physiological relevance in vivo.
By taking advantage of Q-TOF (global lipid screening) and TripleQ (quantitative analyses) mass spectrometry, our new approach has a great potential to identify lipids of interest globally and to identify unknown lipid species in a non-biased
fashion. Also, we are developing a comprehensive analytical platform with an MS/
MS spectra library especially focusing on bioactive lipid mediators and complex
structures of lipid metabolites produced by commensal microbiota. We are also
developing software that enables us to search for lipid structures more precisely
and comprehensively.

39

Core for
Genomic Medicine
T

he Core for Genomic Medicine is performing genomic research on humandiseases, especially the common diseases. The aims of Core for Genomic
Medicine are 1) to identify genetic variations related to disease susceptibility,
disease outcome and drug responses (efficacy/adverse reaction), 2) to provide
useful information about possible molecular targets for drug discovery, 3) toexamine the interactions between genetic and environmental factors to understand the pathogenesis and the progression of diseases, and 4) finally toconstruct the evidence base for the implementation of personalized medicine.
To identify genetic variations related to disease susceptibility and drug
responses, the Core for Genomic Medicine first showed the proof of conceptof the genome-wide association study (GWAS) in 2002. To advance this strategy, the Core for Genomic Medicine has organized laboratories to facilitate
comprehensive genomic research on common diseases. To produce comprehensive genomic information, the Laboratory for Genotyping Development
is mainly working on large-scale SNP genotyping and genome sequencing forvarious diseases. The resulting huge amount of genomic variation data wasmainly analyzed at the Laboratory for Statistical Analysis to extract significant
genomic variations related to disease susceptibility and drug responses. Theselaboratories are in close communication with the research group of pharmacogenomics (Laboratory for Pharmacogenomics and Laboratory for International Alliance on Genomic Research), laboratories for disease-causing mechanisms (Laboratory for Cardiovascular Diseases, Autoimmune Diseases, Digestive Diseases, Bone and Joint Diseases, Endocrinology, Metabolism and Kidney
Diseases, and Respiratory and Allergic Diseases) and many other collaborators
worldwide for further analyses. In addition to this strategy, the Laboratory for
Genome Sequencing Analysis is mainly working on whole genome sequencing of cancer genomes to clarify the pathogenesis of carcinogenesis.

40

Laboratory for

Lab activities

Genotyping Development
Team Leader: Yukihide Momozawa

Figure: Our high throughput dispensing system
necessary for large scale genomic analyses

Recent Major Publications
Akiyama M, Okada Y, Kanai M, Takahashi A, Momozawa Y, Ikeda M, Iwata N, Ikegawa S, Hirata M,
Matsuda K, Iwasaki M, Yamaji T, Sawada N, Hachiya T,
Tanno K, Shimizu A, Hozawa A, Minegishi N, Tsugane
S, Yamamoto M, Kubo M, Kamatani Y. Genome-wide
association study identifies 112 new loci for bodymass index in the Japanese population. Nat Genet 49,
1458–1467 (2017)
Huang H, Fang M, Jostins L, Umićević Mirkov M, Boucher G, Anderson CA, Andersen V, Cleynen I, Cortes A,
Crins F, D'Amato M, Deffontaine V, Dmitrieva J, Docampo E, Elansary M, Farh KK, Franke A, Gori AS, Goyette
P, Halfvarson J, Haritunians T, Knight J, Lawrance IC,
Lees CW, Louis E, Mariman R, Meuwissen T, Mni M,
Momozawa Y, Parkes M, Spain SL, Théâtre E, Trynka
G, Satsangi J, van Sommeren S, Vermeire S, Xavier RJ;
International Inflammatory Bowel Disease Genetics
Consortium, Weersma RK, Duerr RH, Mathew CG, Rioux
JD, McGovern DPB, Cho JH, Georges M, Daly MJ, Barrett
JC. Fine-mapping inflammatory bowel disease loci tosingle-variant resolution. Nature 547, 173–178 (2017)
Ishigaki K, Kochi Y, Suzuki A, Tsuchida Y, Tsuchiya H, Sumitomo S, Yamaguchi K, Nagafuchi Y, Nakachi S, Kato
R, Sakurai K, Shoda H, Ikari K, Taniguchi A, Yamanaka
H, Miya F, Tsunoda T, Okada Y, Momozawa Y, Kamatani
Y, Yamada R, Kubo M, Fujio K, Yamamoto K. Polygenic
burdens on cell-specific pathways underlie the risk ofrheumatoid arthritis. Nat Genet 49, 1120–1125 (2017)

Invited Presentations
Momozawa Y. “Genomic analysis of disease of companion animals in Europe” The 160th meeting of theJapanese Society of Veterinary Science (Kagoshima,
Japan) September, 2017
Momozawa Y. “Germline pathogenic variants of 11
hereditary breast cancer genes” Pharmacogenomics Research Network – RIKEN Center for Integrative Medical
Sciences (IMS) Strategic Alliance Meeting (San Francisco, USA) September, 2017T

he aims of the Laboratory for Genotyping Development are 1) to produce precise
and large-scale genomic data to identify genetic variants related to disease susceptibility, outcomes, and drug responses in close collaboration with the Laboratory for Statistical Analysis and 2) to develop methods and databases useful for personalized medicine.
Our laboratory has worked as a research hub of large-scale genomic analysis, collaborating with domestic and international universities, research institutes, and companies.
Our laboratory contributed to various projects and published 37 papers in 2017.
 Development of a new in silico method from data of genome wide association study
into one causative variant with Broad Institute, Sanger Center, and University of Liege(Nature 547, 173–178).
 Identification of 112 new genomic loci for body mass index in Japanese with the Laboratory for Statistical Analysis (Nat Genet 49, 1458–1467).
 Development of Japanese eQTL dataset in six cell types with the Laboratory for Autoimmune Diseases and the Laboratory for Statistical Analysis (Nat Genet 49, 1120–
1125)
 Identification of the mechanism of CCDC88B in the pathogenesis of inflammatory
bowel disease with McGill University (Nat Commun 8, 932).
 Identification of new protein-altering variants of PTPN2 in childhood-onset Type 1A
diabetes with the National Research Institute for Child Health and Development (Diabetic Med, in press) Identification of ZNF384-related fusion genes consisting of a distinct subgroup of
B-cell precursor acute lymphoblastic leukemia with the National Research Institutefor Child Health and Development (Haematologica 102,118–129)

We will continue to work as a research hub for large-scale genomic analysis so that we
can contribute to the implementation of personalized medicine.

41

Laboratory for

Lab activities

Genome Sequencing
Analysis
Team Leader: Hidewaki Nakagawa

Recent Major Publications
Wardell CP, Fujita M, Yamada T, Simbolo M, Fassan M,
Karlic R, Polak P, Kim J, Hatanaka Y, Maejima K, Lawlor
RT, Nakanishi Y, Mitsuhashi T, Fujimoto A, Furuta M, Ruzzenente A, Conci S, Oosawa A, Sasaki-Oku A, Nakano
K, Tanaka H, Yamamoto Y, Kubo M, Kawakami Y, Aikata
H, Ueno M, Hayami S, Gotoh K, Ariizumi S, Yamamoto
M, Yamaue H, Chayama K, Miyano S, Getz G, Scarpa A,
Hirano S, Nakamura T, Nakagawa H. Genomic characterization of biliary tract cancers identifies their drivergenes and predisposing mutations. J Hepatol 68,
959–969 (2018)
Fujita M, Matsubara N, Matsuda I, Maejima K, Oosawa A, Yamano T, Fujimoto A, Furuta M, Nakano K,
Oku-Sasaki A, Tanaka H, Shiraishi Y, Mateos RN, Nakai
K, Miyano S, Tomita N, Hirota S, Ikeuchi H, Nakagawa
H. Genomic landscape of colitis-associated cancer
indicates the impact of chronic inflammation and its
stratification by mutations in RNF43 and Wnt signaling.
Oncotarget 9, 969–981 (2017)
Van Renne M, Roca Suarez A, Duong F, Gondeau
C, Calabrese D, Fontaine N, Ababsa A, Bandiera S,
Croonenborghs T, Pochet N, De Blasi V, Pessauz P,
Piardi T, Sommacale D, Ono A, Chayama K, Fujita M,
Nakagawa H, Hoshida Y, Zeisel M, Heim M, Baumert T,
Lupberger J. miR-135a-5p-mediated downregulationof protein-tyrosine phosphatase delta is a candidate
driver of HCV-associated hepatocarcinogenesis. Gut,
gutjnl–2016–312270 (2017)

Invited Presentations
Nakagawa H. “Genomic Landscape of Hepato-Biliary
Cancers and Forwarding to Precision Medicine” Molecular Analysis for Personalized therapy (MAP) Conference(Zurich, Switzerland) October, 2017
Nakagawa H. “The Pan-cancer Analysis of Whole
Genome (PCAWG) project in the International Cancer
Genome Consortium” The 76th Annual Meeting ofJapanese Cancer Association (Yokohama, Japan) September, 2017
Fujita M, Nakagawa H. “Precision oncology by genomic
profiling for colitic cancer indicate potentials of mutations for cancer diagnosis and treatment” The 76th
Annual Meeting of Japanese Cancer Association (Yokohama, Japan) September, 2017
Nakagawa H. “Cancer Whole Genome Sequencing for
Precision Oncology and Cancer Immunology” The 2017
Cold Spring Harbor Asia Conference (Suzhou, China)
September, 2017
Nakagawa H, Imoto S. “Immuno-genomic landscape of
pan-cancer reveals diverse pathways related with immune signature, immune escape, and immuno-editing
history” The 13th Scientific Workshop of ICGC (Seoul,
Korea) June, 201742

Figure:We analyzed genomic features of 412 biliary tract cancer (BTC) samples from Japanese and Italian populations by whole genome or exome sequencing. We identified 32 significantly and commonly mutated genes,
some of which negatively affected patient prognosis,
including a novel deletion of MUC17 at 7q22.1, which
was also confirmed by tissue microarray analysis (TMA).

C

Cell-of-origin predictions using whole-genome genetic
and epigenetic features suggest a hepatocyte-originof hepatitis-related intrahepatic cholangiocarcinoma.
Deleterious germline mutations of cancer-predisposing
genes were detected in 11% of BTC patients. BTCs havedistinct genetic features including somatic events andgermline predisposition.

ancer is essentially a “disease of the genome” that evolves in the backgroundof germline variants with the accumulation of diverse mutations causedby environmental exposure and intrinsic factors. Germline variants predispose to cancer development and genetic analysis of certain specific genes, suchas BRCA1/2, is commonly performed for cancer risk, while somatic mutants ofdriver genes have been targeted for cancer treatment and genotype-based personalized cancer therapy is now a reality. Furthermore, immunology is also an
important factor to understand cancer because emerging immune therapies havebeen shown to be effective in many types of cancers. Now we must understandmore about cancer genome-immune interactions and their diversity to develop
new and more effective therapies by capitalizing on new technologies. Recent explosive advances in next-generation sequencing (NGS) and bioinformatics/IT enable a systematic, genome-wide identification of all somatic abnormalities andimmune activity within cancer tissues by combining whole genome sequencing(WGS), RNA sequencing, and single-cell sequencing. It is important to analyze
the likely implications of the huge human genome datasets from NGS and to reacha consensus about how to interpret the biological, immunological and clinical aspects of somatic and germline variants. Our research objectives are to understandcancer genome and microenvironmental activities, including immune activity, byutilizing NGS to identify novel genomic biomarkers and to develop analysis platforms that can be used in clinics for cancer precision medicine.

Laboratory for

Lab activities

Statistical Analysis
Team Leader: Yoichiro Kamatani

Figure: Human traits and cell type specificity
network constructed from GWAS and epigenomedata
We performed GWAS of 58 quantitative traits in
162,255 Japanese individuals and found 1,407 trait-associated loci. By incorporating 32 GWAS results fromcomplex diseases and epigenetic data, we investigatedthe enrichment of the heritability and constructed acell-type specificity network. The network illustrates
where the identified genetic variants may induce functional changes in the human body and thereby affectquantitative trait levels or cause diseases.

Recent Major Publications
Kanai M, Akiyama M, Takahashi A, Matoba N, Momozawa Y, Ikeda M, Iwata N, Ikegawa S, Hirata M, Matsuda K, Kubo M, Okada Y, Kamatani Y. Genetic analysis
of quantitative traits in the Japanese population links
cell types to complex human diseases. Nat Genet 50,
390–400 (2018)
Akiyama M, Okada Y, Kanai M, Takahashi A, Momozawa Y, Ikeda M, Iwata N, Ikegawa S, Hirata M,
Matsuda K, Iwasaki M, Yamaji T, Sawada N, Hachiya T,
Tanno K, Shimizu A, Hozawa A, Minegishi N, Tsugane
S, Yamamoto M, Kubo M, Kamatani Y. Genome-wide
association study identifies 112 new loci for bodymass index in the Japanese population. Nat Genet 49,
1458–1467 (2017)
Low SK, Takahashi A, Ebana Y, Ozaki K, Christophersen
IE, Ellinor PT; AFGen Consortium, Ogishima S, Yamamoto M, Satoh M, Sasaki M, Yamaji T, Iwasaki M, Tsugane
S, Tanaka K, Naito M, Wakai K, Tanaka H, Furukawa T,
Kubo M, Ito K, Kamatani Y, Tanaka T. Identification of
six new genetic loci associated with atrial fibrillationin the Japanese population. Nat Genet 49, 953–958(2017).

Invited Presentations
Akiyama M, Kamatani Y. “Large-scale genome-wide
association study: Past, Present, and Future” JapaneseSociety of Human Genetics Annual Meeting (Kobe,
Japan) November, 2017
Kamatani Y. “GWAS using 200,000 participants of Biobank Japan” Genomic histology of Japonesian (Mishima, Japan) August, 2017O

ur laboratory aims at identifying susceptibility variants of complex traits by using
the genetic association study, as well as then connecting the genetic association
findings with biology and medicine using omics data, including epigenome and transcriptome. Until now, we have used genome-wide SNP array data and performed genome
wide association studies (GWAS) for dozens of traits. In 2017, we have reported results of
GWAS for atrial fibrillation, BMI, and several laboratory tests. These catalogs represent
the largest non-European GWAS ever collected for each trait. After their publication, we
shared these results, which are freely available at http://jenger.riken.jp/.
We are now moving to address three key issues in this field; missing heritability,
functional interpretation of the identified genetic variants, and the genetic architectureof the diseases in question. Firstly, we have finished imputation for the missing rare variants in the SNP results of the ~230,000 subjects described above by using whole genome
sequencing (WGS) data of ~1,000 Japanese individuals. The results clearly demonstrated
the roles of rare variants and highlight population-specific genetic effects. Secondly, we
are now focusing on the interpretation of GWAS signals. Pathway analysis of the GWAS
data for atrial fibrillation indicated that the identified genes were enriched for the fetal
neural crest development pathway, which provides a novel research clue to elucidate how
genetic variants lead to increased risk of developing that disease. We also conducted enrichment of either the lead genetic variants or polygenic effects and found several statistically significant enrichments for cell-type specific regulatory elements. Now we have begun using in-house eQTL data of lymphocyte subtypes generated by the Laboratory for
Autoimmune Diseases and long non-coding RNA expression data from several cell types
as a collaborative project with the RIKEN Center for Life Science Technologies (CLST).
Lastly, we are attempting to use machine-learning techniques to reveal non-additive effects of genomic variants, which have not been investigated well in this field. These novel
machine-learning techniques will facilitate detecting such effects.

43

Laboratory for

Lab activities

Pharmacogenomics
Group Director: Taisei Mushiroda

Figure: Road to implementation of PGx biomarkers into clinical practice
GWAS, HLA genotyping, and the 100 “Pharmacogene”
panel identify PGx biomarkers. After in vitro functional
evaluation of SNPs/rare variants associated with drug
efficacy or risk of adverse drug reactions, the advantages of PGx biomarkers should be demonstrated byconducting prospective clinical trials that can evaluate
the clinical utility of genetic testing for implementationof PGx tests.

Recent Major Publications
Mushiroda T, Takahashi Y Onuma T, Yamamoto Y,
Kamei T, Hoshida T, Takeuchi K, Otsuka K, Okazaki M,
Watanabe M, Kanemoto K, Ohshima T, Watanabe A,
Minami S, Saito K, Tanii H, Shimo Y, Hara M, Saitoh S,
Kinoshita T, Kato M, Yamada N, Akamatsu N, Fukuchi
T, Ishida S, Yasumoto S, Takahashi A, Ozeki T, Furuta
T, Saito Y, Izumida N, Kano Y, Shiohara T, Kubo M,
on behalf of the GENCAT Study Group. Prospective
HLA-A*31:01 screening and the incidence of carbamazepine-induced cutaneous adverse reactions in theJapanese patients. JAMA Neurol in press
Ujiie H, Muramatsu K, Mushiroda T, Ozeki T, Miyoshi
H, Iwata H, Nakamura A, Nomoto H, Cho KY, Sato N,
Nishimura M, Ito T, Izumi K, Nishie W, Shimizu H. HLADQB1*03:01 as a biomarker for genetic susceptibility
to bullous pemphigoid induced by DPP-4 inhibitors. J
Invest Dermatol 135, 1201–1204 (2018)
Giacomini KM, Yee SW, Mushiroda T, Weinshilboum
RM, Ratain MJ, Kubo M. Genome-wide association
studies of drug response and toxicity: an opportunity
for genome medicine. Nat Rev Drug Discov 16, 1(2017)

Invited Presentations
Mushiroda T. “Clinical utility of HLA-A*31:01 test foravoidance of carbamazepine-induced skin rash” The12th Asia-Pacific Conference on Human Genetics(Bangkok, Thailand) November, 2017
Mushiroda T. “Identification of genomic biomarkers
associated with cutaneous adverse drug reactions andvalidation of clinical utility of genetic testing” Genomic
Medicine 2017 (Ho Chi Minh, Vietnam) August, 2017
Mushiroda T. “Validation of clinical utility of
HLA-A*31:01 test for avoidance of carbamazepine-induced skin rash” The 2nd International Stevens-Johnson Syndrome Symposium (Kyoto, Japan) January, 2017

44

G

enomic analyses, such as genome-wide association study (GWAS) and HLA
genotyping, are efficient for the identification of pharmacogenomics (PGx)biomarkers that can predict efficacy or risk of adverse drug reactions for various
drugs. The GWAS presently stands as a standard method in IMS but can explain
only a part of the association of genomic variations with drug responses. Pharmacokinetic variabilities are often responsible for inter-individual differences indrug responses. Thus, genetic variations in “Pharmacogenes” encoding proteins
involved in pharmacokinetics, drug-metabolizing enzymes and drug transporters, are of increasing importance for identification of PGx biomarkers. However, it
has been difficult to examine variations in the pharmacogenes because most of thegenes are located within complex genomic regions. We have developed a targeted
resequencing panel of 100 pharmacogenes related to pharmacokinetics using a
combination of multiplex-PCR and next generation sequencing (NGS), which cananalyze rare variants comprehensively and accurately, and thus will be effective forthe identification of PGx biomarkers. After identification of the biomarkers, we
conduct in vitro metabolic and transport experiments in order to evaluate effectsof the variants on gene function for understanding of the molecular mechanismsof drug responses.
Since our mission is implementation of PGx testing, we also conduct prospective clinical studies to test the clinical utility of genetic tests using the PGx biomarkers identified by our basic research. If successful, this will lead to use of thePGx biomarkers as in vitro diagnostics under the Japan national health insurance
system. Recently, we have completed two prospective PGx clinical trials, GENCAT and GENWAT, which showed clinical utility of the genetic tests for patients
who needed treatment with the antiepileptic drug carbamazepine or the anticoagulant warfarin.

Laboratory for

Lab activities

Cardiovascular Diseases
Team Leader: Kaoru Ito

Figure: The Network for Chronic ThromboEmbolic Pulmonary Hypertension (CTEPH) Research
Samples are provided by multiple centers that performballoon angioplasty for CTEPH. An OMICS approach istaken to elucidate CTPEH disease mechanisms using
collected samples.

Recent Major Publications
Ito K, Patel PN, Gorham JM, McDonough B, DePalma
SR, Adler EE, Lam L, MacRae CA, Mohiuddin SM, Fatkin
D, Seidman CE, Seidman JG. Identification of pathogenic gene mutations in LMNA and MYBPC3 that alter RNA
splicing. Proc Natl Acad Sci U S A 114, 7689–7694(2017)
Nomura A, Won HH, Khera AV, Takeuchi F, Ito K, McCarthy S, Emdin CA, Klarin D, Natarajan P, Zekavat SM,
Gupta N, Peloso GM, Borecki IB, Teslovich TM, Asselta
R, Duga S, Merlini PA, Correa A, Kessler T, Wilson JG,
Bown MJ, Hall AS, Braund PS, Carey DJ, Murray MF,
Kirchner HL, Leader JB, Lavage DR, Manus JN, Hartze
DN, Samani NJ, Schunkert H, Marrugat J, Elosua R,
McPherson R, Farrall M, Watkins H, Juang JJ, Hsiung
CA, Lin SY, Wang JS, Tada H, Kawashiri MA, Inazu A,
Yamagishi M, Katsuya T, Nakashima E, Nakatochi M,
Yamamoto K, Yokota M, et al.
Protein-Truncating Variants at the Cholesteryl Ester
Transfer Protein Gene and Risk for Coronary Heart Disease. Circ Res 121, 81–88 (2017)
Low SK, Takahashi A, Ebana Y, Ozaki K, Christophersen
IE, Ellinor PT; AFGen Consortium, Ogishima S, Yamamoto M, Satoh M, Sasaki M, Yamaji T, Iwasaki M, Tsugane
S, Tanaka K, Naito M, Wakai K, Tanaka H, Furukawa T,
Kubo M, Ito K, Kamatani Y, Tanaka T. Identification of
six new genetic loci associated with atrial fibrillationin the Japanese population. Nat Genet 49, 953–958(2017)

Invited Presentations
Kaoru I. “Cutting Edge of Genomic Research: GWAS,NGS, and Others” The 10th Asia Pacific Heart Rhythm
Society Scientific Session in Conjunction with the Annual Meeting of the Japanese Heart Rhythm Society 2017
(Yokohama, Japan) September, 2017
Kaoru I. “Genomic Analysis for Heart Disease by Bioinformatics and Next-Generation Sequencer.” The 3rd
Kyoto Cardiovascular Basic Research Seminar (Kyoto,
Japan) February, 2017

S

ince cardiovascular diseases cause more than 15% of the deaths in the Japanese population and represent more than 20% of the total medical expenses inJapan, it is important for our society to understand the mechanisms underlying
these disorders and to uncover new therapeutic targets for their treatment. To
achieve these goals, we combine “dry” (NGS technologies, OMICS strategies andcomputer science) and “wet” (so-called conventional molecular biology) technologies, in an attempt to achieve a comprehensive and precise understanding ofthese diseases. In other words, there is no border between “dry” and “wet” research in our lab, since we postulate that both will be required to expand the horizons of our knowledge.
Our diseases of interest to date are coronary artery diseases (CAD), atrial fibrillation (AF), Kawasaki disease (KD), peripheral artery disease (PAD), chronic
thromboembolic pulmonary hypertension (CTEPH), and cardiomyopathy (CM).
We are currently seeking to 1) understand the genetic cause of CAD and highlightthe difference between Japanese and European populations, 2) elucidate themechanism of CTEPH development using human OMICS data from patients in
multiple hospitals (see Figure) and 3) develop a more sophisticated genetic riskscoring system by machine learning algorithms in the AF project. Additionally, in
the CM project, we developed an in silico splicing variant prediction algorithm, ahigh-throughput cell-based splicing assay and a downstream in silico pipeline touncover cryptic splicing variants, which have been overlooked in the currently
established pipeline. Using this pipeline, we are now tackling the TTN (titin) gene,which is expressed in striated muscle and encodes the largest protein in humans,consisting of 34,350 amino acids.
We are conducting our research with not only a scientific mind but also a clinical eye, because our ultimate goal is to provide improved diagnostic / management / therapeutic approaches for patients suffering from those diseases.

45

Laboratory for

Lab activities

Autoimmune Diseases
Team Leader: Kazuhiko Yamamoto

Recent Major Publications
Okubo K, Kurosawa M, Kamiya M, Urano Y, Suzuki A,
Yamamoto K, Hase K, Homma K, Sasaki J, Miyauchi
H, Hoshino T, Hayashi M, Mayadas TN, Hirahashi J.
Macrophage extracellular trap formation promoted byplatelet activation is a key mediator of rhabdomyolysisinduced acute kidney injury. Nat Med 24, 232–238(2018)
Kochi Y, Kamatani Y, Kondo Y, Suzuki A, Kawakami E,
Hiwa R, Momozawa Y, Fujimoto M, Jinnin M, Tanaka
Y, Kanda T, Cooper RG, Chinoy H, Rothwell S, Lamb JA,
Vencovský J, Mann H, Ohmura K, Myouzen K, Ishigaki K,
Nakashima R, Hosono Y, Tsuboi H, Kawasumi H, Iwasaki
Y, Kajiyama H, Horita T, Ogawa-Momohara M, Takamura A, Tsunoda S, Shimizu J, Fujio K, Amano H, Mimori A,
Kawakami A, Umehara H, Takeuchi T, Sano H, Muro Y,
Atsumi T, Mimura T, Kawaguchi Y, Mimori T, TakahashiA, Kubo M, Kohsaka H, Sumida T, Yamamoto K. Splicing
variant of WDFY4 augments MDA5 signalling and therisk of clinically amyopathic dermatomyositis Ann
Rheum Dis annrheumdis–2017–212149 (2018)
Ishigaki K, Kochi Y, Suzuki A, Tsuchida Y, Tsuchiya H, Sumitomo S, Yamaguchi K, Nagafuchi Y, Nakachi S, Kato
R, Sakurai K, Shoda H, Ikari K, Taniguchi A, Yamanaka
H, Miya F, Tsunoda T, Okada Y, Momozawa Y, Kamatani
Y, Yamada R, Kubo M, Fujio K, Yamamoto K. Polygenic
burdens on cell-specific pathways underlie the risk ofrheumatoid arthritis. Nat Genet 49, 1120–1125 (2017)

Invited Presentations
Yamamoto K. “Why should rheumatologists know
genetics?” 19th Asia pacific league of Associations forRheumatology Congress (Dubai, UAE) October, 2017
Yamamoto K. “Polygenic burdens on cell-specific pathways underlie the risk of rheumatoid arthritis” Karolinska University (Stockholm, Sweden) September, 2017
Yamamoto K. “Polygenic burdens on cell-specificpathways underlie the risk of rheumatoid arthritis”
Stanford University School of Medicine (Stanford, USA)
September, 2017
Yamamoto K. “Peptidyl arginine deiminase 4 andrheumatoid arthritis: from human genetics to murine
models” Annual European Congress of Rheumatology(Madrid, Spain) June, 2017
Yamamoto K. “Genetics of rheumatoid arthritis: From
genetic information to functional insights” Advances inTargeted Therapies (Cannes, France) March-April, 201746

Figure: Strategy to identify the candidate causal pathways of immune-related complex disease
Design of the eQTL study and analytical pipeline.
(Zcase-control) was consistent with the activated state of thetarget cytokine, the gene was judged to be an activateQTL analysis was conducted on five major subsets ofing gene. The total effect of each gene on the activity
immune cells and unfractionated PB from healthy Japanese individuals using FACS and RNA sequencing. Weof the target cytokine was summarized, and Zcytokine wascalculated.
developed a three-step analytical pipeline. When the
direction of change in candidate causal gene expressionO

ur immune system consists of higher-order functions mediated through theinteraction of various cell types, molecules and genes. To date, the immune
system has mainly been investigated using mouse models, including through inactivation of specific genes (knockout mice). In general, mouse and human immune systems are similar; however, there are distinct and important differences.
Therefore, immunological research in humans is vital for understanding the human immune system. In this respect, studies that examine only the phenomenaof immune responses may not provide information about causal relationships.
Therefore, similar to gene knockout studies in mice, an investigative methodologythat clarifies both cause and consequence should be adopted for human immunology research. In this context, the study of disease-susceptible genetic variants
is important. With the exception of antigen receptor genes, a patient’s genetic
information exists before the disease onset and does not change. These genetic
findings provide us with evidence into the causal relationship of the observed phenomenon and its pathogenesis. Recently, many of the disease susceptible variants
identified by genome wide association study (GWAS) have been found to function as an expression-quantitative trait locus (e-QTL), regulating the expression
levels of genes. For example, the SNP risk regions associated with rheumatoid
arthritis (RA) significantly overlap the histone mark of an active promoter andenhancer in T cells from patients. Therefore, using global genomic information,
qualitative and quantitative analyses of gene expression, together with information about disease susceptible variants, cell-specific epigenomes and proteins, wewill better understand the pathogenic components of immunocompetent cells invarious immune-related diseases. This research will make it possible to elucidate
causal intermediate phenotypes, such as gene expression, epigenome and protein
expression patterns, in individual diseases. By obtaining a comprehensive understanding of the human immune system, it could be possible to elucidate the immune status of each individual in more detail, making precision medicine a reality.

Laboratory for

Lab activities

Digestive Diseases
Team Leader: Kazuaki Chayama

Figure: Changes in the ctDNA levels of two TP53
mutations over the clinical course
The clinical course of a patient being treated withchemotherapy (mFOLFOX6) and immunotherapy (Bevacizumab, anti-VEGF) was followed by CT scans of liver
metastases at baseline, remission and after progression. Changes in two TP53 ctDNA mutations measured
as % mutant allele frequency and in total cell-free DNA(cfDNA, bars) over the clinical course. Changes in the
ctDNA levels of two TP53 mutations are independent ofchanges in the amount of total cfDNA or tumor markers(CEA and CA19–9).

Recent Major Publications
Yamauchi M, Urabe Y, Ono A, Miki D, Ochi H, Chayama K. Serial profiling of circulating tumor DNA for
optimization of anti-VEGF chemotherapy in metastatic
colorectal cancer patients. Int J Cancer (in press)
Furuta M, Ueno M, Fujimoto A, Hayami S, Yasukawa S,
Kojima F, Arihiro K, Kawakami Y, Wardell CP, Shiraishi Y,
Tanaka H, Nakano K, Maejima K, Sasaki-Oku A, Tokunaga N, Boroevich KA, Abe T, Aikata H, Ohdan H, Gotoh K,
Kubo M, Tsunoda T, Miyano S, Chayama K, Yamaue H,
Nakagawa H. Whole genome sequencing discriminates
hepatocellular carcinoma with intrahepatic metastasis
from multi-centric tumors. J Hepatol 66, 363–373(2017)
Fujimoto A, Furuta M, Totoki Y, Tsunoda T, Kato M, Shiraishi Y, Tanaka H, Taniguchi H, Kawakami Y, Ueno M,
Gotoh K, Ariizumi S, Wardell CP, Hayami S, Nakamura
T, Aikata H, Arihiro K, Boroevich KA, Abe T, Nakano
K, Maejima K, Sasaki-Oku A, Ohsawa A, Shibuya T,
Nakamura H, Hama N, Hosoda F, Arai Y, Ohashi S,
Urushidate T, Nagae G, Yamamoto S, Ueda H, Tatsuno
K, Ojima H, Hiraoka N, Okusaka T, Kubo M, Marubashi
S, Yamada T, Hirano S, Yamamoto M, Ohdan H, Shimada K, Ishikawa O, Yamaue H, Chayama K, Miyano S,
Aburatani H, Shibata T, Nakagawa H. Whole-genome
mutational landscape and characterization of noncoding and structural mutations in liver cancer. Nat Genet
48, 500–509 (2016)

Invited Presentations
Chayama K. “Baseline RAS Test: Clinical practice” The
Liver Week 2017 (Incheon, Korea) June, 2017

A

lthough not directly cytopathic, HBV and HCV are responsible for millions of deaths annually, and the aging patient population presents a critical public health challenge. Using a GWAS approach, we have focused oninvestigating host genetic factors involved in various liver diseases, such as
chronic HBV and HCV infection, HCV-induced liver cirrhosis and cancer,
and responsiveness to therapy. We have now intensively investigated and verified how to apply such genetic information to clinical practice. We demonstrated that a polymorphism in the interferon lambda-4 (IFNL4) gene affects theoutcome of simeprevir, peginterferon and ribavirin therapy for older patientswith genotype 1 chronic hepatitis C (Hepatol Res 2017). In addition, we foundthat an inosine triphosphatase (ITPA) polymorphism influences the decreaseof hemoglobin during the interferon-free regimen of sofosbuvir plus ribavirin for patients with genotype 2 chronic hepatitis C (J Gastroenterol 2017).
We have also participated in whole-genome sequencing (WGS) analysis of liver cancer in collaboration with the Laboratory for Genome Sequencing Analysis(Nat Genet 2016, Nat Commun 2015). We showed that WGS of multiple liver tumors enabled the accurate diagnosis of multi-centric occurrence versus intrahepatic
metastasis prior to selecting a therapeutic strategy for multiple tumors in the liver(J Hepatol 2017). By using WGS data, we analyzed circulating tumor DNA (ctDNA) and found that it reflects tumor progression, microscopic vascular invasion of
the portal vein and cancer recurrence (Cell Mol Gastroenterol Hepatol 2015). Recently, we analyzed ctDNA for optimization of anti-VEGF chemotherapy in metastatic colorectal cancer patients. We finally found that changes in ctDNA levels
could be useful as predictive biomarkers for survival. Mutations newly detected in
ctDNA in the late treatment period might reveal the rise of a minor tumor subclone that may show resistance to the anti-VEGF therapy (Int J Cancer in press).

47

Laboratory for

Lab activities

Bone and Joint Diseases
Team Leader: Shiro Ikegawa

Recent Major Publications
Sakamoto Y, Yamamoto T, Sugano N, Takahashi D,
Watanabe T, Atsumi T, Nakamura J, Hasegawa Y,
Akashi K, Narita I, Miyamoto T, Takeuchi T, Ikari K,
Amano K, Fujie A, Kubo T, Tada Y, Kaneuji A, Nakamura H, Miyamura T, Kabata T, Yamaji K, Okawa T,
Sudo A, Ohzono K, Tanaka Y, Yasunaga Y, Matsuda S,
Imai Y; Japanese Research Committee on Idiopathic
Osteonecrosis of the Femoral Head, Akiyama M, Kubo
M, Kamatani Y, Iwamoto Y, Ikegawa S. Genome-wide
Association Study of Idiopathic Osteonecrosis of the
Femoral Head. Sci Rep 7, 15035 (2017)
Akiyama M, Okada Y, Kanai M, Takahashi A, Momozawa Y, Ikeda M, Iwata N, Ikegawa S, Hirata M,
Matsuda K, Iwasaki M, Yamaji T, Sawada N, Hachiya T,
Tanno K, Shimizu A, Hozawa A, Minegishi N, Tsugane
S, Yamamoto M, Kubo M, Kamatani Y. Genome-wide
association study identifies 112 new loci for bodymass index in the Japanese population. Nat Genet 49,
1458–1467 (2017)
Ogura Y, Kou I, Takahashi Y, Takeda K, Minami S, Kawakami N, Uno K, Ito M, Yonezawa I, Kaito T, Yanagida
H, Watanabe K, Taneichi H, Harimaya K, Taniguchi Y,
Kotani T, Tsuji T, Suzuki T, Sudo H, Fujita N, Yagi M, Chiba K, Kubo M, Kamatani Y, Nakamura M, Matsumoto
M; Japan Scoliosis Clinical Research Group, Watanabe
K, Ikegawa S; Japan Scoliosis Clinical Research Group.
A functional variant in MIR4300HG, the host gene of
microRNA MIR4300 is associated with progression ofadolescent idiopathic scoliosis. Hum Mol Genet 26,
4086–4092 (2017)

Invited Presentations
Ikegawa S. “Axial spondylometaphyseal dysplasia” 13th
International Skeletal Dysplasia Society Meeting (ISDS)(Bruges, Belgium) Sep 2017
Ikegawa S. “Genome study of skeletal dysplasia, rare
orthopedic diseases” The 12th ICORD (International
Conference on Rare Diseases and Orphan Drugs)/The
6th China Rare Disease Summit (Beijing, China) Sep
2017
Ikegawa S. “Genomic approaches to study idiopathic
scoliosis” The combined ICSG and ICVAS meeting (Dallas, Texas, USA) March 2017
Ikegawa S. “Diagnostics of skeletal dysplasias in thenext generation” The 4th Nordic skeletal dysplasia
workshop (Helsinki, Finland) March 2017
Ikegawa S. “How to study genetic diseases.” Taipei
Medical University Invited Seminar (Taipei, Taiwan)
January 201748

Figure: Manhattan plot of imputed
GWAS data for idiopathic osteonecrosis of the femoral head in Japanese (from Sakamoto et al. Sci Rep 2017)(a) Idiopathic osteonecrosis of thefemoral head vs BioBank Japan (BBJ),(b) alcohol-associated osteonecrosisof the femoral head (ONFH) vs BBJ, (c)alcohol-associated ONFH vs BBJ of heavy
drinkers (400 ml/day or more ethanol
consumption), (d) steroid-associated
ONFH vs BBJ, and (e) neither-associated
ONFH vs BBJ. SNPs with genome-wide
significance were identified in (a)12q24.11-12 and 20q12, (b) 12q24.1113 and 20q12, (c) 20q12, and (d) 2q32
and 6p21. The red and blue lines represented the threshold of genome-wide
significance (P = 5 x 10 –8) and suggestive
association threshold (P = 1 x 10 –5),
respectively.

a) Genomic Study of Common Diseases
Common bone and joint diseases have become serious concerns for world health and theeconomy, as exemplified by the WHO initiative “Bone and Joint Decade” (2000–2010)
and the “Locomo” campaign in Japan. We are searching for susceptibility genes for common (polygenic) bone and joint diseases including osteoarthritis (OA), lumbar discdisease (LDD)/herniation (LDH), osteoporosis, idiopathic osteonecrosis of the femoral
head (ION), 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, and then clarify their disease-causing mechanisms at the molecular level. Using the genome information obtainedby these studies, we will realize our final goal, “precision medicine” for these diseases.
GWASs for OA, LDD/LDH, adolescent idiopathic scoliosis (AIS), OPLL, and ION are in
progress and will be followed by functional studies of the genes in vitro and using animalmodels. We have already succeeded in identification of susceptibility genes by GWAS for
ION (Figure) and the pathogenic mechanisms of the disease.
b) Genomic Study of Skeletal Dysplasia
Skeletal dysplasia is a group of heritable (monogenic) disorders affecting the skeleton,with more than 400 diseases belonging to this category. Skeletal dysplasia is an intractable disease and thus many patients are waiting for treatment. We are engaging in clinicaland basic studies of these refractory diseases. By large-scale mutation screening, including exome sequencing, we are identifying the disease-causing genes. So far, we identified
new genes for 27 diseases.
Through analysis of their phenotypes and diseases genes, we approach molecularmechanisms of bone and joint formation, pathogenesis of common bone and joint diseases, as well as the diagnosis and treatment of these crippling intractable diseases (‘nanbyo’). Using the disease genes for skeletal dysplasia as candidate genes, we are performing
association studies for the corresponding common bone and joint diseases.

Laboratory for

Lab activities

Endocrinology, Metabolism
and Kidney Diseases
Team Leader: Momoko Horikoshi

Figure: Results of GWAS meta-analysis for type 2
diabetes in the Japanese population
Names of the previously identified loci are in black andthe seven new loci identified in this study are shownin red.
Recent Major Publications
Mägi R, Horikoshi M, Sofer T, Mahajan A, Kitajima H,
Franceschini N, McCarthy MI; COGENT-Kidney Consortium, T2D-GENES Consortium, Morris AP. Trans-ethnic
meta-regression of genome-wide association studies
accounting for ancestry increases power for discovery
and improves fine-mapping resolution. Hum Mol Genet 26, 3639–3650 (2017)
Horikoshi M, Beaumont RN, Day FR, Warrington NM,
Kooijman MN, Fernandez-Tajes J, Feenstra B, vanZuydam NR, Gaulton KJ, Grarup N, Bradfield JP, Strachan DP, Li-Gao R, Ahluwalia TS, Kreiner E, Rueedi R,
Lyytikäinen LP, Cousminer DL, Wu Y, Thiering E, Wang
CA, Have CT, Hottenga JJ, Vilor-Tejedor N, Joshi PK, Boh
ET, Ntalla I, Pitkänen N, Mahajan A, van Leeuwen EM,
Joro R, Lagou V, Nodzenski M, Diver LA, Zondervan
KT, Bustamante M, Marques-Vidal P, Mercader JM,
Bennett AJ, Rahmioglu N, Nyholt DR, Ma RC, Tam CH,
Tam WH; CHARGE Consortium Hematology Working
Group., Ganesh SK, van Rooij FJ, Jones SE, Loh PR, Ruth
KS, Tuke MA, et al. Genome-wide associations for birthweight and correlations with adult disease. Nature
538, 248–252 (2016)
Imamura M, Takahashi A, Yamauchi T, Hara K, Yasuda
K, Grarup N, Zhao W, Wang X, Huerta-Chagoya A, Hu
C, Moon S, Long J, Kwak SH, Rasheed A, Saxena R, Ma
RC, Okada Y, Iwata M, Hosoe J, Shojima N, Iwasaki M,
Fujita H, Suzuki K, Danesh J, Jørgensen T, Jørgensen
ME, Witte DR, Brandslund I, Christensen C, Hansen T,
Mercader JM, Flannick J, Moreno-Macías H, Burtt NP,
Zhang R, Kim YJ, Zheng W, Singh JR, Tam CH, Hirose
H, Maegawa H, Ito C, Kaku K, Watada H, Tanaka Y,
Tobe K, Kawamori R, Kubo M, Cho YS, Chan JC, et al.
Genome-wide association studies in the Japanese
population identify seven novel loci for type 2 diabetes.
Nat Commun 7, 10531 (2016)O

ur primary focus is on establishing the genetic contribution to type 2 diabetes (T2D) susceptibility in the Japanese population. To that end, we areworking directly with the state-of-the-art genetic resources generated by Biobank
Japan, which includes GWAS data for more than 35,000 T2D subjects. Our recent analyses of a subset of these GWAS data identified seven novel regions of the
genome associated with T2D (Fig). Of the more than 90 T2D loci reported as of2016, we have increased the number of loci reported from the Japanese population
to 14 in total. We are currently expanding this effort to the full set of Biobank
Japan. We have also investigated genomic regions associated with microvascularcomplications of T2D, namely, diabetic retinopathy and nephropathy. GWAS for
these complications have been performed by several groups, but worldwide efforts
to identify susceptibility to these diabetic complications have not met with clear
success. We are strengthening our ties with neighboring collaborators by contributing our T2D association data to the Asian Genetic Epidemiology Network(AGEN) Consortium as well as to the world-wide DIAMANTE Consortium.

Invited Presentations
IHorikoshi M. “Genomic loci associated with birthweight identify genetic links between intrauterine
growth and adult metabolic disease” CRG Symposium 7th International Workshop on Genomic Epidemiology(Barcelona, Spain) September, 2017
Horikoshi M. “Genomic loci associated with birthweight identify genetic links between intrauterine
growth and adult metabolic disease” The 12th International Workshop on Advanced Genomics (Tokyo, Japan)
June, 2017
Horikoshi M. “Linking birth weight and adult diseases
through genetics” RCAST Symposium on New Dietetics(Tokyo, Japan) June, 201749

Laboratory for

Lab activities

Respiratory andAllergic Diseases
Team Leader: Mayumi Tamari

Figure: Effects of the 10 associated loci ofchildhood FA with AD.
Odds ratios (ORs) and 95% confidence intervals (CIs)observed for AD or EoE in original articles versus thosefor FA and FA with AD in this study are shown.

Recent Major Publications
Hirata J, Hirota T, Ozeki T, Kanai M, Sudo T, Tanaka T,
Hizawa N, Nakagawa H, Sato S, Mushiroda T, Saeki
H, Tamari M, Okada Y. Variants at HLA-A, HLA-C, andHLA-DQB1 confer risk of psoriasis vulgaris in Japanese.
J Invest Dermatol (2017) in press
Hirota T, Nakayama T, Sato S, Yanagida N, Matsui T,
Sugiura S, Takaoka Y, Hizawa N, Fujieda S, Miyatake
A, Sasaki T, Amagai M, Doi S, Ito K, Ebisawa M, Tamari
M. Association study of childhood food allergy with
GWAS-discovered loci of atopic dermatitis and eosinophilic esophagitis. J Allergy Clin Immunol 140,
1713–1716 (2017)
Sunadome H, Matsumoto H, Petrova G, Kanemitsu
Y, Tohda Y, Horiguchi T, Kita H, Kuwabara K, Tomii K,
Otsuka K, Fujimura M, Ohkura N, Tomita K, Yokoyama
A, Ohnishi H, Nakano Y, Oguma T, Hozawa S, Nagasaki
T, Ito I, Oguma T, Inoue H, Tajiri T, Iwata T, Izuhara Y,
Ono J, Ohta S, Hirota T, Tamari M, Yokoyama T, Niimi A,
Izuhara K, Mishima M. IL4Rα and ADAM33 as genetic
markers in asthma exacerbations and type-2 inflammatory endotype. Clin Exp Allergy 47, 998–1006 (2017)

Invited Presentations
Tamari M. “Genetic Factors of Allergic Diseases” The 4th
Seminar of Japanese Society of Allergology (Kanagawa,Japan) December, 2017
Tamari M. “Genomics in Atopic Dermatitis and Psoriasis” Seminar in Department of Dermatology, The Jikei
University of Medicine (Tokyo, Japan) July, 2017
Tamari M. “Genetic Factors of Allergic Diseases” Symposium, The 66th meeting of Japanese Society of Allergology (Tokyo, Japan) June, 2017
Tamari M. “Genetic Study of Allergic Diseases” Nature
Conference (Guangzhou, China) May, 201750

T

he aim of our project is to explore genetic components of respiratory andallergic diseases. Genome-wide association study (GWAS) is a method forcomprehensive assessment of genes underlying susceptibility to human disorders.
Food allergy (FA) is a problem throughout the world, but the genetic factors affecting FA susceptibility in children remain largely unexplored. We recruited patientswith FA who had been diagnosed by pediatric specialists based on positive oral
food challenge or a definitive clinical history after food intake. We conducted an
association study of childhood FA with GWAS-discovered loci for atopic dermatitis (AD) and eosinophilic esophagitis (EoE). We assessed 19 and seven susceptibility variants previously reported in GWAS for AD and EoE, respectively, and foundan association between FA and 14 of these loci. We then stratified the case subjects
by AD comorbidity and a total of 10 loci were associated with childhood FA and
AD (Figure). We further assessed associations of a total of six filaggrin (FLG) nullvariants with childhood FA, and found a significant association. These findings
improve our understanding of the complex heterogeneity of FA.
Wheat-dependent exercise-induced anaphylaxis (WDEIA) is severe food allergy that usually develops after ingestion of wheat products followed by physicalexercise. Hydrolysed wheat gluten protein (HWP) is used as an additive for facialsoap. In Japan, a total of 2026 cases of immediate wheat allergy and WDEIA due
to HWP have been reported. Most patients seemed to be sensitized to HWP (Glupearl 19S®) through the use of the facial soap “Cha-no-shizuku”. Glupearl 19S® is adegraded gluten made by the direct resolution of wheat by hydrochloric acid. We
conducted GWAS of WDEIA induced by HWP-containing facial soap of 464 casesand 3,099 controls and identified associated SNPs at a region on chromosome 6.

Program for
Medical Innovations
F

our original projects for clinical applications have been performed: 1) A
chemical compound recently developed using the α-galactosylceramide(α-GalCer) analog, RCAI-X. The RCAI-X-loaded autologous cell therapy has
been studied preclinically for cancer therapy. 2) The artificial adjuvant vector
cell as an anti-tumor vaccine project has been accepted by the translational
research network program and developed. This vaccine can be dosed with tumor antigen mRNA together with α-GalCer, so that it activates both innate
and acquired protective immunity and also induces long-term memory. 3) The
human iPS project for clinical use of in vitro generated NKT cells has been accepted as a Center for Clinical Application Research (Type B) in the ResearchCenter Network for Realization of Regenerative Medicine, Japan in 2013. 4) A
humanized mouse model for MLL gene-rearranged leukemia was established.
Also, certain genes were identified that are differentially expressed between
normal stem cells and leukemic stem cells.

51

Laboratory for

Lab activities

Immune Regulation
Group Director: Masaru Taniguchi

Figure: Superior antitumor activity of dendritic
cells (DCs) pulsed with the novel NKT cell-activating ligand RK(A) Inhibition of B16 melanoma metastasis by specificactivation of natural killer T cells with RK-pulsed DCs.
The antitumor effect was assessed using the B16 melanoma liver metastasis model. Tumor cells were inoculated into B6 mice on day 0, and the indicated numbersof DCs pulsed with RK or the previous NKT cell ligand
α–galactosylceramide (GC) were injected intravenously
on day 4. Untreated control mice were inoculated onlywith the B16 melanoma. Individual liver tissue images
obtained from three mice per experimental group on
day 14 post-injection are shown. (B) Standard curve
generated by melanin measurement using visible light
spectroscopy at 405 nm obtained from serially diluted
B16 melanoma cells. (C) Quantitative analysis of B16
melanoma burden in the liver tissues shown in panel(A). Values represent calculated ratios of melanin concentrations assessed by visible light spectroscopy relative to the untreated animals inoculated only with theB16 melanoma (mean ± SEM, n = 5 mice per group).

Recent Major Publications
Dashtsoodol N, Shigeura T, Tashiro T, Aihara M, Chikanishi T, Okada H, Hanada K, Sano H, Kurogi A, Taniguchi
M. Natural Killer T Cell-Targeted Immunotherapy Mediating Long-term Memory Responses and Strong Antitumor Activity. Front Immunol 8, 1206 (2017)
Dashtsoodol N, Shigeura T, Aihara M, Ozawa R, Kojo S,
Harada M, Endo T, Watanabe T, Ohara O, Taniguchi M.
Alternative pathway for the development of Vα14+ NKT
cells directly from CD4−CD8− thymocytes that bypasses
the CD4+CD8+ stage. Nat Immunol 18, 274–282 (2017)
Dashtsoodol N, Shigeura T, Ozawa R, Harada M, Kojo
S, Watanabe T, Koseki H, Nakayama M, Ohara O, Taniguchi M. Generation of Novel Traj18-Deficient Mice
Lacking Vα14 Natural Killer T Cells with an Undisturbed
T Cell Receptor α-Chain Repertoire. PLoS One 11,
e0153347 (2016)

Invited Presentations
Taniguchi M. “NKT cell-targeted anti-cancer therapy”
2017 World Alliance Forum in San Francisco (San Francisco, USA) November, 2017
Taniguchi M. “Alternative pathway for the developmentof Vα14+ NKT cells directly from CD4−CD8− thymocytesthat bypasses the CD4+CD8+ stage” CD1-MR1 2017
(Napa, USA) November, 2017
Dashtsoodol N. “Revisiting a dogma: Identification of anovel alternative pathway of Vα14+ NKT cell development directly from thymic DN stage bypassing the DP
stage” Annual Scientific Conference of the Mongolian
National University of Medical Sciences (Ulaanbaatar,
Mongolia) April, 201752

C

urrent tumor therapies, including immunotherapies, focus on passive eradication or at least reduction of the tumor mass. However, cancer patients quite
often suffer from tumor relapse or metastasis after such treatments. To overcome
these problems, we have developed an NKT cell-targeted immunotherapy focusing on active engagement of the patient’s immune system, but not directly targeting the tumor cells themselves. Natural Killer T (NKT) cells express an invariant
antigen receptor α chain encoded by Trav11 (Vα14)–Traj18 (Jα18) gene segments
in mice and TRAV10 (Vα24)–TRAJ18 (Jα18) in humans and recognize glycolipid
ligand in conjunction with a monomorphic CD1d molecule. The NKT cells playa pivotal role in the orchestration of antitumor immune responses by mediating
adjuvant effects that activate various antitumor effector cells of both innate andadaptive immune systems and also aid in establishing a long-term memory response. As a result of our group,s long term commitment to translational researchsupported by AMED, we have recently established an NKT cell-targeted therapy
using a newly discovered NKT cell glycolipid ligand, RK, which has a stronger capacity to stimulate both human and mouse NKT cells compared to previously used
NKT cell ligands. Moreover, RK mediates strong adjuvant effects in activating various effector cell types and establishes long-term memory responses, resulting ina continuous attack on the tumor that confers long-lasting and potent antitumor
effects. Since the NKT cell ligand presented by the monomorphic CD1d can beused for all humans irrespective of HLA types, and also because NKT cell-targeted
therapy does not directly target tumor cells, this therapy can potentially be applied
to all cancer patients and any type of tumor.

Laboratory for

Lab activities

Immunotherapy
Team Leader: Shin-ichiro Fujii

Figure: Preclinical study with aAVC-WT1
Mice were inoculated with a WT1-expressing plasmacytoma cell line (J558-WT1) and then treated with mouse
aAVC-WT1 at day 7. In the control untreated group, allof the mice died within 30 days. In contrast, 75% of
the aAVC-WT1-treated mice survived for more than 6months.

Recent Major Publications
Iyoda T, Yamasaki S, Hidaka M, Kawano F, Abe Y,
Suzuki K, Kadowaki N, Shimizu K, Fujii S. Ameliorationof NK cell function driven by Vα24+ invariant NKT cell
activation in multiple myeloma. Clin Immunol S15216616(17)30503-X (2017)
Harrer DC, Simon B, Fujii S, Shimizu K, Uslu U, Schuler
G, Gerer KF, Hoyer S, Dörrie J, Schaft N. RNA-transfection of γ/δ T cells with a chimeric antigen receptor oran α/β T-cell receptor: a safer alternative to geneticallyengineered α/β T cells for the immunotherapy of melanoma. BMC Cancer 17, 551 (2017)
Fujii S, Shimizu K. Exploiting antitumor immunotherapeutic novel strategies by deciphering the cross talkbetween invariant NKT cells and dendritic cells. Front
Immunol 8, 886 (2017)

Invited Presentations
Fujii S. “Development of new cellular vaccine systems
with synergistic immunopotentiating effects” The 46th
Japanese Society for Immunology (Sendai, Japan)
December, 2017
Fujii S. “in vivo DC targeting therapy triggered by NKT
cell activation” The 21st Annual Meeting of Japanese
Association of Cancer Immunology (Tokyo, Japan) June,
2017
Fujii S. “NKT cell-targeted anti-cancer immunotherapy”
The 27th Annual Meeting of Japan Cytometry Society(Kobe, Japan) June, 2017
Fujii S, Shimizu K. “Systemic and Potent Dendritic Cell
(DC) Activation Modulates the Tumor Microenvironment and Shapes the Long-lived Tumor Specific Memory CD8+T Cells” The 8th JSH International Symposium2017 (Miyazaki, Japan) May, 2017
Fujii S. “Development of multifunctional anti-cancer
vaccine - artificial adjuvant vector cells (aAVC)” The54th Annual Meeting of Japan Society of Molecular
Medicine (Tokyo, Japan) April, 2017T

he aims of our laboratory are to extend basic studies for advancing immunotherapy and translational research, from basic studies back and forth to thebedside in the field of cancer and the control of other diseases. In this fiscal year,
we have started the first-in-human clinical trial using artificial adjuvant vector
cells (aAVC), which we first developed in 2009. The aAVC is comprised of allogeneic cells as vector cells, NKT ligand and CD1d complex on the cell surface andcancer-related protein inside of the cells. This aAVC cellular drug therapy activates
dendritic cells in vivo, resulting in multifunctional immune responses, i.e., notonly innate and adaptive immunity, but also memory T cells. Because of this powerful immune response, we observe a strong antitumor therapeutic effect and also
a block in tumor metastasis. Since aAVC is a basic platform, we can replace any
type of cancer antigen and, therefore, it would possibly be applicable for a variety
of diseases. In fact, we have confirmed the activation of multifunctional immune
responses by administration of aAVC-OVA, -MART-1, -WT1 and -TRP2 in different tumor-bearing mouse models. In addition, we demonstrated that therapy with
aAVC-expressing hemagglutinin (aAVC-HA) should also be useful to combat influenza virus infection. We established a human aAVC product, WT-1 tumor antigen-expressing human aAVC (aAVC-WT1) and finished many pre-clinical studies by consulting with the Japan Pharmaceuticals and Medical Devices Agency(PMDA), similar to the US FDA. As discussed above, we have recently launched
an investigator-initiated clinical trial of aAVC-WT1 for relapsed or refractory
acute myeloid leukemia patients in collaboration with the group of the Dept. of
Hematology and Oncology, The University of Tokyo, The Institute of Medical Science. This clinical study has been supported by the Translation Research center ofTokyo University and RIKEN DMP.

53

Lab activities

Drug Discovery
Antibody Platform Unit
Unit Leader: Toshitada Takemori

Figure: Induction of phosphorylated proteins by
mAb treatment.
A mutant B cell lymphoma cell line lacking HLA-DRα
was transfected with HA-tagged HLA-DRα and stimulated with L243 (mIgG2a,κ) or anti-HA (mIgG2a,κ)mAbs. Proteins were extracted from whole cell lysates(nonstimulated (none), stimulated with anti-HA tag
mAb or L243 mAb), digested, followed by enrichmentof phosphopeptides and finally analyzed by LC-MS/MS.
Hierarchical clustering was performed on each protein
and the heat map was generated using Java TreeView
software (http://jtreeview.sourceforge.net/). The boxedclusters indicate phosphorylated proteins that are only
enhanced with L243 stimulation. The color in the map
depicts the relative expression value (log2-scale) for
each sample.

Recent Major Publications
Miyauchi K, Sugimoto-Ishige A, Harada Y, Adachi Y,
Usami Y, Kaji T, , Hasegawa H, Watanabe T, Hijikata A,
Fukuyama S, Maemura T, Ohara O, Kawaoka Y, Takahashi Y, Takemori T, Kubo M. Protective neutralizing influenza antibody response in the absence of T follicularhelper cells. Nat Immunol 17, 1447–1458 (2016)
Kaji T, Hijikata A, Ishige A, Kitami T, Watanabe T, Ohara
O, Yanaka N, Okada M, Shimoda M, Taniguchi M,
Takemori T. CD4 memory T cells develop and acquire
functional competence by sequential cognate interactions and stepwise gene regulation. Int Immunol 28,
267–282 (2016)

Invited Presentations
Harada M, Sugimoto A, Matsuoka S. Takemori T. “CD81is associated with non-apoptotic cell death in B cell
lymphoma cell lines through HLA-DR alpha/beta engagement” The 46th Annual Meeting of Japanese Society for Immunology (Okinawa, Japan) December, 2016

54

N

on-Hodgkin lymphoma is a heterogeneous group of malignancies, most ofwhich have a B cell phenotype. HLA-DR is highly expressed on hematologic
malignancies, and HLA-DR engagement by a pan-HLA-DR mAb recognizing a
conformational epitope in the N-terminal α chain of HLA-DR, such as murine
L243, directly kill the cells by non-apoptotic cell death. However, the mechanism
remains elusive.
HLA-DR molecules do not possess any known signaling motifs in their cytoplasmic domain, but we found that their transmembrane domain is critical to mediate the killing signals, probably via associated molecules including tetraspanin
family proteins.
Due to the importance of protein phosphorylation in many aspects of cell signaling, we have focused on the identification of phosphorylated proteins triggering
non-apoptotic cell death in B cell lymphoma cell lines. To this end, we prepareda mutant B cell lymphoma cell line that is deficient in HLA-DRα expression as aresult of genomic manipulation using the CRISPR-Cas9 system. The mutant wastransfected with HA-tagged HLA-DRα and stimulated with the killing mAb, L243,
or an anti-HA mAb that stimulates cell lines but does not induce cell killing. We
detected a total of 11 proteins (marked by asterisks in Figure), that were phosphorylated on multiple sites upon stimulation with L243 but not with anti-HA mAbs.
These proteins are known as regulators of energy and RNA metabolism, cell cycle
and signal transduction. We are now analyzing signaling pathways related to energy metabolism, which could be involved in HLA-DR mediated direct killing by a
non-apoptotic pathway in B cell lymphomas.
This work is a collaboration with Drs. Ohara and Kawashima (Laboratory for
Integrative Genomics) and Dr. Kawakami (Healthcare and Medical Data Driven
AI based Predictive Reasoning Development Unit).

YCI Laboratory for

Lab activities

Immune Regeneration
Young Chief Investigator: Tomokatsu Ikawa

Figure: Transcriptional network during B cell fate
determination
The heatmap represents gene expression profiles ofhighly variable transcription factors. Networks areshown in three time phases (Early, Mid and Late). The
color of each node represents the transcriptional activity (activation or suppression of expression of their postulated downstream target genes) at the indicated timephase. Thickness of the edge indicates the probabilityof protein-protein interaction (experimental score in the
STRING database).

Recent Major Publications
Miyai T, Takano J, Endo TA, Kawakami E, Agata Y, Motomura Y, Kubo M, Kashima Y, Suzuki Y, Kawamoto H,
Ikawa T. Three-step transcriptional priming that drives
the commitment of multipotent progenitors toward B
cells. Genes Dev 32, 112–126 (2018)
Noguchi S, Arakawa T, Fukuda S, Furuno M, Hasegawa
A, Hori F, Ishikawa-Kato S, Kaida K, Kaiho A, Kanamori-Katayama M, Kawashima T, Kojima M, Kubosaki
A, Manabe RI, Murata M, Nagao-Sato S, Nakazato K,
Ninomiya N, Nishiyori-Sueki H, Noma S, Saijyo E, Saka
A, Sakai M, Simon C, Suzuki N, Tagami M, Watanabe
S, Yoshida S, Arner P, Axton RA, Babina M, Baillie JK,
Barnett TC, Beckhouse AG, Blumenthal A, Bodega B,
Bonetti A, Briggs J, Brombacher F, Carlisle AJ, Clevers
HC, Davis CA, Detmar M, Dohi T, Edge ASB, Edinger M,
Ehrlund A, Ekwall K, Endoh M, Enomoto H, et al. FANTOM5 CAGE profiles of human and mouse samples. Sci
Data 4, 170112 (2017)
Ikawa T, Masuda K, Endo TA, Endo M, Isono K, Koseki Y,
Nakagawa R, Kometani K, Takano J, Agata Y, Katsura Y,
Kurosaki T, Vidal M, Koseki H, Kawamoto H. Conversion
of T cells to B cells by inactivation of polycomb-mediated epigenetic suppression of the B-lineage program.
Genes Dev 30, 2475–2485 (2016)

Invited Presentations
Ikawa T, Miyai T, Takano J. “Three-step transcriptional
priming that drives multipotent progenitors toward B
cells.” The 46th Annual Meeting of The Japanese Society for Immunology. (Sendai, Japan) December, 2017
Ikawa T. “Epigenetic maintenance of T cell identity by
Polycomb-mediated suppression of Pax5.” BMB2017.
(Kobe, Japan) December, 2017
Ikawa T. “Lymphocyte differentiation and Epigenetics.”
Biken Seminar, Osaka University (Suita, Japan) November, 2017
Ikawa T, Miyai T, Takano J. “A road map that guides thedevelopment of B cells” The 3rd Tsinghua-RIKEN Joint
Symposium (Beijing, China) September, 2017

B

lymphocytes are generated from pluripotent hematopoietic stem cells (HSCs)
through a successive series of lineage restriction processes. Although many
essential transcription factors (TFs), such as Ikaros, PU.1, E2A, EBF1 and Pax5
have been implicated in regulating cell fate choice in the B cell lineage, molecularmechanisms underlying the generation of these patterns during cell fate determination remain unexplored because of the absence of suitable experimental systems.
We have recently established an ideal system that can be used to examine gene
regulatory networks during lymphoid lineage specification from HSCs. We overexpressed Id3 protein fused with ERT2 (Estrogen receptor) protein, whose nuclear
translocation is induced by 4-hydroxytamoxifen (4-OHT), in hematopoietic progenitors and cultured them in B cell differentiation conditions. In the presenceof 4-OHT, B cell differentiation of Id3-transduced cells was blocked at an early
developmental stage but the cells grew enormously and maintained multipotency(Ikawa et al. Stem Cell Reports, 2015). We named these multipotent progenitors as
induced leukocyte stem (iLS) cells.
This novel system enabled the analysis of a large set of regulatory moleculesthat control the generation of T and B lymphocytes. We have recently described
the complex transcriptional network operative during B lineage commitment(Figure). This system can also be applied for ex vivo expansion of human hematopoietic stem/progenitors, which will be required for immune cell therapy ortransplantation of HSCs. Thus, the aims of our study are 1) from a basic science
perspective, to elucidate the mechanisms that orchestrate cell fate specification,commitment and differentiation during lymphocyte development and 2) from aclinical medicine perspective, to establish a novel method to expand human hematopoietic stem/progenitors for the development of HSC transplantation as aclinical strategy.

55

YCI Laboratory for

Lab activities

Cellular Bioenergetic
Network
Young Chief Investigator: Toshimori Kitami

Figure: Searching for chemicals that modulate
mitochondrial function using the NLRP3 inflammasome as a disease pathway model
In order to identify chemicals that could activate as wellas suppress the NLRP3 inflammasome pathway, we
performed multiple layers of screens using IL-1β as areadout of the pathway activity.

Recent Major Publications
Kaji T, Hijikata A, Ishige A, Kitami T, Watanabe T, Ohara
O, Yanaka N, Okada M, Shimoda M, Taniguchi M,
Takemori T. CD4 memory T cells develop and acquire
functional competence by sequential cognate interactions and stepwise gene regulation. Int Immunol 28,
267–282 (2016)

Invited Presentations
Kitami T. “Mitochondrial chemical compendium v2:
Building a genotype-chemical interaction databasefor mitochondrial toxicity” The 1st Annual COCKPI-T(Co-create Knowledge for Pharma Innovation with
Takeda) (Kanagawa, Japan) July, 201756

T

he overarching goal of our laboratory is to understand the role of cellular
metabolism in the pathogenesis of complex diseases. Research over the past
decades has shown that monogenic mutations in metabolic pathways cause a wide
variety of human diseases. However, more recent studies have highlighted the roleof cellular metabolism in the development of a wide variety of complex humandiseases. Our laboratory in particular has been studying the function of mitochondrial energy metabolism, which is associated with neurodegeneration, cardiovascular disease, type 2 diabetes, and aging. We hope to identify novel pathways
that restore or improve mitochondrial function through genetic and chemical
screens and to examine their potential therapeutic value using genetically engineered mouse models and unique chemical probes.
Towards our goal, we have begun to explore the role of mitochondria in an
innate immune pathway called the NLRP3 inflammasome, which is involved in avariety of age-associated diseases. The NLRP3 inflammasome is activated by cell
physiological changes, including mitochondrial damage, although the molecular players involved have not been fully elucidated. To systematically identify key
players in this complex pathway, we performed a series of chemical screens andhave successfully identified compounds that can activate as well as suppress the
NLRP3 inflammasome via mitochondria. Our analysis of these unique chemicals
highlighted an important role of mitochondrial energy metabolism in maintaining intracellular ion homeostasis and preventing NLRP3 activation. Moreover,
two outputs of the mitochondria, ATP and reactive oxygen species, both compete
for activation and suppression of the NLRP3 inflammasome.
In the coming year, we hope to gain a more in-depth quantitative understanding of the interplay between mitochondria and the key interacting molecular players we identified from the screen. In addition, we hope to understand the mechanism by which suppressors of the NLRP3 inflammasome pathway alter or restore
the function of mitochondria.

YCI Laboratory for

Lab activities

Trans-omics
Young Chief Investigator: Katsuyuki Yugi

Figure: Metabolic priming in the adipocyte
Integration of time-series phosphoproteome and13
C-labeled metabolome data revealed that insulin-dependent phosphorylation of widespread metabolic
enzymes occurs significantly early before the start ofglucose transport, which potentially could direct glucose flux towards specific metabolic pathways.
(Krycer, Yugi, et al., Cell Rep 2017)

Recent Major Publications†Krycer JR, †Yugi K(† equal contribution), Hirayama
A, Fazakerley DJ, Quek LE, Scalzo R, Ohno S, Hodson
MP, Ikeda S, Soji F, Suzuki K, Domanova W, Parker BK,
Nelson ME, Humphrey SJ, Turner N, Hoehn KL, Cooney
GJ, Soga T, Kuroda S, James DE. Dynamic metabolomics
reveals that insulin primes the adipocyte for glucose
metabolism. Cell Rep 21, 3536–3547 (2017)
Yugi K, Kuroda S. Metabolism-centric trans-omics. Cell
Syst 4, 19–20 (2017)
Yugi K, Kubota H, Hatano A, Kuroda, S. Trans-omics:
how to reconstruct biochemical networks across multiple ‘omic’ layers. Trends Biotechnol 34, 276–290(2016) (Cover Article)

Invited Presentations
Yugi K. “Trans-omic analysis reveals fed and fasting
insulin signal across phosphoproteome, transcriptome,
and metabolome” The 1st International Symposium forTrans-Omics (Tokyo, Japan) November. 2017
Yugi K. “A trans-omic reconstruction of insulin-dependent regulatory networks for metabolism” The 4th International Symposium of Gunma University Initiative forAdvanced Research (Maebashi, Japan) November, 2017
Yugi K. “Reconstruction of insulin-dependent metabolic
regulatory networks from phosphoproteome andmetabolome data” RIKEN IMS-Japan Society for Immunology International Symposium on Immunology 2017
(Tokyo, Japan) June, 2017
Yugi K. “A trans-omic analysis of insulin-dependent
metabolic regulation based on proteomics, metabolomics, and public databases” The 146th Kanto-area
Colloquium, The Mass Spectrometry Society of Japan(Tokyo, Japan) January, 2017T

rans-omics is a discipline that aims to reconstruct a global and multi-layered
molecular network, not as a group of indirect statistical correlations but aschains of direct mechanistic interactions (Yugi et al., Trends Biotechnol 2016; Yugi
and Kuroda, Cell Syst 2017). The network reconstruction is performed based oncomprehensive measurement data of multiple omic layers not taken from heterogeneous sources but measured under an identical condition.
We applied methodologies of trans-omics to reveal how insulin acts on adipocyte metabolism in a global manner by integrating phosphoproteome and 13C-labeled metabolome data (Krycer, Yugi, et al., Cell Rep 2017). It has been thoughtthat the major role of insulin is to provide anabolic substrates by activating GLUT4transporter-dependent glucose uptake. However, recent phosphoproteomic analysis showed us that insulin provides widespread phosphorylation changes in themetabolic enzymes of the adipocyte (Humphrey et al., Cell Metab 2013), and it isunclear how these changes influence the dynamics of glucose metabolism uponinsulin exposure. To examine the implications of phosphorylation of these metabolic enzymes, we performed dynamic tracer metabolomics in cultured adipocytes treated with insulin.
By combining phosphoproteome and 13C-labeled metabolome data, we foundthat insulin-dependent phosphorylation of metabolic enzymes occurs significantly
early before glucose transport begins. This allows activation of key anabolic pathways that guide glucose influx into particular pathways where substrate metabolites are needed. We propose that this is a demand-driven system complementing
a supply-driven mechanism by substrate accumulation. We named this phenomenon ‘metabolic priming’, a phenomenon in which insulin signaling kick starts
catabolic reactions that generate a thermodynamic driving force that eventuallypulls glucose into specific anabolic pathways.

57

YCI Laboratory for

Lab activities

ImmunologicalTranscriptomics
Young Chief Investigator: Hideyuki Yoshida

Figure: Open Chromatin Regions (OCRs) associating with altered gene expressions along T celldifferentiation pathways
Left: k-means clustering of differentially expressed
genes during T cell differentiation. Normalized gene expression is shown. Center: ATAC-seq signals in plausible
enhancers for each gene. Right: Enriched TF motifs incorresponding OCRs in each cluster.

Recent Major Publications
Bansal K, Yoshida H, Benoist C and Mathis D. The
transcriptional regulator Aire binds to and activates
super-enhancers. Nat Immunol 18, 263–73 (2017)
Moodley D, Yoshida H, Mostafavi S, Asinovski N, Ortiz-Lopez A, Symanowicz P, Telliez JB, Hegen M, Clark
JD, Mathis D and Benoist C. Network pharmacology
of JAK inhibitors. Proc Natl Acad Sci U S A 113,
9852–9857 (2016)
Mostafavi S, Yoshida H (Co-first), Moodley D, LeBoite
H, Rothamel K, Raj T, Ye CJ, Chevrier N, Zhang S, Feng
T, Lee M, Casanova JL, Clark JD, Hegen M, Telliez JB,
Hacohen N, DeJager PL, Regev A, Mathis D. Benoist C,
Immunological Genome Project Consortium. Parsing
the Interferon transcriptional network and its diseaseassociations. Cell 164, 564–578 (2016)

Invited Presentations
Yoshida H. “ATACseq, cool results, what next?” 2017
Workshop, Immunological Genome Project (Boston,USA) December, 2017
Yoshida H. “IFN response: analysis of transcriptional
network by an unbiased approach” The 11th International Symposium of The Institute Network Frontiers in
Biomedical Sciences (Tokushima, Japan) January, 2017

58

I

have been engaging two projects employing transcriptomics, a powerful and effective
tool to investigate biological phenomenon.

1) Identifying novel factors involved in thymic negative selection
While some factors including Aire and Fezf2 are known to induce tissue specific antigens(TSAs) in thymic epithelial cells (TECs) and are essential for negative selection, thousands of TSA genes are induced in a manner independent of these factors. By utilizing
publicly available databases, I found RNA-binding proteins that lead to mRNA degradation are specifically down-regulated in TECs and can be involved in the regulation of
TSA expression. We are assessing the possible functions of these candidates using celllines and preparing mouse models to investigate their significance in vivo. As the conceptof TSA regulation by RNA stability is novel, this project can greatly increase our understanding of immune tolerance.
2) Comprehensive analysis of the cis-regulatory elements in immunocytes
The establishment and maintenance the unique transcriptional identity of a differentiated cell is largely driven by the combined activity of transcription factors (TFs) andchromatin remodelers at promoters and/or distal enhancer elements. While the existence of enhancers whose activity is restricted to a given cell-type has been recognized in
specific context, i.e. specific genes or specific cell populations, their broader integrationin related immune cell-types and their cascades along their respective differentiation
pathways were not clear. In collaboration with Immunological Genome Project, I have
performed paired epigenomic mapping by ATAC-seq and gene expression measurements
by RNA-seq to profile 90 immune cell populations and define a cis-regulatory atlas ofthe mouse immune system. This atlas is both comprehensive, likely defining the entiretyof the cis-regulatory elements in immunocytes, and highly granular, due to scanning ofclosely related cell-types in differentiation cascades. We are preparing the manuscript for
submission.

YCI Laboratory for

Lab activities

Next-Generation
Proteomics
Young Chief Investigator: Yibo Wu

Figure: A multilayered omics study of liver mitochondrial activity(A) General model of the multilayered omics approach.
Arrows indicate causality between metabolic layers.
(B) Phenotyping pipeline for all individuals. (C) Body
weight in two BXD strains for both diets over thefull phenotyping experiment. (D) Error in SWATH-MS
measurements due to technical (median CV = 6.5%),
biological (CV = 17.0%), across strain within diet (CV= 31.4% in CD, 29.6% in HFD) and across all measurements (CV = 30.8%). (E) Histogram of 2600 transcript-protein pair Spearman correlations in CD. (F) Diet-consistent cis-pQTLs were observed for COX7A2L. No
significant cis-eQTLs were observed. (G) Super Complex(SC) bands 4 and 5 mapped significantly as cQTLs to alocus on chromosome 17. This region includes Cox7a2l
and overlaps with its cis-pQTLs.

Recent Major Publications
Wu Y, Williams EG, Aebersold R. Application of SWATH
Proteomics to Mouse Biology. Curr Protoc Mouse Biol7, 130–143 (2017)
Williams EG, Wu Y, Jha P, Dubuis S, Blattmann P, Argmann CA, Houten SM, Amariuta T, Wolski W, Zamboni
N, Aebersold R, Auwerx J. Systems proteomics of liver
mitochondria function. Science 52, aad0189 (2016)(*Co-first author)

Invited Presentations
Wu Y. “Systems proteomics of liver mitochondrial activity” The 1st International Symposium for Trans-Omics(Tokyo, Japan) November, 2017

R

ecent improvements in mass spectrometry-based proteomics, including Selected Reaction Monitoring (SRM) and Sequential Window Acquisition of
all Theoretical Mass Spectra (SWATH-MS), have been driving the capacity fordefining relationships between genetics, molecular pathways and overall phenotypes (Wu and Williams, et al. Cell 2014, Williams and Wu, et al. Science 2016).
SWATH-MS has enabled accurate quantification of thousands of proteins across alarge number of cohorts (Wu and Williams, et al. Curr Protoc Mouse.Biol 2017).
Here, we have demonstrated the quantification capacity of SWATH-MS byexamining mitochondrial function and liver metabolism through the genome,transcriptome, proteome and metabolome in 386 individuals of the BXD mouse
genetic reference population. Phenotypic traits, including body weight, vary significantly among these mice due to genetic, environmental and/or gene-by-environment (GxE) factors. SWATH-MS has allowed quantification of 2622 uniqueproteins with excellent reproducibility. Among these 2622 proteins, we have quantified 2600 transcript-protein pairs and observed only a nominal correlation between mRNA and protein levels, indicating the necessity of proteomic measurement of metabolic pathways to identify unknown molecular mechanisms.
We have identified and validated several links between genetic variants toward
transcripts, proteins, metabolites and phenotypes. Among these, sequence variants in Cox7a2l alter its protein levels, but not transcript levels. The differences in
COX7A2L protein in turn lead to downstream differences in mitochondrial supercomplex formation. These findings indicate that data generated by next-generation proteomics and metabolomics have reached a scope to complement genomics, transcriptomics and phenomics for transomic analyses of complex traits. This
integrated omics strategy has provided us a new tool that brings personalized
medicine closer.

59

Central Facilities

Central Facilities
C

entral Facilities in IMS provide all researchers in the Centerwith access to the most advanced equipment and technologies. Central Facilities consist of four sections; the FACS Laboratory
managed by Dr. Takashi Saito, the Confocal Laboratory managed

by Dr. Takaharu Okada, the Genomics Laboratory managed by Dr.
Osamu Ohara, and the Animal Facility managed by Dr. Haruhiko
Koseki.

FACS Laboratory

The FACS Laboratory provides a range of support for flow cytometry
and cell sorting techniques that are essential for nearly all experiments in immunology and disease studies. The FACS Lab has upgraded
all FACS Arias including an Aria Fusion for multi-color analyses. In addition to FACS machines, the lab upgraded CyTOF2, a mass-spectrometry-based cytometer that has the potential to analyze more than 40 markers simultaneously with metal-labeled antibodies.
In 2017, 1496 analytical and 3996 sorting experiments were performed in the lab. Two staff members offer various services for users of
the FACS machines (cell analyzers and cell sorters): (1) Technical support
and training: In 2017, the facility offered 8 technical courses (4 for cellsorting and 4 for cell analysis). Courses were held at 3 different levels,
Calibur basic, Canto II and Aria basic. A total of 31 researchers took thecourses in 2017. (2) Cell sorting operation service: The FACS Lab provides
a cell sorting operation service, in which researchers can ask an experienced operator to conduct the sorting experiment. In 2017, the lab provided 266 such services. Advanced cell sorting techniques, such as single
cell sorting, have also been performed. (3) Management/ maintenanceof FACS machines: FACS machines are available for registered users 24hours a day and reservations are accepted up to one month in advancethrough an internal website. In addition to the in-house FACS Lab staff,
engineers from Becton Dickinson visit once a week to provide maintenance and technical support.
Table: Instruments and the usage in the FACS Lab
Machine types

Machines# ofmachines

# of
users

# of
training
sessions

FACS cell analyzer

Calibur
Canto II

4
2

58
1438

2
12

FACS cell sorter

Aria II
Aria III
Aria Fusion

3
2
1

1971
1985
40

17

CyTOF2

1

18

2

Mass-cytometer

Confocal LaboratoryThe Confocal Laboratory provides equipment for cell and tissue imaging, and coordinates technical support. There areeight fluorescence microscopes available to researchers at IMS.
1. Inverted Leica SP5 system with visible lasers for single-photon
excitation including a 405 violet laser.
2. Inverted Leica SP2 system with visible lasers for single-photon excitation including a 405 violet laser. This microscope isequipped with a chamber system that controls CO2 concentration, temperature and humidity for live cell imaging.
3. Inverted Leica SP8 system with two femtosecond Ti:Sa lasers for
multiphoton excitation. This system is equipped with two typesof scanners (resonant and galvano) and hybrid detectors withhigh sensitivity and low background noise. One of the two Ti:Sa lasers is connected to an optical parametric oscillator (OPO)
that enables two-photon imaging by long wavelength excitation.
4. Upright Leica SP5 system with two femtosecond Ti:Sa lasers for
multiphoton excitation. This system utilizes resonant scanners
that enable high-speed acquisition of large z-stacks for live tissue
imaging.
5. Inverted Olympus FV1200 system with visible lasers for sin-60

Photo: Leica SP8 multiphoton microscope (3), Nikon N-SIM/N-STORM
super-resolution microscope (6), GE Healthcare DeltaVision Elite system (7), and Keyence BZ-X700 microscope (8).

gle-photon excitation.
6. Inverted Nikon N-SIM/N-STORM super-resolution microscopefor dual color imaging.
7. GE Healthcare DeltaVision Elite system.
8. Keyence BZ-X700 all-in-one fluorescence microscope.

Central Facilities

Genomics LaboratoryWe are a technical support service lab that provides genomeand proteome-wide analysis for research groups in IMS. We
offer a variety of services to suit the needs of different labs. These
include DNA sequencing, proteomics analysis, multiplex suspension array, cDNA/Genomic clone distribution, and Primer/labeledprobe distribution for qRT-PCR analysis of immune cells (Table).
Supplying advanced technologies on demand, we provide comprehensive interrogation of nucleic-acid based information in a cellat single-base resolution with the Illumina HiSeq1500 and as wellas proteomic approaches using the AB SCIEX TripleTOF 5600.
Using this unbiased sequencing approach, we have interrogated:transcription units, mapping/genome annotation, alternative splicesites, and transcription factor binding sites. Our mass spectrometry system will make it possible to use quantitative proteomic approaches in various immunological studies. These technologies will
help to reveal additional hidden features of the dynamic genomic
and proteomic landscape that are regulated by both genetic and epigenetic pathways in all organisms.

Table: Central services provided by the Genomics Lab in 2017
Next-generation DNA sequencing
RNA-sequencing
Chip-sequencing
Others (Exome etc)
Proteomics
Mass Spectrometry Analysis
Multiplex suspension array
Sanger DNA sequencing# of samples# of teams

1,756
432
49

24
5
2

# of samples# of teams

1
1,219

1
8

# of samples# of teams

36cm capillary
50cm capillary

6,856
3,336

13
15

cDNA clone delivery# of samples# of teams

43
Primer/labeled probe delivery# of samples
36

5# of teams
2

Animal FacilityW

e continue to maintain over 50,000 mice in the SPF area, and1,500 mice in an isolated area. The SPF area also contains
550 germ-free or gnotobiotic mice in Vinyl Isolator rooms, and in
Vinyl Isolator bio-bubble rooms. The former is used by several IMS
research groups, in particular the mucosal immunologists, and thelatter is for “humanized mice”. We introduce mouse lines into the
SPF area via a combination of in vitro fertilization (IVF) and embryotransfer methods, and have also generated cryostocks of genetic resources (frozen embryos and sperm) for 782 lines. We also maintainrelatively large colonies of several commonly used strains such as
Rag1 KO and Cre deleters, and provide them to users on demand.
We have also provided technical assistance to generate knockout andtransgenic mice (80 lines). In addition, we made KO and KI mice
(73 lines) using the CRISPR/Cas system and have created 17 linesof germ-free mice. We have provided space for new experiments,
e.g., behavioral testing for germ-free mice, in the animal facility.

We generated mice to improve the efficacy of transplantationof human hematopoietic stem cells into NOD.Cg-Prkdc scid Il2rgπ/
SzJ (NSG) mice by better “humanizing” the host strain. For thispurpose, we have introduced large genomic fragments containing
human genes encoding MHC, cytokines, adhesion molecules, virus
receptors and others into the NSG mice. We maintain transgenic mice and knock-in mice with confirmed expression of humangenes on a C57BL/6 background and have begun backcrossing thesemice onto the NSG background using the speed-congenic method.

Photo: Behavioral testing equipment for germ-free mice
Vinyl Isolator in a soundproof room in the SPF area

61

RIKEN International Program Associate
(IPA)

I

MS accepted three 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 toa maximum of three years.

Other programs

The IPA students who studied at IMS in 2017 were
Krutula Nair (Graduate School of Frontier Biosciences, Osaka University) from India studied in the Laboratory for Transcriptional
Regulation.
Su Yean Ong (University of Science, Malaysia) in the Laboratory
for Integrated Bioinformatics
Yan Yan Hor (University of Science, Malaysia) in the Laboratory for
Intestinal Ecosystem.

RIKEN Foreign Postdoctoral Researcher (FPR) ProgramT

he RIKEN Foreign Postdoctoral Researcher (FPR) program offers aspiring young foreign researchers with creative ideas andwho show promise of becoming internationally active in the future
the opportunity to pursue innovative research at RIKEN under the
direction of a RIKEN laboratory head. The FPR Program is one of
RIKEN’s initiatives to open up its facilities and resources to the forefront of global science and technology.

In 2017, two young researchers studied at IMS as RIKEN FPRs.
Michelle Kendle Maslowski studied in the Laboratory for Intestinal Ecosystem.
Ealey Nequan Kafi studied in the Laboratory for Innate Immune
Systems.

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 thedevelopment of these young scientists while also energizing RIKEN
with their innovative thinking.
This year, 26 JRA students studied in IMS.
Junichiro Takano (Laboratory for Developmental Genetics)
Yoshihiro Ito (Laboratory for Skin Homeostasis)
Eiichiro Watanabe (Laboratory for Gut Homeostasis)
Satoko Yokoyama (Laboratory for Intestinal Ecosystem)
Yuki Furuichi (Laboratory for Skin Homeostasis)
Tadashi Takeuchi (Laboratory for Intestinal Ecosystem)
Rintaro Ono (Laboratory for Human Disease Models)
Yurina Miyajima (Laboratory for Innate Immune Systems)

Takato Kobayashi (Laboratory for Innate Immune Systems)
Takaaki Kawaguchi (Laboratory for Gut Homeostasis)
Keiko Usui (Laboratory for Skin Homeostasis)
Natsuko Otaki (Laboratory for Innate Immune Systems)
Mamoru Ogawa (Laboratory for Metabolomics)
Hiroki Sugishita (Laboratory for Developmental Genetics)
Hiroe Tetsu (Laboratory for Innate Immune Systems)
Manabu Nagayama (Laboratory for Gut Homeostasis)
Daisuke Hisamatsu (Laboratory for Developmental Genetics)
Ari Morimoto (Laboratory for Skin Homeostasis)
Tomoko Yoshihama (Laboratory for Pharmacogenomics)
Yuki Ariyasu (Laboratory for Metabolomics)
Shohei Egami (Laboratory for Skin Homeostasis)
Shintaro Ono (Laboratory for Integrative Genomics)
Ryota Sato (Laboratory for Lymphocyte Differentiation)
Kyosuke Shishikura (Laboratory for Metabolomics)
Iori Motoo (Laboratory for Gut Homeostasis)
Tsuyoshi Yamane (Laboratory for Metabolomics)

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 research in line withRIKEN objectives and research fields. The positions are competitive, but if selected, researchers receive salaries and research budgets (1 million yen) from RIKEN and they are able to conduct theirresearch at one of its laboratories.
This year, seven postdocs conducted their research at IMS
through the SPDR program.

62

Yosuke Isobe (Laboratory for Metabolomics)
Yasutaka Motomura (Laboratory for Innate Immune Systems)
Eiji Miyauchi (Laboratory for Intestinal Ecosystem)
Alexis Vogelzang (Laboratory for Mucosal Immunity)
Keiichiro Shiraga (Laboratory for Skin Homeostasis)
Xiaoxi Liu (Laboratory for Genotyping Development)

Part 3
Research
Projects

iPS projectI

nduced pluripotent stem (iPS) cells possess tremendous therapeutic potential in many areas, including regenerative medicine and immune therapy. We have begun an activity to apply iPS
technology to both mouse and human immunology research andto develop therapeutics. On a collaborative basis with individual
RCAI-IMS research laboratories, the core facility for iPS researchis engaged in developing efficient protocols to reprogram various
types of lymphocytes into iPS cells as well as to induce differentiation of iPS cells into a variety of lymphoid lineage cells. This activity
is partly supported by the Research Center Network for Realizationof Regenerative Medicine from the Japan Agency for Medical Research and Development (AMED) and CREST, Japan Science andTechnology Agency.
This year, the facility established bioluminescent human iPSVα24+iNKT cells for in vivo live-cell imaging. We were able to introduce GFPLuc into the human AAVS1 (adeno-associated virus
integration site 1) locus in NKT-iPSC using CRISPR/Cas9 andthen differentiate the cells into iPS-Vα24+iNKT cells. These iPSVα24+iNKT cells showed GFP expression and luciferase activity invitro. Furthermore, the iPS-Vα24+iNKT cells could be monitored

Project

by luciferase activity for at least 19 days after inoculation into immunodeficient mice.
The facility has also managed an IMS Cell Manufacturing Unit
(CMU) to produce iPS-Vα24+iNKT cells under GMP (Good Manufacturing Practice)/GCTP (Good Gene, Cellular, and Tissue-based
Products Manufacturing Practice) guidelines and has started preclinical studies on the safety of these iPS-Vα24+iNKT cells. The facility has also started PMDA (Pharmaceuticals and Medical Devices
Agency) consultation for eventual clinical trials of iPS-Vα24+iNKT
cell mediated-tumor immunotherapy.

Figure: Live-cell imaging of iPS-Vα24+iNKT cells in vitro and in vivo.
(A) Representative phase contrast and fluorescence microscope images of human
iPS-Vα24+iNKT cells containing introduced GFPLuc. (B) A representative flow cytometry plot of GFPLuc-expressing human iPS-Vα24+iNKT cells. (C) Luciferase activity of
GFPLuc-expressing human iPS-Vα24+iNKT cells (GFPLuc). Wild type (WT) human iPSVα24+iNKT cells were used as a control. (D) GFPLuc iPS-Vα24+iNKT cells were intraperitoneal injected into human cytokine knock-in NSG mice (kindly provided by the animal
facility) and then monitored at the indicated time points for bioluminescence using the
IVIS imaging system.

Medical Sciences Innovation Hub Program (MIH)P

tersonalized medicine is a new paradigm that represents a
shift from a statistical abstraction of the patients toward theview that each patient is unique. This is a new scientific challenge
as well as a new social challenge. Although linear causations andcorrelations have been used in the explanation of biological phenomena, biological systems form complex network whose collective behavior cannot be reduced to simple correlations. In addition,
explanations usually eliminate information on differences between
each individual patient. To overcome this problem, we are developing a new biomedical science based on pure description of diseases by using multiomics data. To describe personal differences, it isnecessary to consider the life course trajectory. We have applied aMarkov chain model, which is a well-known tool to model temporal properties of many phenomena, to describe life-course changes

Figure: Description of life course trajectory by Markov chain and reverse
translation
The state allocation is done by the reduction of dimensionality and data granularity
using machine learning and energy land scale analysis The relation between thepresent and future state is described by Markov constraints. The causality model isdeveloped by animal studies. Knowledge obtained from human data is applied indeveloping the animal models.

64

in individual conditions. The data are being gathered from patientswith immune disorders, cancer and developmental disorders. Human studies are then reversed translated in animal studies. We arecollaborating with IMS in these studies.

Project

Integrated omics approach toelucidate the impact of the gut microbiomeon the pathogenesis of type 2 diabetesR

ecent findings in gut microbiome studies indicate that the lossof microbial diversity, a condition termed dysbiosis, is not theconsequence but rather the cause of various diseases including type2 diabetes (T2D). As an IMS Center project, we are applying a comprehensive integrated omics approach to elucidate the impact of thegut microbiome on the pathogenesis of T2D. This is a collaborative
effort with Professors Takashi Kadowaki and Tsutomu Yamazaki from the University of Tokyo Hospital. From RIKEN IMS, theLaboratories for Metabolic Homeostasis, Intestinal Ecosystem, Microbiome Sciences, Metabolomics, Integrative Genomics, and Integrated Bioinformatics are taking the lead on this project. This year,
we have started a collaboration with the National Institute of Healthand Nutrition to collect data on the nutritional intake and activityof the many participants in this study. Fecal metagenomic, metatranscriptomic and metabolomic data, as well as plasma and urine
metabolomic data are obtained from three groups of volunteers
undergoing a complete medical checkup at the University of Tokyo

Hospital (n=100 each): 1) no abnormal examination outcome, 2)
obesity (BMI 25), and 3) glucose intolerance (fasting blood glucose ≥ 110 mg/dl and HbA1c 6.0%). In addition, exomes and
SNPs of T2D susceptibility genes are being analyzed. The goal of the
project is to identify T2D risk factors, such as certain bacteria and/or their metabolites, by analyzing the metadata from the comprehensive multiple omics analyses, combined with clinical and genetic datasets. We have already finished the recruitment of one hundred volunteers for each group and data acquisition is underway.

Figure: Analytical scheme to identify microbial biomarkers for type 2
diabetes
Metadata sets shown in the figure are collected from the volunteers (three groups:
healthy, obese without metabolic abnormality, and those with impaired glucose tolerance; 100 each) and comprehensively analyzed to identify differential microbial and/or
microbial metabolic factors among the groups, which should be candidate biomarkers
for the pathogenesis of type 2 diabetes.

NKT cell projects

N

KT cells have the capacity to enhance immune responses.
The medical innovation groups in IMS have launched projects aimed at application of NKT cell-mediated therapy to cancer
as translational research. Here we introduce four NKT cell-related
projects aimed at cancer treatment.
In the first project, we have been collaborating with 15 National Hospital Organization (NHO) hospitals on clinical therapeuticstudies using the NKT glycolipid, α-GalCer pulsed autologous DCs(DC/Gal) in a randomized phase IIa trial in early stage lung cancer.
At present, we have been performing immunological analyses on
53 DC/Gal-treated and control cancer patients. As a second project, IMS was selected to be part of the research center network forrealization of regenerative medicine. So far, we have been performing a preclinical study of human iPS-NKT cells for clinical application. Third, as a new type of cancer vaccine, we established artificial adjuvant vector cells (aAVC). In this fiscal year, we launched
an investigator-initiated clinical trial of aAVC-WT1 for relapsed or

refractory acute myeloid leukemia patients by collaborating withThe University of Tokyo, The Institute of Medical Science. This is
the First in Man trial. Fourth, we developed several new NKT cell
ligand candidates and have been testing their efficacy in preclinicalstudies for next generation NKT cell ligand cancer immunotherapy.
Three of these projects (iPS-NKT therapy, and aAVC therapy and
new NKT ligand therapy) have been supported by the Japan Agency for Medical Research and Development (AMED) and are also
supported by the RIKEN Drug Discovery and Medical Technology
Platforms (DMP).

Figure: NKT cell-mediated anti-cancer projects in IMS as translational
research
We have four NKT cell-mediated anti-cancer projects underway. Three are cancer therapy translational research projects and the fourth is the analysis of the patients in the
Phase II clinical study. All have progressed in this fiscal year.

65Project

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

MS collaborates with DMP to develop innovative new pharmaceuticals and medical technologies by facilitating the transfer ofbasic research within the institute. DMP was founded in RIKEN in2010 in order to support all phases of development of new therapeutics, from the discovery of promising targets to the identification of potential lead compounds, such as small molecules andantibodies, and the acquisition of intellectual property rights to
drugs and technologies that can then be brought to the development phase.
To achieve effective progress in this area, 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
contributes to this effort in several ways, including by setting up afacility for the development of antibody drugs, the Drug Discovery

Antibody Platform Unit. In addition, IMS now has eight collaborative programs with DMP: Artificial adjuvant vector cells (Shin-ichiro Fujii), Cancer therapy with iPS-derived NKT cells (Haruhiko
Koseki), Cancer therapy with NKT cells (Masaru Taniguchi), Drugs
for allergic diseases (Yasushi Ishii), Leukemia treatment mAb targeting leukemic stem cells (Fumihiko Ishikawa), mAb therapy for
lymphomas (Yasushi Ishii), neutralizing mAb for HBV infection(Daiki Miki) and therapeutic mAb for IBD (Takashi Saito). The preclinical study of the Artificial adjuvant vector cell project for cancer
therapy has been completed and, therefore, Fujii et al. are preparing
for an investigator initiated-clinical trial.

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

PGRN-RIKEN IMS ProjectT

he US NIH Pharmacogenomics Research Network (PGRN)
is a consortium of research groups funded as individual cooperative agreements with the NIH. PGRN investigators are top
researchers from US academic institutions and conduct pharmacogenomics (PGx) studies to identify genes associated with drug
responses. We run the PGRN-RIKEN IMS Project under a PGRNHub, a resource established to enhance scientific exchange between
the PGRN and the scientific community at large, for identificationof genetic factors associated with drug efficacy and risk of severe
adverse drug reactions.
In this international collaboration, the PGRN has been successfully assembling a very large collection of DNA samples fromwell-phenotyped patients receiving specific drugs and drug combinations in clinical trials conducted in the US. RIKEN IMS focuses

Figure: The Pharmacogenomics Research Network (PGRN)-RIKEN IMS strategic alliance
Please visit http://www.pgrn.org/pgrn-riken.html

66

on high-throughput genome-wide SNP scans and targeted sequencing of selected genes or regions using next generation sequencing(NGS) and also provides technological and methodological expertise to identify genomic biomarkers. Together, the PGRN-RIKENIMS Project capitalizes on these strengths to advance discoveries in
PGx research. To date, we have initiated 48 collaborative projects
and have 60 publications through the collaboration, which willlead to development of better and safer medications and realize the
dream of global precision medicine. This year, we are going to expand the collaborative activity in the global PGx network involving US, Europe and Japan for implementation of PGx in clinicalpractice.

Collaboration with Asian institutes
and SEAPharmI

t has been noticed that severe cutaneous adverse drug reactions(ADRs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), occur at a much higher frequency in Asian populations, and several genomic biomarkers have been reported to be associated with the risk of cutaneous ADRs. In the case of the anti-epileptic drug
carbamazepine, the US FDA now recommends HLA-B*15:02 screening
prior to the administration of this drug for Han Chinese and other Asian
populations with a high prevalence of HLA-B*15:02, due to the risk of
SJS-TEN associated with this allele. To tackle this problem regionally, in2012 we established the South East Asian Pharmacogenomics Research
Network (SEAPharm) together with five other Asian countries (Korea,
Indonesia, Malaysia, Taiwan, and Thailand). Membership has been steadily increasing, with Singapore joining in 2014, and Vietnam in 2016. This
year, SEAPharm has three newcomers, Nepal, Laos and the Philippines,on the team.
The aim of the collaboration is to identify genomic biomarkers associated with ADRs, such as skin rash induced by anti-epileptics and antibi-

Project

otics, and hepatic injury induced by anti-tuberculosis agents. In addition,
we have started a new project involving next generation sequencing ofgenomic DNA from 1,000 people from 10 countries to clarify the genetic
diversity of drug-metabolizing enzymes and drug transporters in Southeast Asian populations. The discoveries from our collaborative efforts willlead to the establishment of “stratified medicine” based on pharmacogenomic-guided drug therapies.

Figure: Members of the South East Asian Pharmacogenomics Research
Network (SEAPharm)
Please visit
http://www.pharmagtc.org/seapharm/index.php/seapharm/about-seapharmInternational Cancer Genome Consortium (ICGC)
and PCAWG
Laboratory for Genome Sequencing Analysis

Laboratory for Medical Science Mathematics

T

he primary goals of the ICGC is to generate comprehensive catalogues of genomic abnormalities in ~25,000 cases of different cancer types and to make the data available to the entire research community
with minimal restrictions. At the end of 2017, 78 cancer genome projects
across 16 countries and the EU were ongoing, and the ICGC released
genomic data from more than 17,000 donors as Release 26 (November,2017). For this release, the RIKEN group performed whole genome sequencing (WGS) and analysis on 300 liver cancer samples. ICGC launcheda “pan-cancer” whole genome project (PCAWG) in 2014, in which WGS
data together with RNA-Seq of 2834 donors were analyzed in uniform
pipelines within the same computational environment. RIKEN and
IMUT are contributing to this project as a member of a technical working group arranging ten cloud data centers and PI/researchers in working
groups for driver gene, mutational signature, germline, immuno-genomics, and mitochondrial genomics. We also provided sample data from 270
liver cancers to the PCAWG (10% of the total), making us the most pro-Laboratory for Digestive Diseases

ductive group within the ICGC. In 2017, as a PCAWG-15 working group,
we analyzed the immuno-genomic landscape from PCAWG data, including mutations in the HLA/antigen presentation complex and immune
suppressor genes, neo-antigen profiles from somatic SNVs and indels,
GSEA (gene-set enrichment analysis), and immune micro-environmental
signatures from RNA-seq data. We observed that tumors acquired many
types of immune escape mechanisms through genomic alterations of
selective copy number gain of immune genes and failure of the antigen
presentation system and immune checkpoint molecules in a tumor-specific manner.

Figure: Immuno-genomic landscape of pan-cancer in PCAWG-15 working
group
PCAWG-15 and RIKEN analyzed the immuno-genomic landscape of 2800 WGS
pan-cancer data. Neoantigens and neoantigen presentation mechanisms are examined by using information on HLA genotype and somatic mutations (SNVs, indels, andSVs) from the WGS. Immune microenvironment or signatures are analyzed by combined RNA expression profiles of immuno-genes and GSEA. We are exploring immune
escape mechanisms and cancer genome evolution and history by analysis of these
Immuno-genomic landscapes.

67

ProjectHumanized mouseO

ne of the obstacles to treating malignant diseases is their biological heterogeneity and genetic complexity. Recent reports
have identified pre-malignant stem cells that may foster emergenceof malignant stem cells, which can progress to overt disease. To
understand the pathophysiology of pre-malignant and malignant
cells in human hematopoiesis, we took an approach to link in vivo
disease biology with genomic profiling by combining a humanizedmouse model with single-cell sequencing using human acute myeloid leukemia (AML) samples This integrative approach enableddemarcation of pre-malignant versus malignant cells and the identification of permissive versus disease-initiating mutations among
multiple mutations within patient specimens. Inhibition of pathways activated by disease-initiating mutations resulted in efficient

eradication of human leukemia cells in AML-engrafted humanized
mice. This integrative approach using humanized mice may help
our understanding of malignant hematopoiesis in humans and development of new therapeutic strategies for human leukemia.

Figure: Heterogenous hematopoietic cells are present in blood or bonemarrow of AML patients.
By injecting multiple blood/BM subsets into immune-deficient NOD/SCID/Il2rgKO
mice, we identified hematopoietic stem cells and leukemia-initiating stem cells ineach patient. With single cell sequencing, we found somatic mutations in functionally-defined normal and leukemic stem cells. The genomic profiling of single humanstem cells enabled us to demarcate leukemia-initiating and permissive mutations.

Award winners 2017
Name of the awardee

Name of the award

Date of theannouncement

Kazuhiko Yamamoto,Team Leader, Laboratory for Autoimmune Diseases

Medal with Purple Ribbon

Apr, 2017

Fumihiko Ishikawa,Group Director, Laboratory for Human Disease Models

German Innovation Award “Gottfried Wagener Prize 2017”

Jun, 2017

Kazuyo Moro,Team Leader, Laboratory for Innate immune systems

The 13th JSPS PRIZE

Jan, 2017

Kazuyo Moro,Team Leader, Laboratory for Innate immune systems

The13th Japan Academy Medal

Jan, 2017

Yoichiro Kamatani,
Team Leader, Laboratory for Statistical Analysis

The Young Scientists’ Prize (The Commendation for Science and Technology
by the Minister of Education, Culture, Sports, Science and Technology)

May, 2017

Mariko Okada,Team Leader, Laboratory for Integrated Cellular Systems

Nagase Foundation Award

Apr, 2017

Momoko Horikoshi,
Team Leader, Laboratory for Endocrinology, Metabolism and Renal diseases

The 4th Yamato Science Award

Mar, 2017

Tetsuya Kubota,
Senior Researcher, Laboratory for Metabolic Homeostasis

The 38th Japan Society for the Study of Obesity (JASSO) Academic Award

Oct, 2017

Yasutaka Motomura,Special Postdoctoral Researcher, Laboratory for Innate immune systems

SMI/MI Journal Poster Award

Jul, 2017

Naoko Satoh,Research Scientist, Laboratory for Intestinal Ecosystem

The 12th JSI Young Investigator Award ( The Japanese Society for
Immunology)

Nov, 2017

Chikashi Terao,
Senior Scientist, Laboratory for Statistical Analysis

Incentive Award (The 62nd Annual Meeting of the Japan Society of Human
Genetics)

Nov, 2017

Nyambayar Dashtsoodol,
Research Scientist, Laboratory for Immune Regulation

Best Paper Award (Mongolian National University of Medical Sciences)Feb, 2017

Nyambayar Dashtsoodol,
Research Scientist, Laboratory for Immune Regulation

Best Presentation Award (The 45th Annual Meeting of the Japanese Society
for Immunology)

Feb, 2017

Hiroe Tetsu,
Junior Research Associate, Laboratory for Innate immune systems

Ursula and Fritz Melchers Travel Award (The Japanese Society for
Immunology)

Dec, 2017

Takaharu Sasaki,
Postdoctoral Researcher, Laboratory for Intestinal Ecosystem

Young Investigator Travel Award (The 18th International Congress of
Mucosal Immunology)

Apr, 2017

Takaharu Sasaki,
Postdoctoral Researcher, Laboratory for Intestinal Ecosystem

Tadamitsu Kishimoto International Travel Award (The Japanese Society for
Immunology)

Apr, 2017

Hirokuni Miyamoto,
Senior Visiting Scientist, Laboratory for Intestinal Ecosystem

Technical Award of the Society for Biotechnology, Japan

Sep, 201768Part 4
Events

Events

RIKEN
IMS
Summer
Program (RISP)
2017

The IMS-JSIInternational
Symposium on
Immunology
2017

I

T

MS was delighted to once again successfully organize the11th RISP (RIKEN IMS Summer Program). RISP began as
the RCAI International Summer Program (RISP) in 2006 andhas been continued by IMS, beginning 4 years ago. The aim of
this activity is to provide networking opportunities on a broadinternational scale for young scientists, as well as to encourage
future collaboration and postdoctoral training experiences in Japan. Due to the broadened research activities of the new IMS,
the RISP 2017 program included topics in genomic studies tounderstand human health and diseases, in addition to its original focus on immunology. The internship program, in which theparticipants perform research in IMS laboratories, has also been
maintained. RISP 2017 was co-organized by the Chiba University Leading Graduate School Program.
We were pleased to welcome 42 graduate students and postdoctoral fellows from 11 countries, including 14 participantsfrom Japan, who gathered at Yokohama from June 16 to 23. The
scientific sessions consisted of 15 lectures presented by IMS PIs
and other invited senior scientists from Japan and abroad. RISP
students also presented their research in both oral and poster
sessions. The RISP program ended with participation in a twoday International Symposium on Immunology, co-organized by
IMS and the Japanese Society for Immunology.
RISP2017 was again a success; we received excellent feedback
comments in the evaluation survey, and many students indicatedthat they would recommend this program to colleagues. From
the other perspective, many lecturers commented on how impressed they were with the quality of the RISP students. In orderto make this successful program even more recognized internationally, IMS is considering a renewal of the RISP and is planning
to relaunch the program in a new format in 2019.

70

he IMS-JSI International Symposium on Immunology, hosted by the RIKEN Center for Integrative Medical Sciences(IMS) in conjunction with the Japanese Society for Immunology(JSI), was held June 22–23 at the International Conference Hall,
Plaza Heisei, Tokyo International Exchange Center. The symposium, entitled “Decoding Immune Complexity from Cell to
System”, included 19 outstanding speakers presenting their cutting-edge research and attracted close to 400 participants. There
were four sessions: (1) Functional genomics of lymphocytes, (2)Animal model and immunotherapy, (3) Interface between the
immune system and environment, and (4) Functional aspectsof immunology. In the “Functional genomics of lymphocytes”
session, several state-of-the-art research tools and statistical genetics recruiting diverse biological information resources wereintroduced. The “Animal model and immunotherapy” session
expanded our knowledge on how we could apply basic immunology to translational medicine. Control of Treg developmentby manipulating super-enhancers, epigenetic and transcriptional
regulation might open new avenues to prevent autoimmune diseases. Combining conventional electron-microscopic and new
two-photon imaging technologies helps to advance our understanding of the pathogenesis of viral infections. The “Interface
between the immune system and environment” session updated
our view of host-microbe interactions by revealing the importance of innate lymphoid cells, neuro-immune regulation andthe adaptive immune system for gut and body homeostasis. In
the “Functional aspects of immunology” session, live-imaging
technologies revealed new aspects of the dynamics of cell-cell interactions with functional implications for the immune responses. The possibility that a “neo-self ” antigen derived from misfolded proteins and its occupation of MHC II might be linked
to autoimmune diseases was also discussed. How Aire governs
the thymic microenvironment through a unique tissue structure,
Hassall’s corpuscles, was revealed by elegant studies combining histological studies, molecular biology and immunologicalapproaches. This year we hosted several young investigators
to present their work in newly established short talk sessions.

Events

14th/15th
PGRN-RIKEN
Strategic
Alliance
Meetings

RIKEN IMSLuxembourg FNR
Joint
SymposiumTO

he Global Alliance for Pharmacogenomics (GAP), a collaborative program between the former RIKEN Center for Genomic
Medicine (now RIKEN IMS) and the US National Institute of Health(NIH) Pharmacogenomics Research Network (PGRN), was formed in2008 with the objective of identifying the relationship between genetic variants and individual responses to drugs, including efficacy andside effects. PGRN-RIKEN strategic alliance meetings, held alternately in Japan and the United States, allow for face-to-face discussions
about the progress of ongoing projects and future directions for the
PGRN-RIKEN collaboration.
In 2017, the 14th and 15th PGRN-RIKEN Strategic Alliance Meetings were held in Yokohama on January 18–19 and in San Francisco on
September 8-9, respectively.
The meetings provided a valuable forum for exchanging information on ongoing collaborative activities as well as for presenting interesting topics from both parties.
In addition to these presentations, some 40 participants also explored new research proposals from PGRN members, ultimately deciding to adopt the following themes as additional collaboration projects,
and then the meetings concluded successfully.
Projects accepted at the 14th meeting:1) Genetic biomarkers of thrombotic risk in African American cancer
patients (PGRN PI: Minoli Perera, Northwestern University).
2) The relationship of the pharmacogenetics of enzalutamide to its
pharmacokinetic disposition/metabolism and clinical pharmacodynamics in advanced prostate cancer patients enrolled in the
Alliance A031201 study (PGRN PI: Lionel Lewis, Geisel School of
Medicine and The Norris Cotton Cancer Center at Dartmouth).
Projects accepted at the 15th meeting:1) Deep Sequencing to Identify Genetic Determinants of Heparin-Induced Thrombocytopenia (PGRN PI: Dan Roden, Vanderbilt University School of Medicine).
2) The Genetic Determinates of Metformin Pharmacokinetics (PGRN
PI: Kathy M. Giacomini, University of California San Francisco).

n October 4, 2017, the Luxembourg Institute of Health(LIH), the Luxembourg Center for Systems Biomedicine(LCSB) in University of Luxembourg, and RIKEN IMS held ajoint symposium at IMS in Tsurumi, Yokohama. The symposium began with a special greeting from H. E. Ms. Lydia Mutsch,
Luxembourg’s Minister of Health, and opening remarks by Professor Marc Schiltz of the National Research Fund, Luxembourg(FNR) and Dr. Shigeo Koyasu, the Executive Director of RIKEN.
In her message, the minister expressed her expectations for thefurther development of research collaborations with RIKEN andresearch institutions in Luxembourg.
At the Symposium, eight research scientists from LIH and
LCSB, and nine Japanese researchers from three RIKEN institutions [RIKEN IMS, RIKEN Center for Lifescience Technologies (CLST), RIKEN Medical Innovation Hub Program (MIH)and Juntendo University] gave presentations and discussed thelatest research trends in the fields of immunology and systems
biomedicine.
Professor Markus Ollert (LCSB) introduced the financial
support for the collaboration by FNR and, in a keynote lecture,
Dr. Kenya Honda (IMS) introduced an on-going collaboration
between RIKEN and LCSB. The two organizers, Drs. Haruhiko
Koseki (IMS) and Markus Ollert (FNR), discussed the expansionof the collaboration and the next joint symposium to be held in
Luxembourg in 2019.

Photo: Front row, from left to right: Mr. Jean-Claude Schmit (Chief
Medical Officer, Ministry of Health), Ms. Beatrice Kirsch (Ambassador of
Luxembourg in Japan), Ms. Mutsch, Dr. Koyasu, Dr. Tadashi Yamamoto(Director, IMS), Mr. Takashi Suzuki (Director, Yokohama Branch)71

Events

Tsinghua-RIKEN
Joint Symposium on
Immunology and
Immunotherapy

RIKEN IMSMcGill
SymposiumTR

he third joint workshop between RIKEN IMS and Tsinghua University Institute of Immunology (IITU) was held
on September 22nd and 23rd, 2017, at Tsinghua University inBeijing. The first day was a symposium with 14 speakers, sixfrom IMS, four from IITU, and four guest speakers from Harvard Medical School and Amgen Inc.
At the opening remarks, Dr. Chen Dong, Director of IITU
and Dr. Tadashi Yamamoto, Director of IMS, described a newtie between the two institutions. The research presentations
widely covered topics in T cell immunology, immunoregulatory cytokines, antitumor immunity, B cell development, innate
lymphoid cells, the neural immune system, and genomics. There
were active questions from the audience, especially from the
IITU students. In addition to the presentations, an IITU-RIKEN
IMS collaboration agreement was signed by the two Directors
on the first day.
The second day was reserved for individual discussions
among the researchers.
In the morning of the second day, Dr. Yamamoto and the organizers of the symposium, Drs. Tomohiro Kurosaki and Yuncai Liu, visited Professor Qi-kun Xue, the Deputy President ofTsinghua University, to discuss strengthening the ties between
Tsinghua University and RIKEN.
Based on the great success of this third joint workshop, both
institutions agreed to cooperate with further collaborations.

Photo: From left: Drs. Tadashi Yamamoto and Chen Dong in the front row
and Takashi Tanaka, Tomohiro Kurosaki, Yun-cai Liu and Yan Shi
in the back row.

72

IKEN and McGill made comprehensive cooperation agreements/MOUs beginning in July 2010. In order to strengthen the relationship between RIKEN and McGill University, weorganized the first RIKEN IMS - McGill Symposium, entitled“Excellence in Immunology & Genetics”, which was held on 8th9th May, 2017, at McGill University, Montreal, Canada. The goalof the symposium was not only to exchange information about
research activity at each organization, but also to begin to establish international collaborative projects between the two organizations. There were eight sessions that covered a broad rangeof biological research areas including Genetics, Immunology, Inflammation, Tissue Dynamics, Cancer and Technology Development. In the two-day symposium, a total of 30 talks, fifteen fromeach side, were presented to about 200 participants, including
post-docs and students at McGill University. At the close of themeeting, we discussed how we can proceed to set up collaborative projects. Both sides agreed on the importance of having
an exchange of young researchers between the participating
laboratories, as well as continuing the joint symposium within ashort interval. Upon these agreements, the second RIKEN IMS McGill Symposium will be held on 19th–20th February, 2018 in
Yokohama, Japan.

Events

Harvard
SummerSchool2017

Adjunct
Professorship
Programs

I

I

MS offers a summer internship program for undergraduate
students from Harvard University. In this program students
do a research internship in IMS laboratories, have basic biomedical sciences lectures given by PIs from IMS and other centers
and attend a Japanese language course. They also participate in
the RIKEN IMS Summer Program (RISP) and the RIKEN IMSJSI International Symposium on Immunology. The participantsreceive a letter grade from IMS and course credit from Harvard.
In 2017, we accepted three students from Harvard University,
Gui Zhen Chen, Krystal Katherine Phu, and Lily Xu into thesummer program, which was held from June 5 to August 14.
Mr. Chen conducted his research on the theme of “Memory
and GC B cell selections” in the Drug Discovery Antibody Platform Unit (Dr. Takemori). He found that selection of high-affinity memory and GC B cells is differentially regulated in the
GC reaction. Ms. Phu studied “Analysis of cell and nuclear polarities in epidermis” in the Laboratory for Skin Homeostasis(Dr. Amagai). She found that in differentiated keratinocytes,
several polycomb markers were highly localized in pericentricheterochromatin. Ms. Xu worked on “Evaluation of the cytokine
response and antitumor effect between NKT cells and iPS-NKT
cells” in the Laboratory for Immunotherapy (Dr. Fujii). She
studied a synergistic antitumor effect of IL-18 and IL-2 in not
only human NKT cells, but also iPS-NKT cells. During their internships, the students had numerous discussions with IMS researchers and, at the end of the program, they gave oral presentations describing their research results.

Photo: From left: Mr. Chen, Ms. Xu, Ms. Phu and Dr. Tadashi Yamamoto(Dicrector, IMS)

MS collaborates with and accepts graduate students from 8
domestic university graduate schools. There are now a total of
28 adjunct professors/associate professors in IMS (Table), and 55
students studied at IMS in 2017. On September 23rd, IMS helda briefing session on adjunct graduate school programs to provide 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 School of Medicine,
Osaka University

Takashi Saito (Visiting Professor),
Takashi Tanaka (Visiting Professor)

Department of Immunology,
Graduate School of Medicine,
Chiba University

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

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

Ichiro Taniuchi (Visiting Professor)

Graduate School of Medicine,
Yokohama City University

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

Graduate School of Medical Life
Science,
Yokohama City University

Hiroshi Ohno (Visiting Professor), Makoto
Arita (Visiting Professor), Takaharu Okada(Visiting Professor), Kazuyo Moro (Visiting
Professor), Hidehiro Fukuyama (Visiting
Associate Professor)

Research Institute of Biological
Sciences,Tokyo University of Science

Masato Kubo (Professor),
Takashi Saito (Visiting Professor)

Graduate School of Medicine,
Kyoto University

Fumihiko Ishikawa (Visiting Associate
Professor)

Graduate School of Medicine,
Keio University

Masayuki Amagai (Professor),
Kenya Honda (Professor),
Shigeo Koyasu (Visiting Professor),
Haruhiko Koseki (Visiting Professor)

73

Guest lectures 2017
Table: Guest Lectures Jan–Dec, 2017
Date

Speaker

Affiliation

Country

Title

16–Jan–17

Dr. Masakatsu Yamashita

Ehime University Graduate School of Medicine

Japan

Metabolic and epigenetic regulation of T-cell senescence

25–Jan–17

Dr. Keisuke Chris Nagao

National Cancer Institute, National Institutes of Health (NIH)

USA

Regulation of skin immunity during homeostasis andinflammation

8–Feb–17

Dr. Nisar Malek

University Hospital Tübingen

Germany

Integrating principles of personalized medicine at the university
hospital in Tübingen-challenges and opportunities

8–Feb–17

Dr. Rudi Balling

Luxembourg Centre for Systems Biomedicine

Luxembourg

From systems biology to systems medicine – a long road ahead

9–Feb–17

Dr. Yibo Wu

ETH Zurich, Institute of Molecular Systems Biology

Switzerland

Systems proteomics of liver mitochondorial activity

10–Feb–17

Dr. Takashi SatohWPI Immunology Frontier Research Center (IFReC), Osaka
University

Japan

Functional diversity of various disorder-specific macrophages

16–Feb–17

Dr. Jason E. Shoemaker

University of Pittsburgh

USA

Emergent properties of influenza virus infections

27–Feb–17

Dr. Hiroshi Kurosaka

Graduate School of Dentistry, Osaka University

JapapnInvestigating the etiology of craniofacial abnormalities

9–Mar–17

Dr. Keiji Hirota

Institute for Frontier Life and Medical Sciences,
Kyoto University

JapapnTissue inflammation mediated by Th17 cells

10–Mar–17

Dr. Florent Ginhoux

Singapore Immunology Network (SIgN), A*STAR

Singapore

Dendritic cell biology: from development to functions

14–Mar–17

Dr. Claus Schneider

Vanderbilt University Medical School

USA

Novel substrates and products in cyclooxygenase catalysis

17–Apr–17

Dr. Masaru Ishii

Graduate School of Medicine, Osaka University

Japan

In vivo dynamics and function of osteoclasts, bone-destroying
macrophages

23–May–17

Dr. Rahul Sinha

Stanford University School of Medicine

USA

Single-cell RNA-seq: limitations and challenges

7–Jun–17

Dr. Florian Winau

Harvard Medical School

USA

Lipids in immunology: antigens and regulators of immune
responses

21–Jun–17

Dr. Azusa Inoue

Harvard Medical School

USA

Discovery of polycomb-mediated genomic imprinting

27–Jun–17

Prof. Koji Hase

Faculty of Pharmaceutical Science, Keio University

JapapnMicrobial fermentation products shape host immune systemthrough epigenetic modifications

18–Jul–17

Prof. Irena Mlinaric-Rascan

Faculty of Pharmacy, University of Ljubljana

Slovenia

Immunoproteasome targeting

26–Jul–17

Dr. Zhuoming Sun

Beckman Research Institute of the City of HopeUSA

Mechanism for RORgammat-regulated Th17 function

4–Aug–17

Dr. Asuka Inoue

Graduate School of Pharmaceutical Sciences,
Tohoku University

JapapnDeveloping methods to dissect GPCR signaling in health anddisease17–Aug–17

Dr. Kazuki Nagashima

Graduate School of Medicine and Faculty of Medicine,
The University of Tokyo

JapapnIdentification of microfold cell-inducer (MCi) cells that promote
IgA production and diversify the gut microbiota

22–Aug–17

Dr. Kyle M. Loh

Institute for Stem Cell Biology and Regenerative Medicine,
Stanford University School of Medicine

USA

Understanding how early human tissue progenitors develop byreconstituting them from stem cells

29–Aug–17

Dr. Osamu Takeuchi

Institute for Frontier Life and Medical Sciences,
Kyoto University

JapapnPosttranscriptional control of inflammatory responses

8–Sep–17

Dr. Yuichi Hirata

Columbia University

USA

Identification of specific Treg subset that regulates stem cells

19–Sep–17

Dr. Keiji Kuba

Akita University Graduate School of Medicine

JapapnmRNA deadenylation-guided regulation of cardiac homeostasis

21–Sep–17

Dr. Charles N. Serhan

Brigham and Women’s Hospital and Harvard Medical SchoolUSA

Pro-resolving mediators & mechanisms in infectious
inflammation: metabololipidomics in human disease andmodel organisms

29–Sep–17

Dr. Nada Jabado

McGill University

CanadaOncohistones in cancer: professional highjackers of theepigenome

16–Oct–17

Prof. Neil Brockdorff

University of Oxford

UK

Advances towards understanding the mechanism of X
chromosome inactivation

19–Oct–17

Dr. Ferdinando CercielloUniversity Hospital Zurich

Switzerland

Multiplexed biomarkers strategies for the detection ofmalignant pleural mesothelioma in blood based on targeted
proteomics

25–Oct–17

Dr. Toshiro Moroishi

Moores Cancer Center, University of California at San Diego

USA

Hippo pathway in immunity and tissue homeostasis

27–Oct–17

Dr. Ludmila Prokunina-Olsson

National Cancer InstituteUSA

From genetics to translational genomics of infection and cancer

30–Oct–17

Dr. Marius Wernig

Stanford University

USA

How to make a neuron

2–Nov–17

Dr. Alejo Chorny

Journal of Experimental Medicine

USA

Scientific publishing: what, how and why

6–Nov–17

Dr. Sara Mostafavi

Centre for Molecular Medicine and Therapeutics, University of
British Columbia

CanadaIdentifying and interpreting genomic patterns in large
population studies.

10–Nov–17

Dr. Heidi H. Kong

National Institute of Arthritis and Musculoskeletal and Skin
Diseases, NIH

USA

The microbiome in healthy skin and atopic dermatitis

20–Nov–17

Dr. Craig Mak

Cell Systems

USA

How to publish with Cell Systems

21–Nov–17

Dr. Hiroyuki Hosokawa

California Institute of Technology

USA

Dynamic and competitive deployments of transcription factor
ensembles mediate T-cell lineage commitment

24–Nov–17

Dr. Yuki Sugiura

Keio University

Japan

Visualization of immune-brain signaling in tissues by mass
spectrometry based imaging

24–Nov–17

Dr. Keisuke Kataoka

National Cancer Center Research InstituteJapan

Genetic landscape in adult T-cell leukemia/lymphoma

25–Dec–17

Dr. Toru Hirota

The Cancer Institute Japanese Foundation for Cancer ResearchJapan

Molecular grounds underlying chromosomal instability incancers74

Part 5
Data andStatistics

Publications 2017

1

2

3

Table: IMS Publications Jan-Dec, 2017

JournalNat Rev Drug Discov
Nat Biotechnol
NatureNat Rev Immunol
Nat Nanotechnol
Science
Nat MedNat Genet
Cell Stem Cell
Immunity
Nat Immunol
Nat Cell Biol
Cancer Discov
Gastroenterology
Cell MetabSci Transl Med
Gut
JAMA Oncol
Mol CellCirc Res
Mol Psychiatr
J Allergy Clin Immun
Ann Rheum Dis
J Clin Invest
J Hepatol
Nat Commun
J Exp Med
Biol Psychiat
Nat Plants
EMBO J
Proc Natl Acad Sci U S AClin Cancer Res
Immunol Rev
Gene Dev
Dev Cell
Am J Hum Genet
Diabetes
Cell Syst
Kidney Int
Curr Opin Immunol
Cancer Immunol Res
Cell Rep
Elife
Haematologica
J Autoimmun
Oncogene
Bioinformatics
Clin Pharmacol Ther
Arthritis Rheumatol
Front Immunol
Breast Cancer Res
J Invest Dermatol
J Infect Dis
PLOS Genet
Lab Chip
StrokeOthersTOTAL

76

IF (2016)
57.0
41.7
40.1
39.9
39.0
37.2
29.9
28.0
23.4
22.8
21.5
20.1
20.0
18.4
18.2
16.8
16.7
16.6
14.7
14.0
13.2
13.1
12.8
12.8
12.5
12.1
12.0
11.4
10.3
9.8
9.7
9.6
9.6
9.4
9.2
9.0
8.7
8.4
8.4
8.4
8.3
8.3
7.7
7.7
7.6
7.5
7.3
7.3
6.9
6.4
6.3
6.3
6.3
6.1
6.0
6.0

Number ofPapers 2017
1
3
3
1
1
3
1
5
1
4
4
1
1
1
1
1
2
1
1
1
1
5
1
1
1
7
5
1
1
1
8
2
2
1
1
1
2
1
1
1
1
6
1
1
1
1
1
2
1
3
1
2
1
1
1
1
206
312

4

5

6
7
8

9

10

11
12
13
14

15

16

17
18

19

20
21
22
23
24
25

26

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83Budget, personnel and patents

IMS Budget FY2017

Personnel FY2017
JPY Million

IMS Budget FY2017

Category

NumberGovernment funding for operations

2,394

Director

1

Commissioned research

1,036

Deputy Director

3839

Senior Advisor

1

4,269

Group Director

10Team Leader

23

Coordinator

2

Partnership-Promotion Coordinator2

Deputy Team Leader

7

Senior Scientist

22

Senior Research Scientist

1

Research Scientist

38

Postdoctoral Researcher

16

Special Postdoctoral Researcher

6

Foreign Postdoctoral Researcher

2

Research Fellow

5

Research Associate

9

Senior Technical Scientist

3Technical Scientist

9Technical Staff I

51

Technical Staff II

62

International Program Associate

1

Junior Research Associate

26Intern1Student Trainee

99

Assistant

26

Part-time Staff

28

Senior Visiting Scientist

11

Visiting Scientist

190

External competitive funding
Total

Patents
There were 31 patents filed from January to December in 2017.
Patents

2017

Total

International
patents (PCT)31

20

Domestic patents(Japan)11

Visiting Technical Scientist

5

Visiting Researcher

1

Temporary Staffing

13

Research Consultant

4

Consultant

1

Total

84

679

RIKEN Center for Integrative Medical Sciences
Organization Chart

Access to RIKEN Yokohama Campus

Local Access

RIKEN President
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.

Hiroshi Matsumoto

Director

Buses depart Tsurumi every 5–15 minutes. It takes
about 15 minutes to arrive at RIKEN Yokohama. The
fare is 220 yen.

Tadashi Yamamoto

Integrative
Medical Sciences
Planning Office

By Train
A 15-minute walk from JR Tsurumi-Ono Station (JRTsurumi Line), which is directly accessible by transferfrom JR Tsurumi Station.

Senior Advisor

rains run about every 10 minutes during morning andevening rush hour, but less frequently at other times.

Masaru Taniguchi
Shizuo Akira

Searchable train timetables in English are available at
http://www.hyperdia.com/en/

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.

RIKEN Center for
Integrative
Medical Sciences
Advisory Council
Deputy Director
Michiaki Kubo
Haruhiko Koseki
Kazuhiko Yamamoto

Max Cooper (chair)Mark Lathrop (vice chair)
Hiroyuki Aburatani
Rudi Balling
Riccardo Dalla-Favera
Michel Georges
Ronald N. Germain
Hajime Karasuyama
Yutaka Kawakami
Paul W. Kincade
Bernard MalissenJohn O’Shea
Fiona Powrie
Peter Sorger
Kiyoshi Takatsu
Katsushi Tokunaga
Dale Umetsu
Arthur Weiss

From the Airport
From Haneda Airport

From Narita Airport

Route 1
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.

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 themost 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(18 minutes). 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).

* A reserved seat express that requires payment of asurcharge in addition to train fare.
Searchable train timetables in English are available at
http://www.hyperdia.com/en/*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).

85

http://www.ims.riken.jp/english/
RIKEN Yokohama Campus
1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City,
Kanagawa, 230-0045, Japan
Tel : 045-503-9111
Fax : 045-503-9113
Email : yokohama@riken.jp

RIKEN IMS
Annual Report 2017

RIKEN IMS Annual Report 2017 RIKEN Center for Integrative Medical Sciences

RIKEN Center for
Integrative Medical Sciences

RIKEN IMS
Annual Report 2017
RIKEN Center for Integrative Medical Sciences

RIKEN 2017-059