RIKEN Center for Integrative Medical Sciences
Organization Chart

Access to RIKEN Yokohama Campus

Local Access

RIKEN President
Hiroshi Matsumoto

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.

Director
Shigeo Koyasu(until September)
Tadashi Yamamoto(from October)

Integrative
Medical Sciences
Planning Office

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

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

Senior Advisor

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

Masaru Taniguchi
Shizuo Akira

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

Max Cooper (chair)Mark Lathrop (vice chair)
Ronald N. Germain
Paul W. Kincade
Bernard Malissen
William E. Paul
Dale Umetsu
Arthur WeissJohn O’Shea
Fiona Powrie
Peter Sorger
Rudi Balling
Kiyoshi Takatsu
Hajime Karasuyama
Yutaka Kawakami
Michel Georges
Edison Tak-Bun Liu
Katsushi Tokunaga
Hiroyuki Aburatani

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.

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: Shohei HoriLab. 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 Immunogenetics: Hisahiro YoshidaLab. for Metabolomics: Makoto Arita

Core for Genomic Medicine
Lab. for Genotyping Development: Yukihide Momozawa

Lab. for Cardiovascular Diseases: Toshihiro Tanaka

Lab. for Genome Sequencing Analysis: Hidewaki Nakagawa

Lab. for Autoimmune Diseases: Kazuhiko Yamamoto

Lab. for Medical Science Mathematics: Tatsuhiko Tsunoda

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:

Ming Ta Michael Lee

Shiro Maeda
Lab. for Respiratory and Allergic Diseases: Mayumi Tamari

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

Lab. for Allergic Disease: Toshiaki KawakamiLab. for Immunotherapy: Shin-ichiro Fujii

Drug Discovery Antibody Platform Unit: Toshitada TakemoriLab. for Vaccine Design: Yasuyuki Ishii

Young Chief Investigator Program
YCI Laboratory for Stem Cell Competency: Hayato Kaneda
YCI Laboratory for Immune Regeneration: Tomokatsu Ikawa

YCI Laboratory for Cellular Bioenergetic Network:

Toshimori Kitami

YCI Laboratory for Quantitative Omics: Katsuyuki ShiroguchiiContents

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

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

Part 1
Research Highlights
Good neighbors make good defenses ................................. 2
Global genes for gut disorders ............................................. 3
Immune gene map for Japan ............................................... 4
How the body stops an immune response fromtriggering allergic diseases ............................................. 5
Research on 377,000 people worldwide highlights
the role of genes in eczema ............................................ 6
Controlling inflammation in fat cells ................................. 7

Genome-wide homozygosity influences statureand cognition .................................................................. 8
The genetic roots of adolescent scoliosis ............................ 9
Blocking differentiation is enough to give cells“stemness” ........................................................................ 10
CRTAM determines the CD4+ cytotoxic
T lymphocyte lineage ..................................................... 11
In memory of Dr. William Paul .......................................... 12Part 2Lab Activities
Core for Homeostatic Regulation ........................... 14
Laboratory for Cell Signaling ........................................ 15
Laboratory for Lymphocyte Differentiation ................ 16
Laboratory for Transcriptional Regulation .................. 17
Laboratory for Immune Cell Systems .......................... 18
Laboratory for Human Disease Models ....................... 19
Laboratory for Intestinal Ecosystem ............................ 20

Laboratory for Integrated Bioinformatics .................... 35
Laboratory for Tissue Dynamics .................................. 36
Laboratory for Integrated Cellular Systems ................. 37
Laboratory for Metabolomics ....................................... 38
Core for Genomic Medicine ....................................... 39
Laboratory for Genotyping Development ................... 40
Laboratory for Genome Sequencing Analysis ............. 41

Laboratory for Mucosal Immunity ............................... 21
Laboratory for Gut Homeostasis .................................. 22
Laboratory for Immune Homeostasis .......................... 23
Laboratory for Skin Homeostasis ................................. 24
Laboratory for Metabolic Homeostasis ........................ 25
Laboratory for Immune Crosstalk ................................ 26

Laboratory for Medical Science Mathematics ............. 42
Laboratory for Statistical Analysis ................................ 43
Laboratory for Pharmacogenomics .............................. 44
Laboratory for Cardiovascular Diseases ...................... 45
Laboratory for Autoimmune Diseases ......................... 46
Laboratory for Digestive Diseases ................................ 47

Laboratory for Inflammatory Regulation .................... 27
Laboratory for Cytokine Regulation ............................ 28
Laboratory for Innate Immune Systems ...................... 29
Core for Precise Measuring and Modeling ......... 30
Laboratory for Developmental Genetics ...................... 31

Laboratory for Bone and Joint Diseases ....................... 48
Laboratory for Endocrinology, Metabolism andKidney Diseases ........................................................ 49
Laboratory for Respiratory and Allergic Diseases ...... 50
Program for Medical Innovations .......................... 51

Laboratory for Integrative Genomics ........................... 32
Laboratory for Disease Systems Modeling .................. 33
Laboratory for Immunogenetics ................................... 34

Laboratory for Immune Regulation ............................. 52
Laboratory for Immunotherapy .................................... 53
Laboratory for Vaccine Design ..................................... 54ii

Laboratory for Allergic Disease .................................... 55

Animal Facility ................................................................ 60

Drug Discovery Antibody Platform Unit .................... 56
YCI Laboratory for Stem Cell Competency ................ 57
YCI Laboratory for Immune Regeneration ................. 57

Award Winners 2015 .................................................... 61
Other Programs
RIKEN International Program Associate (IPA) .......... 62

YCI Laboratory for Quantitative Omics ...................... 58
YCI Laboratory for Cellular Bioenergetic Network ... 58
Central Facilities

RIKEN Foreign Postdoctoral Researcher (FPR)
Program ..................................................................... 62
RIKEN Junior Research Associate (JRA) Program .... 62

FACS Laboratory ............................................................. 59
Confocal Laboratory ....................................................... 59
Genomics Laboratory ..................................................... 60

RIKEN Special Postdoctoral Researcher (SPDR)
Program ..................................................................... 62

Part 3
Research Projects
Projects
iPS project ........................................................................ 64
Modeling skin diseases .................................................. 64
Impact of host-gut microbiome interactions
on the pathogenesis of diabetes .............................. 65
Humanized mouse .......................................................... 65
NKT cell projects ............................................................ 66

Linkage to RIKEN Program for Drug Discovery andMedical Technology Platforms (DMP) .................. 66
PGRN-RIKEN project .................................................... 67
Collaboration with Asian institutes and SEAPharm .. 67
International Cancer Genome Consortium (ICGC) .. 68
Commissioned Research
The Biobank Japan project ............................................. 68

Part 4
EventsRIKEN IMS Summer Program (RISP) 2015 ..................... 70

The 2nd IMS Symposium .................................................... 71

The IMS-JSI International Symposium on
Immunology 2015 .......................................................... 70
12th PGRN-RIKEN Strategic Alliance Meeting ............... 71

Harvard Summer School 2015 ............................................ 72
Adjunct Professorship Programs ........................................ 72

Part 5
Data and Statistics
Publlications 2015 ................................................................. 74
Guest lectures 2015 ............................................................... 83

Budget, personnel and patent .............................................. 84
Access to RIKEN Yokohama Campus ..................... 85iii

Director’s ReportT

his is my first annual report since becoming Director of
RIKEN Center for Integrative Medical Sciences (IMS) in
October 2015. I assumed this responsibility from former Director
Shigeo Koyasu, who was promoted to RIKEN Executive Director.
It is my great honor to work at IMS, one of the leading research
institutes in medical life sciences in Japan. When I moved to IMS,
I visited each laboratory and talked with all the principal investigators. My first impression was that IMS has a core of remarkably
good and solid scientists.
IMS was established in 2013 by the integration of two former
RIKEN Centers, the Research Center for Allergy and Immunology(RCAI) and the Center for Genomic Medicine (CGM), both ofwhich had independently achieved outstanding reputations in theirrespective fields. I am a molecular biologist and have been working
in the field of oncogene research and signal transduction, so mybackground and approaches did not fit perfectly with either genomics or immunology, but science is science. My interests in studying
how gene expression is controlled in a context-dependent manner,and how cells respond to their environment to maintain homeostasis, were also common topics at IMS. During my first discussions
with IMS researchers, I felt that genomic and immunology research
had been well-integrated beyond my expectations. They talked
about how to tackle the existing research boundaries to create new
future directions. I believed that the efforts by each IMS member tounderstand their different scientific cultures would push collaborations and move the Center forward.
IMS is a unique Center in RIKEN, because of its mandate toconnect basic medical and life science research with clinical medicine. Researchers are aspiring to understand the relationships
between genes and diseases, environment and homeostatic regulation, internal body changes and disease onset, and are modelingand stratifying these processes. IMS has a strong support system
for research conducted in the Center as well as for external collaborative research. This includes state of the art technologies in theiv

Animal Facility, GWAS studies, and metabolomics. We continue tostrengthen and expand support activities for studying internal andexternal triggers of diseases and the delicate equilibrium existing intimes of health.
Healthy aging is a concerning issue in Japan. Living in Okinawa
for the past five years, I became interested in the aging problem in
relation to diet and lifespan. Okinawa is rich in herbs, vegetables,and seafood, and Okinawans used to have the longest life expectancy in the world. However, this is no longer true due to lifestylechanges, particularly the choice of diet. Yet, no national institution
has been investigating the relationship between Okinawan lifespanand diet, and there is not even a pharmaceutical school in Okinawa.
RIKEN is going to promote an aging research program that should
be complementary to our ongoing microbiota research in IMS. I
would also like to keep in mind that there is a lot to do in Okinawa
in aging research.
To nurture young researchers who will become leaders in future
multidisciplinary research, IMS established its unique Young Chief
Investigator (YCI) system, which was approved as RIKEN’s official
system in 2015. In this program, the selected YCI heads an independent research laboratory and has access to mentoring by multiple senior specialists in related research fields. The YCI laboratory
shares space, equipment and facilities with a host laboratory within
IMS. In the 5th year, each YCI is reviewed for promotion. In 2016,YCI Katsuyuki Shiroguchi, was promoted to PI at the RIKEN Quantum Biology Center.
IMS also promoted three young leaders in 2015. Yoichiro
Kamatani, Yukihide Momozawa, and Kazuyo Moro became Team
Leaders of the Laboratory for Statistical Analysis, Laboratory for
Genotyping Development and the Laboratory for Innate Immune
System, respectively.
IMS researchers continue to perform outstanding research, publishing papers in significant journals in 2015. Kenya Honda reported
Th17 cell induction by adhesion of microbes to intestinal epithelial
cells (Cell, 2015). Yukinori Okada and Michiaki Kubo reported apopulation-specific HLA imputation reference panel and its application to Graves' disease risk in Japanese (Nature Genetics, 2015).
Kazuyo Moro reported that IFN and IL-27 antagonize ILC2 function (Nature Immunology, 2015). There were 279 papers publishedfrom IMS in 2015. I believe that with our continuous challenges, wewill flourish as pioneers in integrative medical sciences.

Tadashi Yamamoto
Director,
RIKEN Center for Integrative Medical Sciences

Part 1
Research
Highlights

Good neighbors make good
defenses

Research highlights

A tight physical association between gut
bacteria and the intestinal wall helps
establish robust immune defenses

Figure: Electron micrograph showing TH17-inducing bacteria isolated from the human intestine.
© 2016 Kenya Honda, RIKEN IMS

A

recent study by RIKEN researchers has shed light on
the conundrum of how microbes in the gut can influence the host’s immune system, despite being separated by
the gut lining.
The intestinal wall is a major entry point for infection,and immune cells known as TH17 cells reinforce this barrier
and fend off pathogens. Certain ‘commensal’ bacteria in theguts of mammals stimulate the proliferation of TH17 cells.
In rodents, one subset of gut bacteria plays a particularly strong role in this process. “We had previously identified
segmented filamentous bacteria (SFB) as one of the mostpotent inducers of TH17 cells,” explains Takeshi Tanoue, amember of the team, which was led by Kenya Honda of the
RIKEN Center for Integrative Medical Science. “Tight adhesion to intestinal epithelial cells is a remarkable characteristic of these microbes.”
The researchers explored whether this adhesion plays amajor role in activating immunity in the gut. They began
by exploiting the strikingly distinct SFB populations in rats
and mice. “About 5–10 percent of the genes are specific toeach strain,” notes Tanoue. Although rat-derived SFBs could
proliferate in the mouse intestine and vice-versa, neither
population was able to adhere tightly to the intestinal wallafter transplantation. This reduced adhesion correlated witha sharp decrease in TH17 induction, indicating that the mere
presence of these commensals is insufficient—a tight epi-

This article was reproduced from RIKEN Research withpermission
http://www.riken.jp/en/research/rikenresearch/highlights/8168/

2

thelial interaction is essential. Indeed, pathogenic bacteriathat bind to the surface of the intestinal wall during infection
also stimulate TH17 proliferation, apparently via a similar
mechanism.
These results offer only limited insights into humans,
however. “SFBs haven’t been found in the human intestine, and the counterpart TH17-inducing bacteria have notyet been identified,” says Tanoue. The researchers therefore
collected fecal samples from human subjects and examinedwhich specimens could act on TH17 cells when transplanted
into mice. The results enabled them to identify 20 bacterial
strains that appear to play a similar role to mouse SFBs (Figure).
Abnormalities in TH17 activation can contribute to inflammatory bowel disease, and hence a detailed bacterial
census may help to diagnose or treat this disorder.
Since the human commensals isolated in the present
study came from a patient with inflammatory bowel disease,further experiments are needed to identify the ‘optimal’
gut bacterial community. “We don’t know if these bacteria
are pathogenic or beneficial to the host,” explains Tanoue.
“We’re now trying to isolate TH17-inducing bacteria fromhealthy human samples.” In principle, such bacteria could
be delivered clinically as ‘probiotics’ to help normalize disease-associated disruptions of gut immunity.

Original article:
Atarashi, K., Tanoue, T., Ando, M., Kamada, N., Nagano,Y., Narushima, S., Suda, W., Imaoka, A., Setoyama, H.,
Nagamori, T. et al. Th17 cell induction by adhesionof microbes to intestinal epithelial cells. Cell 163,
367–380 (2015)

Global genes for gut disorders

Research highlights

People with inflammatory bowel disease sharethe same genetic risk factors the world overFigure: Inflammatory bowel disease is increasingly afflicting people of Asian ethnicity.
© deeepblue/iStock/ThinkstockT

he genetic regions that underlie susceptibility to inflammatory bowel disease (IBD) are almost the samein people of diverse ancestries around the world, a recent international study has found. One implication of this findingis that drugs developed to target the genetic causes of thetwo forms of IBD—ulcerative colitis and Crohn’s disease—should prove effective for sufferers regardless of their ethnicity or genetic background.
“The basic mechanisms of IBD are common across populations,” says Atsushi Takahashi, a bioinformatics researcher
at the RIKEN Center for Integrative Medical Sciences and amember of the International IBD Genetics Consortium that
led the project. He added that since the mechanisms of other diseases are also shared across populations, international collaborations are important for developing insights into
these diseases.
Unlike most previous investigations, which considered
only individuals of one descent, the present study explored
the genetic underpinnings of ulcerative colitis and Crohn’sdisease in populations of four ancestries—East Asian, Indian, Iranian and European.
The researchers analyzed close to 200,000 DNA lettersof each person from about 43,000 people with IBD and
53,500 healthy controls. Of these DNA samples, just under
10 percent were from people of East Asian, Indian or Iranian descent, while the others were from people from Europe,

This article was reproduced from RIKEN Research withpermission.
http://www.riken.jp/en/research/rikenresearch/highlights/8110/

North America and Oceania.
The results confirmed many genetic variants previously
recognized as risk factors for IBD as well as revealing 38 regions of the genome that had not been implicated before. Of
these newly identified regions, 27 were associated with bothCrohn’s disease and ulcerative colitis, 7 with Crohn’s alone
and 4 only with colitis.
Their findings bring the number of gene regions known
to be linked to IBD to 200. Notably, the vast majority of the
newly discovered gene regions were found in people with
IBD from diverse ancestry groups. “Almost all the genes
associated with IBD are shared between European andnon-European populations,” Takahashi says.
With IBD increasing around the world–especially in
Asia, where lifestyle changes brought about by economic
growth have dramatically increased the incidence of thesegut disorders—new treatments options are urgently needed.
The 38 new gene regions offer a range of potential avenues for drug development. Some genes are involved in cell
degradation pathways, while others are responsible for activating specialized immune cells known as T cells. “Scientists
can now investigate these gene loci in more detail, and new
drugs may be developed,” Takahashi says.

Original paper:
Liu, J. Z., van Sommeren, S., Huang, H., Ng, S. C., Alberts, R., Takahashi, A., Ripke, S., Lee, J. C., Jostins, L.,
Shah, T. et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlightshared genetic risk across populations. Nature Genetics 47, 979–986 (2015)3

Immune gene map for Japan

Research highlights

New resource enables scientists to findimmunity genes linked to Graves’ disease

Figure: Three-dimensional ribbon models of
the four HLA proteins that the study associatedwith Graves’ disease risk. The colored spheres
indicate residues at the amino acid positions
associated with Graves’ disease risk.
© 2015 Macmillan Publishers Ltd: Nature Genetics(Ref.)

A

comprehensive panel of the common gene variants that
affect the immune system among Japanese individuals
has been established by a RIKEN-led team. The researchers
have used this new resource to identify specific immune-related genes that are most strongly associated with the risk ofa person developing Graves’ disease, an autoimmune disorder that affects about 30 million people around the world.
“These biomarkers are the best candidates for personalized or precision medicine,” says Yukinori Okada, a genetic
epidemiologist at the RIKEN Center for Integrative Medical
Sciences, who led the study. He notes that these immune-related genes affect disease risk much more than the othertypes of gene variants usually used by researchers whensearching for predictors of disease.
The stretch of DNA known as the major histocompatibility complex (MHC) includes more than 200 genes that help
the immune system recognize foreign substances. It is one of
the most genetically diverse regions of the genome. The variation contained within the MHC—specifically in genes thatcode for the human leukocyte antigen (HLA) genes—underlie individual susceptibility to many diseases, including cancers, mental illnesses, infectious diseases and autoimmune
disorders.
Fine mapping of risk variants within HLA genes has
mostly been limited to people of European ancestry. Consequently, the resulting databases are not representative ofThis article was reproduced from RIKEN Research withpermission
http://www.riken.jp/en/research/rikenresearch/highlights/8086/

4

populations found elsewhere in the world. To address thisimbalance, Okada, in collaboration with RIKEN geneticist
Michiaki Kubo and other colleagues, decided to build a reference dataset of HLA gene variation among individuals ofJapanese origin. They did so by inspecting more than 7,000
single DNA polymorphisms in the genomic region encoding
the MHC.
The researchers then used this new resource to analyze
the association of HLA genes with Graves’ disease, a disorder of the immune system that results in the overproductionof thyroid hormones. Also known as Basedow’s disease, thiscondition additionally causes bulging eyes, heat intolerance
and weight loss. Okada’s team combined their immune gene
map with data from a genome-wide association study that
included close to 2,000 Japanese individuals with Graves’disease and around 7,000 healthy controls. They discoveredthat common variants in four HLA genes (Figure) each independently increase the risk of a person developing thedisease.
This knowledge can now help doctors to more effectively
identify patients that are most likely to suffer the autoimmune disorder. The Japanese map of HLA genes can also be
used to discover risk variants associated with other disorders.

Original article:
Okada, Y., Momozawa, Y., Ashikawa, K., Kanai, M.,
Matsuda, K., Kamatani, Y., Takahashi, A. & Kubo, M.
Construction of a population-specific HLA imputationreference panel and its application to Graves' diseaserisk in Japanese. Nature Genetics 47, 798–802 (2015)

How the body stops an immune
response from triggering allergic
diseases

Research highlights

Figure: IFN and IL-27 suppress ILC2s-induced
allergic response in innate immunityT

he innate immune response, which is the body’s rapid andnon-specific response to pathogens, was once believed to bea simple system relying on short-lived effector cells alone, but it is
now known to be more complex, involving long-lived lymphoidcells. Researchers from the RIKEN Center for Integrative Medical
Sciences (IMS) in Japan have now shown how the body suppresses the activation of the long-lived cells after infection, preventing
the response from continuing when it is no longer needed.
Parasitic worms, known as helminths, are a formidable challenge to human health, being a major cause of mortality in thedeveloping world. The body’s key first-line defense against theseparasites and some fungal infections is called the type 2 innate
immune response, which is preceded by a more specific one called
the type 2 adaptive immune response. It actually turns out to be adouble-edged sword, as it has been implicated in allergic inflammatory responses such as asthma caused by fungal infections.
“This immune response is important, but also can be dangerous if it lasts beyond its necessity,” says Kazuyo Moro, team leader of the Laboratory for Innate Immune Systems in IMS, “It wasonce believed that the response was mainly mounted by shortlived cells, but now we know that it also involves a population of
longer-lived innate lymphoid cells. Since a continuing response
is associated with allergic inflammation, it is important for us tounderstand how these cells are turned off.”
A key finding of the study, published in Nature Immunology,
are that these innate lymphoid cells can be shut off by certain cy-

This article was reproduced from RIKEN Press Release
http://www.riken.jp/en/pr/press/2015/20151124_1/

tokines—interferon-beta, -gamma and interleukin-27—to end
the immune response and ensure that the inflammation does notlast. In addition, the scientists helped clear up a mystery about
these cells by showing that they do not circulate to tissues that require an immune response but are actually located in the tissues,
and are only turned on when a threat is detected. “This shows,”
says Moro, “that the response is mounted locally in a very specificway. This may be another way for the body to prevent the lasting
inflammation that can be associated with the response.”
According to Shigeo Koyasu, group director of the Laboratory
for Immune Cell Systems, who led the group, “These findings arehelpful in understanding how the type 2 innate response changes
to be both beneficial and harmful. Learning how these cells areactivated and inactivated can give us clues for understanding andtreating how the body reacts to such infections.”
He continues, “We are beginning to gain insights into theinnate immune response, which was previously thought to be
simpler than our understanding today. I hope that our work willencourage researchers to look for similar regulatory mechanisms
in type 1 and type 3 innate immune responses as well, as this will
help us to gain a broader understanding of the complexity of ourimmune response.”

Original paper:
Kazuyo Moro, Hiroki Kabata, Masanobu Tanabe, Satoshi Koga, Natsuki Takeno, Miho Mochizuki, Koichi
Fukunaga, Koichiro Asano, Tomoko Betsuyaku, andShigeo Koyasu. Interferon and IL-27 antagonize ILC2
function and type 2 innate immune responses. Nature
Immunology 17, 76–86 (2015)5

Research on 377,000 people
worldwide highlights the role ofgenes in eczema

Research highlights

Figure: Atopic dermatitis is the most common
form of eczema that causes dry and itchy skincondition.
Copyright: Dr.Tamotsu Ebihara, Department of Dermatology, Keio University School of Medicine

E

czema – an itchy dry-skin condition – affects an estimated one in five children and one in 12 adults in the
UK. Genes play an important role in determining how likely
we are to develop eczema but the majority of the genes thatcause the condition have yet to be detected.
Now, in the largest genetic study of eczema in the world
to date, a group of international researchers including Drs.
Tomomitsu Hirota, Mayumi Tamari and Michiaki Kubo of
RIKEN Center for Integrative Medical Sciences (IMS) and
Dr. Lavinia Paternoster from the University of Bristol, has
combined data on 377,000 participants involved in 40 research studies worldwide.
The team used a technique called ‘genome-wide association analysis’ to look at the genomes of these 377,000 people
and to identify small changes (variants) in the genes commonly found in people with eczema. They found 10 new
variants, bringing the total number of variants known to berelated to eczema to 31.
What all these new genetic variants have in common isthat they all play a role in regulating our immune system,
highlighting potential new targets for therapeutic researchfor eczema.
The researchers also found some evidence of genetic
overlap between eczema and other diseases like inflammatory bowel disease. This suggests that studying these diseases
together in the future could give important insights into theThis article was edited from the University of Bristol
Press Release with permission
http://www.bristol.ac.uk/news/2015/october/eczema-genes.html

6mechanisms of disease and potentially identify new treatments.
Speaking about the discovery, Dr. Paternoster said:“Though the genetic variants identified in this current study
represent only a small proportion of the risk for developing
eczema (they are in no way deterministic, rather they slightly increase your risk), they do give new insights into important disease mechanisms and through on-going research inthis area these findings could be turned into treatments ofthe future.”
Dr. Sara Brown, an academic dermatologist who contributed to the research from the University of Dundee, said:“Eczema runs in families so we know that genetic factors are
an important part of the cause. The very large numbers ofparticipants in this research has allowed us to ‘fine-tune’ ourunderstanding of eczema genetic risk, providing more detailon how the skin immune system can go wrong in eczema.”

Original paper:
Paternoster L, Standl M, Waage J, Baurecht H, Hotze M,
Strachan DP, Curtin JA, Bønnelykke K, Tian C, Takahashi
A, et al. Multi-ancestry genome-wide association studyof 21,000 cases and 95,000 controls identifies new
risk loci for atopic dermatitis. Nature Genetics 47,
1449–56 (2015)

Controlling inflammation in
fat cells

Research highlights

A signaling mechanism that controls
inflammation in fat cells could offer a
way to prevent obesity-induced
diabetes Controlling inflammation in
fat cells
Figure: Administering interleukin-33 increased
the number of Treg cells in fat tissue in obese
mice, improving glucose tolerance.
© CamiloTorres/iStock/ThinkstockThe excess fat tissue associated with obesity causes inflammation and reduces glucose tolerance, which increases the risk of diabetes. The mechanism responsible forthese physiological effects, however, has been unclear. An
international team including researchers from the RIKEN
Center for Integrative Medical Sciences (IMS) has now identified a signaling pathway that is crucial for controlling obesity-associated inflammation, offering hope for a therapeutictarget to prevent glucose intolerance.
The researchers focused on immune cells called regulatory T (Treg) cells. These cells respond to inflammation andproliferate within inflamed tissue. “Whereas most T cells
are activated by a specific antigen and induce inflammation,
Treg cells suppress inflammatory responses,” explains Shigeo
Koyasu from the Laboratory for Immune Cell Systems at the
IMS.
Previous work by the Walter and Eliza Hall Institute(WEHI) of Medical Research in Australia showed that Treg
cells can be in either an activated state in which they suppress inflammation, or a resting state. In collaboration with
the WEHI, Koyasu and his RIKEN colleagues searched forgenetic differences between resting and activated Treg cells.
By analyzing gene expression in the two states, they discovered approximately 2,700 differences.
Interestingly, the researchers discovered that Treg cells in
fat tissue, known as visceral adipose tissue (VAT), expressed

This article was reproduced from RIKEN Research withpermission
http://www.riken.jp/en/research/rikenresearch/highlights/7988/

an exceptionally high level of a receptor called ST2 for thesignaling molecule interleukin-33 (IL-33). By geneticallymanipulating the expression of ST2 in mice, the researchers
showed that IL-33 signaling is crucial for the developmentof VAT-Treg cells. When applied to cultured cells and injected into mice, IL-33 was found to induce the proliferation of
VAT-Treg cells, increasing their population by over ten fold.
“Treg cells suppress inflammation, which improves glucose tolerance, so an increase in Treg cells is beneficial,” says
Koyasu. “A lack of IL-33 greatly reduced VAT-Treg numbers,
resulting in impaired glucose tolerance. Administration of
IL-33 restored glucose tolerance.”
Finally, the team administered IL-33 to mice that were
either genetically obese or obese owing to a high fat diet. In
both cases, IL-33 increased the number of VAT-Treg cells andimproved glucose tolerance. The findings have therapeuticpotential.
“Human Treg cells in fat tissue also express IL-33 receptors, so it is possible that IL-33 could increase Treg cells inhumans,” explains Koyasu. As a possible therapy, however,IL-33 comes with strings attached. “IL-33 also induces allergic inflammation, so it is critical to control the dose to avoid
an allergic response while maintaining the ability to control
VAT-Treg cells.”

Original paper:
Vasanthakumar, A., Moro, K., Xin, A., Liao, Y., Gloury, R.,
Kawamoto, S., Fagarasan, S., Mielke, L. A., Afshar-Sterle, S., Masters, S. L. et al. The transcriptional regulators
IRF4, BATF and IL-33 orchestrate development andmaintenance of adipose tissue-resident regulatory T
cells. Nature Immunology 16, 276–285 (2015)7

Genome-wide homozygosity
influences stature and cognition

Research highlights

Figure: Effects of genome-wide homozygosity
on 16 traitsAn international research project including researchers
from RIKEN Center for Integrative Medical Sciences(IMS), revealed that greater genetic diversity is linked to increased height and lung capacity, as well as to better cognitive skills and educational attainment.
Inbreeding within related populations increases thenumber of inherited identical copies of genes from bothparents. These genomic regions, where the copies inheritedfrom parents are identical, are called “runs of homozygosity(ROH)”, and are used as indicators that an individual’s ancestors were related.
To investigate the influence of genetic diversity, researchers from more than one hundred research institutions
worldwide launched an international project “Runs of Homozygosity Genetics (ROHgen) Consortium” in 2013. Using the medical records and genetic information of morethan 350,000 people, the Consortium members determined
if there was any correlation between genome-wide homozygosity and a variety of phenotypic traits, including bodymeasurement (height, body mass index, waist-hip ratio),
blood chemistry (blood glucose, HbA1c, insulin, cholesterol, triglycerides), physiological parameters (blood pressure
and lung function), cognitive functions and educational attainment.
The researchers found that a decrease in homozygosity tends to correlate with an increase height, lung capacity,

Original paper:Peter K. Joshi, Tonu Esko, Hannele Mattsson, Niina
Eklund, Ilaria Gandin, Teresa Nutile, Anne U. Jackson,
Claudia Schurmann, Albert V. Smith, Weihua Zhang,
Yukinori Okada, Alena Stančáková, Jessica D. Faul, Wei
Zhao, Traci M. Bartz, Maria Pina Concas, Nora Franceschini, Stefan Enroth, Veronique Vitart, Stella Trompet,
Xiuqing Guo, Daniel I. Chasman, Jeffery R. O'Connel,

8

and cognitive skills and to higher levels of educational attainment. However, the study found no link between genetic
diversity and high blood pressure or cholesterol levels. It had
been thought that close family ties would raise a person’s riskof complex diseases, but the researchers found this not to be
the case in general.
“The ROHgen consortium highlighted the power oflarge-scale genetic analyses to uncover the link between
genetic homozygosity and phenotypic traits,” says Yukinori
Okada of RIKEN IMS.
“Our research answers questions first posed by Darwin
as to the benefits of genetic diversity. Our next step will be tohone in on the specific parts of the genome that most benefit
from diversity,” commented Peter Joshi of The University of
Edinburgh.

Tanguy Corre, Suraj S. Nongmaithem, et al. Directional
dominance on stature and cognition in diverse humanpopulations. Nature 523, 459–62 (2015)

The genetic roots of adolescentscoliosis

Research highlights

Figure: The effect of BNC2 on zebrafish development

A

dolescent idiopathic scoliosis (AIS)—a condition featuring
curvature of the spine—affects tens of millions of children
worldwide, but does not have a known cause. Now, scientists at
the RIKEN Center for Integrative Medical Sciences in collaboration with Keio University in Japan have discovered a gene that is
linked to susceptibility to the condition. Published in the American Journal of Human Genetics, the work details how the susceptibility gene is associated with increased expression of the protein
BNC2, which is in turn regulated by another protein called YY1.
“AIS is a complex and mysterious disease with awkward spinal
deformities that can be a nightmare for affected people,” explainsteam leader Shiro Ikegawa. “We were excited to find a single nucleotide polymorphism located on human chromosome number
nine that is significantly associated with the disease.”
The discovery began with a genome-wide association study
using more than ten thousand volunteers with and without scoliosis. This type of study looks for small differences in genes—
called single nucleotide polymorphisms, or SNPs—that occur
more frequently in people with a certain disease. After confirming the association between a particular SNP (pronounced “snip”)
in two additional independent populations—one in Japan and
one in China—they determined that it is located near the part of
the DNA that codes for the protein BNC2.
The team then examined where BNC2 is expressed in humans. Using quantitative RT-PCR, they found that it is most highly expressed in the uterus, spinal cord, bone, and cartilage. “ThisThis article was reproduced from RIKEN Press Release
http://www.riken.jp/en/pr/press/2015/20150724_1/

result told us that we were on the right track,” says Ikegawa, “andevidence that the SNP variation associated with the disease led
to higher levels of BNC2 expression told us that this SNP has thepotential to regulate expression of BNC2.”
The team tested this hypothesis and found that not only was
BNC2 expression triggered by the protein YY1—which binds to
the DNA around the SNP—but that for genes with the at-risk SNPvariant, the amount of BNC2 produced when YY1 was present
was much greater than for genes with the non-risk variant.
The BNC2 gene is highly conserved across diverse species,
and plays roles in a variety of tissues. To test how over-expressionof BNC2 affects development, the team expressed it in zebrafish
embryos and found that it resulted in severe body curvature thatwas positively correlated to the amount of BNC2.
These results and the abundance of BNC2 in the human spineand bones make it likely that adolescents with the disease-associated SNP variant may begin to produce excess BNC2 at puberty ifother genetic or environmental factors are also present.
The next step is to understand how BNC2 causes scoliosis andwhy it is so much more prevalent in women than in men. “Theexpression of BNC2 in the uterus and changes that occur duringpuberty could help explain the large sex difference,” explains
Ikegawa. “Additionally, knowing what genes are downstream of
BNC2 will provide us with potential targets for therapeutic interventions.”

Original paper:
Yoji Ogura, Ikuyo Kou, Shigenori Miura, Atsushi Takahashi, Leilei Xu, Kazuki Takeda, Yohei Takahashi, Katsuki Kono, Noriaki Kawakami, Koki Uno, Manabu Ito,
Shohei Minami, Ikuho Yonezawa, Haruhisa Yanagida,
Hiroshi Taneichi, Zezhang Zhu, Taichi Tsuji, Teppei Suzuki, Hideki Sudo, Toshiaki Kotani, Kota Watanabe, Naobumi Hosogane, Eijiro Okada, Aritoshi Iida, Masahiro

Nakajima, Akihiro Sudo, Kazuhiro Chiba, Yuji Hiraki,
Yoshiaki Toyama, Yong Qiu, Chisa Shukunami, Yoichiro
Kamatani, Michiaki Kubo, Morio Matsumoto and Shiro
Ikegawa. A functional SNP in BNC2 is associated withadolescent idiopathic scoliosis. American Journal of
Human Genetics 97, 337–42 (2016)9

Blocking differentiation isenough to give cells “stemness”

Research highlights

Figure: Schematic representation of the method
for the production of Id3-induced hematopoietic
progenitor (IdHP) cells (lower) and photomicrograph of IdHP cells (upper)Though immune therapy and regenerative medicine arepromising areas of research for future medical therapies,
they are limited today by the difficulty of creating stem cells, andscientists around the world are searching for ways to create somatic stem cells in the easiest way possible. Now, a collaboration
between the RIKEN Center for Integrative Medical Science (IMS)
and other institutions in Japan and Europe have found that inimmune cells, simply blocking a transcription factor that leads
to differentiation is sufficient to keep cells in a multipotent stem
cell-like state where they can continue to proliferate and can later
differentiate into various cell types.
Efforts in the past to create stem cells have typically involved
finding ways to take target cells and “dedifferentiate” them into
multipotent cells, but this is typically a painstaking process.
According to Tomokatsu Ikawa, the first and corresponding
author of the paper published in Stem Cell Reports, “We decided to look at the possibility that somatic stem cells could bemaintained in a stem cell-like state where they could proliferate
without undergoing differentiation.” To test this, the team tookmouse hematopoetic progenitor cells—cells that give rise to allwhite blood cells—and modified them to overexpress a protein
called Id3. Id3 inhibits the expression of E-proteins, which are
involved in differentiation in somatic cells. They then placed thecells into culture conditions containing certain cytokines, and instead of differentiating into B-cells, the cells continued to divide
as stem cells. When placed in a culture that did not contain thoseThis article was reproduced from RIKEN Press Release
http://www.riken.jp/en/pr/press/2015/20151023_1/

10

cytokines, the cells differentiated into various immune cells. To
test whether the cells would maintain their multipotency in living animals, the researchers transplanted them into mice whose
white blood cells had been depleted, and showed that the newcells could expand and differentiate into various types of whiteblood cells.
To explore the potential for therapeutic application, the groupthen attempted a similar experiment using human blood stem
cells taken from umbilical cords, which they transfected with avector encoding human Id3. They found that, like the mouse cells,
these human cells could be maintained in a dividing state andthen prompted to differentiate by changing the conditions.
“With this work we have succeeded in showing,” says Ikawa,“that the cells can be kept in a state of undifferentiation where
they will proliferate extensively. This is both a useful tool for giving us a better understanding of the genetic and epigenetic program controlling the self-renewal of stem cells, and on a practicalside, it could allow us to inexpensively produce large numbers of
immune cells, which could then be used for regenerative medicine or immune therapy.”
The research was done by RIKEN in collaboration with Kyoto
University, Maastricht University Medical Centre in the Netherlands, Osaka University, and Nihon University School of
Medicine.

Original article:
Tomokatsu Ikawa, Kyoko Masuda, Mirelle J. A. J. Huijskens, Rumi Satoh, Kiyokazu Kakugawa, Yasutoshi
Agata, Tomohiro Miyai, Wilfred T. V. Germeraad,
Yoshimoto Katsura, and Hiroshi Kawamoto. Induced developmental arrest of early hematopoietic progenitors
leads to the generation of leukocyte stem cells. Stem
Cell Reports 5, 716–727 (2015)

Determination of the CD4cytotoxic T lymphocyte lineage+

Research highlights

Figure: CRTAM determines the CD4+ cytotoxic T
lymphocyte lineage
A. CD4+ CTL are generated from CRTAM-expressing
CD4+ T cells.
B. Full-length CRTAM- but not tail-less CRTAM-expressing T cells generate CD4+ CTL.
C. CRTAM+ but not CRTAM- CD4+ T cells exhibit cytotoxicity similar to CD8+ T cells (left). Upon influenza
virus infection, lung T cells from CRTAM-deficient
mice showed reduced influenza-specific killing of
infected target cells compared to normal mice(right).

Tcell precursors differentiate into CD4+ and CD8+ T cells
during their development in the thymus. The CD4+ T
cells then differentiate into various helper T cells that help
activation of B cells for antibody production, and the CD8+
T cells differentiate into cytotoxic T cells that kill cancer cells
and virus-infected cells.
However, there have been reports that some CD4+ T cells
could acquire cytotoxic ability and directly kill infected cells.
These CD4+ cytotoxic T cells were identified in the peripheral blood of human and mouse after chronic viral infections,
but little was known about how CD4+ T cells differentiate
into cytotoxic lymphocytes.
The research group led by Takashi Saito in RIKEN IMS
discovered that a protein called “class I-restricted T cell-associated molecule (CRTAM)” has an essential role in the
differentiation of CD4+ T cells to acquire cytotoxic abilities.
The research group previously reported in 2009 that
CRTAM regulates the immune response by CD8+ cytotoxic
T cells. Recently, they found that CRTAM is expressed not
only in CD8+ T cells but also in a small fraction of CD4+ T
cells, and they decided to study the function of CRTAM-expressing CD4+ T cells.
First, they isolated CRTAM-expressing CD4+ T cells(CRTAM+CD4+ T cells) and compared their gene expression
pattern with CD4+ T cells and CD8+ T cells. Although CD4+
T cells and CD8+ T cells had different gene expression pat-terns, they found that the CRTAM+CD4+ T cells share somecharacteristics of both CD4+ and CD8+ T cells.
Next, they analyzed cytotoxic functions of CRTAM+CD4+
T cells and found that they have cytotoxic activity in vitro
similar to CD8+ T cells, while the CRTAM–CD4+ T cells did
not exhibit cytotoxicity. More importantly, when mice were
infected with influenza virus, CRTAM+CD4+ T cells wereincreased in their lungs and exhibited influenza-specific cytotoxic activity. On the other hand, CRTAM-deficient mice
had much diminished cytotoxic activity compared to normal mice (Figure.)
To study the role of CRTAM in cytotoxic activity, theygenerated transgenic mice in which all T cells expressed CRTAM. In this mouse, all CD4+ T cells immediately expressed
CRTAM upon stimulation, and efficiently differentiated into
CD4+ cytotoxic T cells. However, when a truncated CRTAM
mutant lacking its cytoplasmic domain was expressed, CD4+
T cells did not develop cytotoxic functions.
“The results indicate that CRTAM-mediated signal iscritical for differentiation of CD4+ cytotoxic T cells and CRTAM is the first marker of CD4+ cytotoxic T cells. Regulation of CRTAM expression would be useful for therapeutic
aims, such as in chronic virus infection, antitumor responses
or inflammatory diseases,” says Takashi Saito of IMS.

Original paper:
Takeuchi A, Badr Mel S, Miyauchi K, Ishihara C, Onishi
R, Guo Z, Sasaki Y, Ike H, Takumi A, Tsuji NM, Murakami
Y, Katakai T, Kubo M, Saito T. CRTAM determines theCD4+ cytotoxic T lymphocyte lineage. Journal of Experimental Medicine 213, 123–38 (2016)11

In memory of
Dr. William Paul

Photo: Dr. William E. Paul at RCAI in 2005

I

t is very sad and a great loss to IMS that Dr. William E.
Paul passed away on September 18th, 2015. Dr. Paul wasa member of the Advisory Council of the Center for Integrative Medical Sciences (IMS, 2013–2015) and of the former Research Center for Allergy and Immunology (RCAI,
2004–2013). In his role as an advisory council member, hevisited the Center in Tsurumi, Yokohama almost every year.
Because of his expertise in the fields of cytokine biology and allergy, Dr. Paul was an invaluable supporter of theCenter's allergy-related research projects and researchers.
He was a textbook of knowledge of immunology and maintained a global view of the field, thus he was always able togive critical but encouraging comments and advice on any
research project. We learned from him the importance ofbasic science and the establishment of proof of concept intranslating basic research findings to humans. We always
had to consider how to tackle global cutting edge scienceand to compete with major laboratories throughout theworld with our limited resources. Following his advice, IMS
created strong central research facilities (Animal Facility,
FACS Lab, Imaging Lab and Genomics Lab) that gave IMS
laboratories access to state-of-the-art technologies and excellent experimental support. For our ENU (N-ethyl-N-nitrosourea) mutagenesis project, without his critical advice
on how to deal with the low mutation rate we would not havesucceeded in isolating the Spade mutant mouse, which has
an atopic dermatitis phenotype. We also learned from him
the importance of considering human immunology, eventhough most of our experiments were done with mice.

12

Dr. Paul was a wonderful advisor, not only to IMS researchers but also to many other Japanese immunologists.
The Japanese Society for Immunology was established in1970 and Japanese immunologists started to study abroad in
the 70’s. Many of those pioneering Japanese immunologists
visited Dr. Paul in his NIH laboratory at the National Institute of Allergy and Infectious Diseases because of his deep
knowledge of immunology and because he was very fairand open to anyone, even young inexperienced researchers.
Without his help, immunology would not have flourished inJapan like now. Dr. Paul was a very compassionate humanbeing. In 2011, we experienced the Great East Japan magnitude 9.0 earthquake. Dr. Paul was one of the advisory council members who immediately contacted Dr. Taniguchi, thenDirector of RCAI, and with their help, the Center launcheda systematic effort to provide research supplies, biologicalsamples, and mice to the affected laboratories, as well as support for graduate students and researchers to attend immunology meetings.
We will never forget what Dr. Paul taught us and his warm
words always with a smile. In his honor, IMS will move forward to pioneer a new era of human immunology researchin combination with human genetics and genomics.

Shigeo Koyasu
Director,
RIKEN Center for Integrative Medical Sciences

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 diseasemodels established by the Core for Precise Measuring and Modeling in a multitier timeframe 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 (S. Hori), 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
cell systems (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 andallergic diseases [4].

14

Laboratory for

Lab activities

Cell Signaling
Group Director: Takashi Saito

Figure: CRTAM determines the CD4+ CTL lineage[A] CD4+CTLs are generated from CRTAM-expressing
CD4+T cells[B] Full-length CRTAM (FL)- but not tail-less CRTAM(TL)-expressing T cells induce cytotoxic CD4+ CTL.

Recent Major Publications
Hashimoto-Tane A., Sakuma M., Ike H., Yokosuka T., Kimura Y., Ohara O. and Saito T. The Micro adhesion-ringsurrounding each TCR microclusters forms synapse-likestructure essential for T cell activation. J Exp Med 213,
1609–1625 (2016)
Takeuchi A, Badr MESG, Miyauchi K, Ishihara C, Onishi
R, Guo Z, Sasaki T, Ike H, Takumi A, Tsuji NM, Murakami
Y, Katakai T. and Saito T. CRTAM determines the CD4+
cytotoxic T lymphocyte lineage. J Exp Med 213,
123–138 (2016)
Hara H, Yokosuka T, Hirakawa H, Ishihara C, Yasukawa
S, Yamazaki M, Koseki H, Yoshida H and Saito T. Clustering of CARMA1 through SH3-GUK domain interactions is required for its activation of NF-κB signaling.
Nat Commun 6, 5555 (2015)

Invited Presentations
Saito T. “Development and function of CD4+CTL in
inflammation diseases” SICORP Japan-New Zealand
Joint Research on Functional Foods (Wellington, New
Zealand) February, 2016
Saito T. “Regulation of T cell activation at Immune synapse” Advanced Seminar Series on Microbiology and
Immunology (Osaka, Japan) November, 2015
Saito, T. “Microsynapse is an essential structure for T
cell activation” FASEB Science Research Conference (BigSky, USA) June, 2015
Saito, T. “Spatiotemporal regulation of T cell activation”
OIST Seminar (Okinawa, Japan) April, 2015T

he objective of our group is to determine the molecular mechanisms of T cell
activation, differentiation and homeostasis. Toward this goal, basic mechanisms such as antigen recognition, T cell activation, T cell differentiation, andfunctional regulation have been studied from a signaling perspective. Both processes of recognition and activation at the single cell level and T cell development/
homeostasis within clonal populations are being investigated.
After our finding of TCR-microclusters (MC), which initiate T cell activation,
we began to understand that formation of signal clusters in a single cell is a key
event for signal regulation. Thus, we analyzed clustering of CARMA1 for regulating NF-κB activation for T cell activation and tumorigenesis, and also the uniqueclustering of RasGRP1 for Ras activation formed by assembly with cytoskeletal
linker molecules. These analyses have provided a dynamic view of signal regulation within a single cell as well as new insights into how to modify the various
signaling pathways upon activation through TCR-MC.
In addition, we have analyzed several molecules, isolated as early expressed
genes upon T cell activation, as possible targets to modulate T cell activation andfunction. These are adhesion molecules, transcription factors, nucleic acid-sensors, and cytoskeletal molecules, all of which may regulate T cell-specific functions. CRTAM, which was cloned as an adhesion receptor, is now found to play a
critical role in development of CD4+ cytotoxic T cells (Figure).
The ultimate aim of our these approaches is to elucidate the onset of T cellfunction/activation and to be able to modulate it in order to inhibit/prevent immune diseases such as autoimmunity and allergic inflammation by developmentof effective modulators of T cell activation.

Saito, T. “Spacial regulation of T cell activation at Immune synapse” The Fourth Bizan Immunology Symposium at University of Tokushima (BISUT4) (Tokushima,
Japan) January, 201515

Laboratory for

Lab activities

Lymphocyte
Differentiation
Group Director: Tomohiro Kurosaki

Figure: An instructive model for how memory B
cells are selected and generated
Once light zone (LZ) GC cells with high-affinity BCRs
(shown in red) begin receiving ‘strong’ help from T
cells, the level of the transcription factor Bach2 goes
down, thereby facilitating their differentiation towardplasmablasts (lower). In contrast, selection of LZ GC
cells into the memory cells with low-affinity BCRs
(shown in black) requires a specific range of T cell
help of a weaker magnitude than that needed forplasmablast differentiation. The relatively weak help
from T cells keeps Bach2 expression relatively high, astate advantageous for entry into the memory B cellcompartment (upper).

Recent Major Publications
Shinnakasu R, Inoue T, Kometani K, Moriyama S, Adachi
Y, Nakayama M, Takahashi Y, Fukuyama H, Okada T,
Kurosaki T. Regulated selection of germinal-center cells
into the memory B cell compartment. Nat Immunol
17, 861–869 (2016)
Inoue T, Morita M, Hijikata A, Fukuda-Yuzawa Y, Adachi
S, Isono K, Ikawa T, Kawamoto H, Koseki H, Natsume
T, Fukao T, Ohara O, Yamamoto T, Kurosaki T. CNOT3
contributes to early B cell development by controlling
Igh rearrangement and p53 mRNA stability. J Exp Med
212, 1465–1479 (2015)
Kometani K, Kurosaki T. Differentiation and maintenance of long-lived plasma cells. Curr Opin Immunol
33, 64–69 (2015)

Invited Presentations
Kurosaki T. “Instructive selection of germinal center B
cells into the memory compartment” The 3rd Symposium of International Immunological Memory and Vaccine Forum (IIMVF) “What´s Immunological Memory?”(Berlin, Germany) October, 2015
Kurosaki T. “Selection of germinal centre B cells intomemory compartment” International Symposium on B
cells: Immunity and Autoimmunity (Erlangen, Germany)
October, 2015
Kurosaki T. “Regulatory functions of B lineage cells”
Institute of Molecular Medicine University Hospital Düsseldorf (Düsseldorf, Germany) September, 2015
Kurosaki T. “Calcium Signaling in B lymphocytes” FASEB
Signal Transduction in the Immune System (Big Sky,USA) June, 201516

H

umoral memory relies on the development of memory B cells and long-lived
plasma cells. Our lab has been focusing on characterizing of these two typesof cells and on clarifying how these cells are generated, maintained, and activated.
Most memory B cells responding to T cell-dependent antigens arise from the germinal center (GC) reaction. However, how such memory B cells are selected anddeveloped during GC reactions remains unclear. By employing GC-specific fatemapping mice, we found that light-zone (LZ) GC B cells with BCRs of lower affinity were prone to enter the memory pool. Mechanistically, cells in this memory-prone fraction had higher expression of the transcriptional repressor Bach2
than in the cells bearing higher affinity BCRs. The importance of high Bach2 wasunderscored by the fact that Bach2 haploinsufficiency resulted in suppression ofmemory B cell generation. Given our evidence that Bach2 expression was inversely correlated with the strength of T cell help, we propose an instructive model inwhich weak help from T cells maintains relatively high expression of Bach2, which
predisposes GC cells to enter the memory pool (Figure).
After secondary exposure to antigens, memory B cells rapidly generate high-affinity antigen-specific antibodies (Abs), mostly of the IgG isotypes in the case of
systemic immune responses. It has been thought that the unique cytoplasmic domain of IgG causes the prompt activation of antigen-experienced IgG memory B
cells. By establishing a mouse containing IgG1 B cells that have never encounteredantigen, we show that antigen-experienced IgG1 memory B cells rapidly differentiated into plasma cells, whereas non-experienced IgG1 B cell did not, suggesting
the importance of the stimulation history, rather than the IgG cytoplasmic domain. Moreover, in addition to the differentiation activity of IgG1 memory B cells,
their antigen presentation activity is critical for rapid activation of the TFH memory T cells residing in the follicular region, which, in turn, contributes to activationof the memory B cells.

Laboratory for

Lab activities

Transcriptional
Regulation
Group Director: Ichiro Taniuchi

Figure: Role of Cbfβ2 in regulation of thymic
homing activity via activation of an enhancer in
the Ccr9 gene+
Migration of Ikaros hematopoietic cells into fetal thymus was decreased in Cbfβ2-deficient mice (A) due to++impaired induction of CCR9 in IL7R PIR fetal liver cells(B). ChIP-Seq detected binding of Runx/Cbfβ complexes
to -13 and -10kb upstream regions in the Ccr9 gene (C).
Runx-site dependent enhancer activity was detected inreporter transfection assay.

Recent Major Publications
Hao B, Naik AK, Watanabe A, Tanaka H, Chen L, Kondo M, Taniuchi I, Kohwi Y, Kohwi-Shigematus T andKrangel MS. An anti-silencer- and SATB1-dependent
chromatin hub regulates Rag1 and Rag2 gene expression during thymocyte development. J Exp Med 212,
809–24 (2015)
Mishima Y, Wang C, Miyagi S, Saraya A, Hosokawa H,
Mochizuki-Kashio M, Nakajima-Takagi Y, Koide S, Negishi M, Sashida G, Naito T, Ishikura T, Onodera A, Nakayama T, Tenen D.G, Yamaguchi N, Koseki H, Taniuchi
I, Iwama A. Histone acetylation mediated by Brd1 is
crucial for Cd8 gene activation during early thymocyte
development. Nat Commun 5, 5872 (2014)
Tanaka H, Naito T, Muroi S, Seo W, Chihara R, Miyamoto
C, Kominami R and Taniuchi I. Epigenetic Thpok silencing limits the time window to choose CD4+ helper-lineage fate in the thymus. EMBO J 32, 1183–94 (2013)

Invited Presentations
Taniuchi I. “Molecular mechanisms that control thymocyte differentiation” Seminar at Mie University (Tsu,JAPAN) October, 2015
Taniuchi I. “Repression of CCL5 by Runx/Cbfb is essential to prevent lung infiltration” RUNX 2015 (Rehovot,
Israel) October, 2015
Taniuchi I. “Roles of Bcl11b and SATB1 during thymocyte differentiation” Venice Thymus Meeting (Venice,
Italy) April, 2015
Taniuchi I. “Transcriptional Regulation of T Cell Development in the Thymus” Keystone Symposium “T Cells:
Regulation and Effector Function” (Utah, USA) March,
2015
Taniuchi I. “Transcriptional Regulation of T Cell Development in the Thymus” Functional Genomics and Experimental Medicine (Sendai, JAPAN) February, 2015

O

ne of the major questions in developmental biology is how environmental cues aresensed and integrated into developmental programs encoded by the genome. My
laboratory has been addressing how shaping of the primary T lymphocyte pool in thethymus upon receiving T-cell receptor (TCR) signals is regulated at the layer of gene regulation. For this purpose, we have mainly been studying mechanisms that control helper
versus cytotoxic lineage dichotomy as a model. Our previous findings showed that antagonistic interplay between two transcription factors, ThPOK and Runx3, serves as a key
regulation point to dissect these two lineages. To further understand how expression of
the Zbtb7b gene (hereafter referred to as the Thpok gene) encoding ThPOK is controlled,
we first isolated both transcriptional enhancer and silencer in the Thpok locus, and are
examining how these two regulatory elements with opposite function operate to control
helper-lineage specific ThPOK expression under TCR signals. To this aim, we are testing
the positional effect of regulatory elements on Thpok expression and are characterizing
the function of their trans-acting factors, Bcl11b and Satb1. Our current results suggestthat coupling of TCR signaling with mechanisms that activate regulatory regions in thegenes encoding lineage-specification factors requires prior priming by Bcl11b, which isfollowed by Satb1-dependent activation.
Our second objective is to unravel functions of Runx transcriptional factor complexes, which consist of a Runx protein and non-DNA binding Cbfβ protein. Runx complexes
act as both transcriptional activators and repressors in a context-dependent manner, andplay multiple important roles to control differentiation of many types of hematopoietic
cells. Our goal is to reveal regulatory mechanisms that modulate the function of Runx
complexes, as well as to provide insights into how Runx complexes regulate immune
system development and immune responses. We are addressing these questions mainly
by analyzing a series of mutant mouse strains harboring specific mutations in the Runx
family genes and by identification and characterization of Runx interacting molecules,
including functional RNA.

17

Laboratory for

Lab activities

Immune Cell Systems
Group Director : Shigeo Koyasu

Figure: IL-27 suppresses lung inflammation
triggered by Alternaria alternata.
Alternaria alternata induces IL-33 production by damaged epithelial cells. IL-33 activates lung NH cells andinduces production of IL-5 and IL-13, which cause
eosinophilia and goblet cell hyperplasia with mucin
production, respectively, and allergic inflammation in
the lung. IL-27 is known to be produced by dendritic
cells (DC) and acts on NH cells to suppress their proliferation and cytokine production.

Recent Major Publications
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 group 2 innate lymphoid cell function and type 2 innate immune responses. Nat Immunol 17, 76–86 (2016)
Morita H, Arae K, Unno H, Miyauchi K, Toyama S,
Nambu A, Oboki K, Ohno T, Moromura K, Matsuda A,
Yamaguchi S, Narushima S, Kajiwara N, Iikura M, Suto
H, McKenzie AN, Takahashi T, Karasuyama H, Okumura
K, Azuma M, Moro K, Akdis C, Galli SJ, Koyasu S, Kubo
M, Sudo K, Saito H, Matsumoto K, Nakae S. An interleukin-33-mast cell-interleukin 2 axis suppresses papain-induced allergic airway inflammation by promoting
the expansion of regulatory T cell numbers. Immunity
43, 175–186 (2015)
Moro K, Ealey KN, Kabata H, Koyasu S. Methods for
isolation and analysis of group 2 innate lymphoid cells
in mice. Nat Protoc 10, 792–806 (2015)

Invited Presentations
Koyasu S. “Innate lymphoid cells in allergic inflammation” The 24th World Allergy Congress (Seoul, Korea)
October, 2015
Koyasu S. “Regulation of activities of group 2 ILCs
(ILC2s) in allergic inflammation” The 6th FIMSA Congress (Singapore, Singapore) July, 2015
Koyasu S. “Group 2 innate lymphoid cells and allergic
inflammation” Tsinghua Symposium on Immunity and
Infection (Beijing, China) May, 2015
Koyasu S. “Group 2 innate lymphoid cells and Th2-typeinnate immunity” The 9th World Immune Regulation
Meeting (Davos, Switzerland) March, 201518

W

e have been working on the role of the natural helper (NH) cell, one of thegroup 2 innate lymphoid cells (ILC2). We have already shown that NH
cells are involved in anti-helminth innate immune responses and in the innate
phase of allergic inflammation, such as in protease-induced lung inflammation.
Because NH cells are lymphocytes and have a long lifespan in the body, it was important to understand how NH cell-mediated responses are terminated. We employed a fungal infection model to determine the mechanisms used to terminate
NH cell functions. Alternaria alternata is a fungus that causes allergic asthma-like
symptoms in humans. It has been shown that Alternaria extract strongly induces
IL-33 in airways and triggers lung inflammation. As a result, both NH cells andTh2 cells are activated and induce type 2 immune responses with eosinophilia andmucin production in the airways. We examined the activity of various cytokines
on NH cells and found that IL-27 strongly suppressed NH cell proliferation andcytokine production in a Stat1-dependent manner. In vivo administration of IL27 was able to suppress the induction of NH cells in the lung. Interestingly, IL-27
showed stronger activity on NH cells than on Th2 cells, partly because NH cells
express the IL-27 receptor, composed of WSX-1 and gp130, at higher levels thanTh2 cells. We thus conclude that IL-27 produced by dendritic cells acts on NH
cells as an important suppressive mechanism for downregulating NH cell functions and contributing to the termination of innate type 2 responses.

Laboratory for

Lab activities

Human Disease Models
Group Director & Chief Scientist: Fumihiko Ishikawa

Figure: Modeling immune-therapy with NSG
humanized mice.

Recent Major Publications
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 )Saito Y, Yuki H, Kuratani M, Hashizume Y, Takagi S,
Honma T, Tanaka A, Shirouzu M, Mikuni J, Handa N,
Ogahara I, Sone A, Najima Y, Tomabechi Y, Wakiyama
M, Uchida N, Tomizawa-Murasawa M, Kaneko A,
Tanaka S, Suzuki N, Kajita H, Aoki Y, Ohara O, Shultz LD,
Fukami T, Gogo T, Taniguchi S, Yokoyama S, Ishikawa F.
A pyrrolo-pyrimidine derivative targets human primary
AML stem cells in vivo. Sci Transl Med 5, 181ra52(2013)

Invited Presentations
Ishikawa F. “Dissecting leukemia initiation and creating therapeutic strategies in FLT3-ITD+ human acute
myeloid leukemia” Tenth AACR-JCA Joint Conferenceon Breakthroughs in Cancer Research: From Biology to
Therapeutics (Maui, Hawaii) February, 2016
Ishikawa F. “Exploring complexity and heterogeneity ofhuman acute myeloid leukemia using humanized mice”
5th International Workshop on Humanized Mice (Zurich,
Switzerland) January, 2016
Ishikawa F. “Exploring complexity and heterogeneity of human hematopoiesis in vivo” Deutsches
Krebsforschungzentru(dkfz) seminar (Heidelberg, Germany) November, 2015
Ishikawa F. “Understanding in vivo kinetics of humanhematopoietic stem/progenitor cells” The 3rd Symposium of International Immunological memory and Vaccine Forum (IIMVF) (Berlin, Germany) October, 2015
Ishikawa F. “Developing Therapeutic Strategies Targeting Poor Prognosis Acute Myeloid Leukemia” ISEH 44th
Annual Scientific Meeting (Kyoto, Japan) September,
2015

W

e have developed a humanized mouse model by intravenously injecting
human hematopoietic stem cells (HSCs) into immune-compromised
NOD/SCID/Il2rgKO (NSG) newborns. The humanized mouse model has allowed
us to investigate how human myeloid and lymphoid cells differentiate from HSCs
in multiple organs. One of the limitations of the humanized mouse could be thespecies barrier between human hematopoietic cells and the mouse environment.
To address this issue, we have created an NSG mouse strain expressing humanenvironmental factors and are assessing to what extent humanized mice can recapitulate physiological human hematopoietic and immune systems.
We have also been studying the pathogenesis of acute myeloid leukemia(AML). By understanding malignant hematopoiesis in this disease entity, we further aim to identify the leukemic cells that are resistant to therapy and are responsible for AML relapse. Our long-term goal is to create novel therapeutic strategies
targeting the therapy-resistant leukemic cells and to achieve long-term survival of
leukemia patients. The NOD/SCID/IL2rgKO mouse transplantation model of human primary AML has enabled us to conduct the following: 1. Prospective isolation of AML initiating stem cells 2. Characterization of genes and gene mutationsin leukemogenesis, and 3. Evaluation of novel anti-leukemia agents by developing
a sensitive in vivo bioassay.
Through integrative analyses of normal and diseased human hematopoiesis
and immunity, we continue our best efforts to help patients in the future.

Ishikawa F. “Chemotherapy-resistance of human acute
myeloid leukemia” 2015 US-Japan Meeting on Malignant Hematopoiesis and Stem Cells (Hawaii, USA)
March, 2015

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Laboratory for

Lab activities

Intestinal Ecosystem
Group Director: Hiroshi Ohno

Figure: Effect of Bifidobacterium longum BB536
on the metabolism of the human gut-derived
microbiota in gnotobiotic mice.
Orally administered B. longum BB536 increases the
fecal level of butyrate by increasing the proportion of
butyrate-producing Eubacterium rectale. By contrast, thenumber of biotin-producing Bacteroides caccae is notaffected, but instead the genes involved in biotin synthesis are upregulated in the bacterium in the presenceof BB536, resulting in the increase of biotin in the feces.

Recent Major Publications
Watanabe T, Kawakami E, Shoemaker JE, Lopes TJ,
Hashimoto M, Bhuyan F, Hiyoshi M, Noyori O, Nasseer
H, Miyazaki M, Saito T, Kondo Y, Osada H, Kimura S,
Hase K, Ohno H, Suzu S. Potential role of the formationof tunneling nanotubes in HIV-1 spread in macrophages. J Immunol 196, 1832–1841 (2016)
Sugahara H, Odamaki T, Fukuda S, Kato T, Xiao JZ, Abe
F, Kikuchi J, Ohno H. Probiotic Bifidobacterium longum
alters gut luminal metabolism through modification of
the gut microbial community. Sci Rep 5, 13548 (2015)
Matsumura T, Sugawara Y, Yutani M, Amatsu S, Yagita
H, Kohda T, Fukuoka S-I, Nakamura Y, Fukuda S, Hase
K, Ohno, H., Fujinaga, Y. Botulinum toxin A complex
exploits intestinalM cells to enter the host and exert
neurotoxicity. Nat Commun 6, 6255 (2015)

Invited Presentations
Ohno H. “Colonic Treg induction by butyrate produced
by gut microbiota” 14th Transplantation Science Symposium (Lorne, Australia) November, 2015
Ohno H. “Integrated Omics Approach for Understanding
the Gut Ecosystem” International Scientific Conference
on Probiotics and Prebiotics 2015 (Budapest, Hungary)June, 2015
Ohno H. “Structure and function of M-Sec-mediatedtunneling nanotube” EMBO Workshop “Cellular synapsis for cell-cell signalling” (Madrid, Spain) May, 2015
Ohno H. “Gut microbiome in the host defense and gut
immune regulation” 6th Congress of the Korean Societyof Surgical Metabolism and Nutrition & 2015 International Symposium (Seoul, Korea) March, 2015
Ohno H. “Gut microbiome in the host defense and gut
immune regulation” The Microbiome Forum: Asia (Kuala Lumpur, Malaysia) January, 201520

G

ut microbiota significantly impact physiology and pathology of the host;nevertheless, the gut does not unconditionally accept commensal microorganisms. Our intestinal immune system somehow senses the type and quantity ofbacteria existing in the gut lumen and tries to contain them. The aim of this laboratory is to understand the mechanisms by which the host and its gut commensal
microbiota interact, especially focusing on how gut microbes are delivered acrossthe intestinal epithelial barrier to be recognized by the intestinal immune system,
how gut microbiota shape host defense and immune systems, and how host-gut
microbiota interactions affect host health and disease status.
The delivery of particulate antigens such as bacteria is thought to be mainly
achieved by a unique subset of epithelial cells, M cells, residing in a limited regionof the epithelial layer called the follicle-associated epithelium (FAE), which covers
the lymphoid follicles of gut-associated lymphoid tissue (GALT) such as Peyer’s
patches (PP). We are studying the function and differentiation of M cells at themolecular level. Identified M cell-specific bacterial uptake receptors could serve
as a vaccine delivery target, and we have also been studying this possibility.
Regarding the host-gut microbiota interactions, we are employing a comprehensive multiple omics approach, combining exhaustive (meta) genomic, (meta)transcriptomic, and metabolomic analyses. This approach is applied to understand the molecular basis for regulation of the host by gut microbiota in mice, as
well as the impact of gut microbiota on human diseases such as infantile allergic
diseases and type 2 diabetes.

Laboratory for

Lab activities

Mucosal Immunity
Team Leader: Sidonia Fagarasan

Figure: System immunology.
An image scheme portraying the superorganism andpresenting a few questions relevant to achieving a
global understanding of the physiology of the superorganism. We aim at understanding the role of the immune system in symbiosis, by asking how the immune
cells modify the microbiota structure and function. We
further wish to elucidate how the microbiota feedback
to the system, by asking how molecules or signaling
pathways originating from the microbiota modulate
the development and function of the immune systemand the implications for the homeostasis of other major
physiological systems of the body.

Recent Major Publications
Kumar R, Bach MP, Mainoldi F, Maruya M, Kishigami
S, Jumaa H, Wakayama T, Kanagawa O, Fagarasan S,
Casola S. Antibody repertoire diversification through VH
gene replacement in mice cloned from an IgA plasma
cell. Proc Natl Acad Sci U S A 112, E450–457 (2015)
Kawamoto S, Maruya M, Kato LM, Suda W, Atarashi K,
Doi Y, Tsutsui Y, Qin H, Honda K, Okada T, Hattori M,
Fagarasan S. Foxp3(+) T cells regulate immunoglobulin
a selection and facilitate diversification of bacterial species responsible for immune homeostasis. Immunity
41, 152–165 (2014)
Magri G, Miyajima M, Bascones S, Mortha A, Puga I,
Cassis L, Barra CM, Comerma L, Chudnovskiy A, Gentile M, Llige D, Cols M, Serrano S, Aróstegui JI, Juan
M, Yagüe J, Merad M, Fagarasan S, Cerutti A. Innate
lymphoid cells integrate stromal and immunologicalsignals to enhance antibody production by splenic marginal zone B cells. Nat Immunol 15, 354–364 (2014)

Invited Presentations
Fagarasan S. “On germinal centers, IgA synthesis andthe intestinal ecosystem” Keystone T Follicular Helper
Cells and Germinal Centers (Monterey, USA) March,
2016
Fagarasan S. “ How adaptive immune system contributes to maintenance of diversified and balanced microbiota in the gut”, Keynote Lecture, The 17th International
Congress of Mucosal Immunology (Berlin, Germany)
July, 2015
Fagarasan S. “Symbiotic regulatory loop between
Foxp3+ T cells, IgA and microbiota in the gut” Microbe-host mutualism in the shaping of host immunitythe109th International Titisee Conference (Titisee,
Germany), April, 2014
Fagarasan S. “TFR/TFH cells in mucosal immunity”
Gordon Research Conferences: T follicular Helper Cells(Hong-Kong, China) July, 2013

D

ysfunction of normal homeostasis leads to diseases, whose pathogenesis
includes genetic and environmental factors. For example, epidemiologicalstudies suggested that adult disease risk is associated with adverse environmental
conditions early in development (nutrition, chemicals, stress caused by maternal
separation, etc.) that cause epigenetic changes persisting throughout life. We aim
at understanding the role of the “internal environment”, represented by commensal bacteria inhabiting mucosal surfaces, for host health and disease through thelens of the immune system. Although the individual’s primary microbiota may reflect maternal hand-over during or immediately after birth, the subsequent shaping of the microbial landscape is driven by complex interactions with the hostimmune system. Indeed, central to our research is the concept that the emergenceof the adaptive immune system with its diversified antigen-recognition receptors
contributes to the establishment of advanced symbiotic relationships with the gut
microbiota.
We are interested in exploring the bidirectional flux of information between
the host immune system and bacterial communities contributing to the establishment of symbiotic and beneficial relationships, as a basis to understand thecauses of breakdown in this cooperation that lead to diseases. Our objectives are:1) to understand the factors that forge the establishment and stability in the function of the microbiota of host organisms, focusing on the question of how theadaptive immune system mediates this complex host-bacterial mutualism; 2) tointegrate the immune-bacteria crosstalk in the context of whole body physiology.
In our quest to decipher the basic principles of symbiosis and systems immunology we employ approaches that combine genetic and immunologic methods withmetagenomic, mass spectrometry-based proteomic and metabolomic approaches,
together with extensive phenotypic and functional studies in vivo.

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Laboratory for

Lab activities

Gut Homeostasis
Team Leader: Kenya Honda

Figure: Th17 cell induction by adhesion of
microbes to intestinal epithelial cells.
Scanning electron micrograph showing the small
intestine of germ-free mice colonized with segmented
filamentous bacteria (SFB) (magnification ~2,500x).
SFB elicit a strong T helper 17 (Th17) response, which
contributes to enhancement of mucosal barrier function
and has been implicated in several immune disorders.
Adhesion of SFB to intestinal epithelial cells (ECs) is oneof the critical cues for Th17 induction. Photo taken by
Seiko Narushima and Kiminori Toyooka.

Recent Major Publications
Atarashi K, Tanoue T, Ando M, Kamada N, Nagano Y,
Narushima S, Suda W, Imaoka A, Setoyama H, Nagamori T, Ishikawa E, Shima T, Hara T, Kado S, Jinnohara
T, Ohno H, Kondo T, Toyooka K, Watanabe E, Yokoyama
S, Tokoro S, Mori H, Noguchi Y, Morita H, Ivanov II,
Sugiyama T, Nuñez G, Camp JG, Hattori M, Umesaki Y,
Honda K. Th17 Cell Induction by Adhesion of Microbes
to Intestinal Epithelial Cells. Cell 163, 367–380 (2015)
Narushima S, Sugiura Y, Oshima K, Atarashi K, Hattori
M, Suematsu M, Honda K. Characterization of the 17
strains of regulatory T cell-inducing human-derived
Clostridia. Gut Microbes 5, 333–339 (2014)
Atarashi K, Tanoue T, Oshima K, Suda W, Nagano Y,
Nishikawa H, Fukuda S, Saito T, Narushima S, Hase K,
Kim S, Fritz JV, Wilmes P, Ueha S, Matsushima K, Ohno
H, Olle B, Sakaguchi S, Taniguchi T, Morita H, Hattori M,
Honda K. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota.
Nature 500, 232–236 (2013)

Invited Presentations
Honda K. “Th17 cell induction by adhesion of microbes
to intestinal epithelial cells” Cold Spring Harbor Laboratory Meeting on Fundamental Immunology & its Therapeutic Potential (Cold Spring Harbor, USA) April, 2015
Honda K. “Regulation of T Cells by the Gut Microbiota”
Keystone Symposia, Gut Microbiota Modulation of Host
Physiology: The Search for Mechanism (Keystone, USA)
March, 2015
Honda K. “Regulation of Th17 and Treg cells by the gut
microbiota” The 109th International Titisee Conference,
Microbiome-host mutualism in the shaping of hostimmunity (Titisee, Germany) April, 2014
Honda K. “Regulation of Th17 and Treg cells by thegut microbiota” International Congress of Immunology(Milan, Italy) Aug, 2013
Honda K. “Clostridia strains from human microbiota for
Treg induction” Cell Symposia Microbiome and Host
Health (Lisbon, Portugal) May, 201322

O

ur team has been aiming to identify members of the gut microbiota thathave a deep impact on the immune system. We have succeeded in isolationof 17 human gut-associated commensal bacterial strains belonging to the class
Clostridia that can potently trigger accumulation of colonic CD4+Foxp3+ regulatory T (Treg) cells. The collected genomes of the 17 Treg-inducing strains ofClostridia contain abundant genes predicted to be involved in the biosynthesis ofshort-chain fatty acids (SCFAs), and our results suggest that SCFAs contribute to
the induction of Treg cell accumulation. The induced Treg cells expressed RORγt
and IL-10 and had strong suppressive activity for effector T cells, and introducing
the 17 Clostridia strains reduced GVHD severity.
We have also focused on Th17 cells, which are known to accumulate in response to colonization with a subgroup of intestinal microbes such as segmented filamentous bacteria (SFB). SFB indigenous to mice and rats are geneticallydistinct host-specific members of the gut microbiota. Upon monocolonization ofgerm-free (GF) mice or rats, mouse SFB and rat SFB expanded in the gut lumen irrespective of species, but bound to SI epithelial cells (ECs) and induced Th17 cells
strictly in a host-specific manner. The physical interaction of SFB with the gut epithelium is thus likely to be essential for Th17 cell differentiation. The causality of
the relationship between epithelial adhesion and induction of Th17 cells is further
supported by the analysis of Th17 cell induction by the intestinal pathogens, Citrobacter rodentium and Escherichia coli O157:H7. Upon monocolonization of mice,these pathogens triggered Th17 responses, but adhesion-defective mutants failed
to do so. Moreover, a mixture of 20 bacterial strains isolated from fecal samples ofa patient with ulcerative colitis on the basis of their ability to robustly induce Th17
cells in the mouse colon also exhibited EC-adhesive characteristics.

Laboratory for

Lab activities

Immune Homeostasis
Team Leader: Shohei Hori

Figure: A model of regulatory T cell fate determination and maintenanceDuring Treg cell differentiation, uncommitted precursor
cells adopt either Treg cell or conventional T (Tconv)
cell fates. The commitment to the Treg cell fate is madebefore (and thus independently of) Foxp3 expression
and executed by a transcription factor network elicitedby extrinsic signals from the extracellular environment.
The same signals also induce epigenetic changes,
including DNA demethylation of the Foxp3 locus. Foxp3
is incorporated into the pre-existing transcription
factor network and the resulting “Foxp3 interactome”
establishes the characteristic Treg cell phenotype andfunction in cooperation with the epigenetic modifications. Although Treg cells may down-regulate Foxp3
expression under certain circumstances, these “latent”
Treg cells retain the epigenetic memory of, and thus
remain committed to, the Treg cell fate. On the other
hand, when expressed in activated T cells without
engagement of the epigenetic changes and the Foxp3
interactome, Foxp3 by itself cannot establish the characteristic Treg cell phenotype.

Recent Major Publications
Hori S. Lineage stability and phenotypic plasticity of
Foxp3+ regulatory T cells. Immunol Rev 259, 159–172(2014)
Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G,
Takahashi D, Nakanishi Y, Uetake C, Kato K, Kato T,
Takahashi M, Fukuda NN, Murakami S, Miyauchi E,
Hino S, Atarashi K, Onawa S, Fujimura Y, Lockett T,
Clarke JM, Topping DL, Tomita M, Hori S, Ohara O,
Morita T, Koseki H, Kikuchi J, Honda K, Hase K and
Ohno H. Commensal microbe-derived butyrate induces
the differentiation of colonic regulatory T cells. Nature
504, 446–450 (2013)
Toker A, Engelbert D, Garg G, Polansky JK, Floess S,
Miyao T, Baron U, Duber S, Geffers R, Giehr P, Schallenberg S, Kretschmer K, Olek S, Walter J, Weiss S, Hori S,
Hamann A and Huehn J. Active demethylation of theFoxp3 locus leads to the generation of stable regulatory
T cells within the thymus. J Immunol 190, 3180–3188(2013)

Invited Presentations
Hori S. “Foxp3-dependent control of Treg cell function
and homeostasis in tissues.” 44th Japanese Society for
Immunology (Sapporo, Japan) November, 2015
Hori S. “Foxp3-dependent control of regulatory T cellfunction and homeostasis.” Academy of Immunology
and Microbiology seminar series (Pohang, Korea)
March, 2015
Hori S. “Genetic control of regulatory T cell fitness intissues” 7th International Leukocyte Signal Transduction
Conference (Kos, Greece) September, 2013

R

egulatory T (Treg) cells expressing the transcription factor Foxp3 play an indispensable role in the establishment and maintenance of immunological self-tolerance
and tissue homeostasis, a concept well illustrated by the finding that defective generation or function of Treg cells underlies the development of a fatal autoimmune diseasein Foxp3-mutant mice and in humans suffering from the IPEX syndrome. Findings that
Foxp3+ Treg cells exert tissue-protective or immune-suppressive functions under diverse
circumstances have raised the question of what mechanisms ensure the robustness ofTreg cell functions, and thus of immunological self-tolerance, in the face of unpredictable
perturbations in the extracellular environment. To answer this question, we have focusedon the mechanisms that control lineage stability and adaptability of Treg cells in changing environments.
We have previously shown that Foxp3 expression alone does not specify the Treg celllineage in that activated conventional T cells can promiscuously and transiently express
Foxp3 while committed Treg cells can transiently and reversibly down-regulate Foxp3.
Despite this phenotypic plasticity, Treg cells retain epigenetic memory of, and thus remain committed to, Foxp3 expression and regulatory functions. We are now addressing
the mechanisms underlying this epigenetic memory of Treg cell phenotype and function.
Another focus of our research is to understand how Foxp3 and Treg cells control immunological self-tolerance and tissue homeostasis in changing environments. To address
this question, we have addressed how Foxp3 gene mutations found in human IPEX impinge on Treg cells in vivo using knock-in mutagenesis in mice. Our analysis revealed
that, while many mutations are amorphic or hypomorphic, one particular mutation acts
as a gain-of-function mutation that alters DNA binding specificity of Foxp3 and preferentially impairs the ability of Treg cells to adapt to certain non-lymphoid tissue environments. By taking advantage of this unique animal model, we are currently investigating
how Treg cells adapt to diverse and fluctuating tissue environments.

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Laboratory for

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Skin Homeostasis
Team Leader: Masayuki Amagai

Figure: Comprehensive analyses 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.

Recent Major Publications
Kobayashi T, Glatz M, Horiuchi K, Kawasaki H, Akiyama
H, Kaplan DH, Kong HH, Amagai M, Nagao K: Dysbiosis
and Staphyloccus aureus Colonization Drives Inflammation in Atopic Dermatitis. Immunity 42, 756–766(2015)
Yoshida K, Kubo A, Fujita H, Yokouchi M, Ishii K, Kawasaki H, Nomura T, Shimizu H, Kouyama K, Ebihara
T, Nagao K, Amagai M: Distinct behavior of human
Langerhans cells and inflammatory dendritic epidermal
cells at tight junctions in atopic dermatitis. J Allergy
Clin Immunol 134, 856–864 (2014)
Sasaki T, Shiohama A, Kubo A, Kawasaki H, Ishida-Yamamoto A, Yamada T, Hachiya T, Shimizu A,
Okano H, Kudoh J, Amagai M: A homozygous nonsense
mutation in the gene for Tmem79, a component for thelamellar granule secretory system, produces spontaneous eczema in an experimental model of atopic dermatitis. J Allergy Clin Immunol 132, 1111–1120 (2013)

Invited Presentations
Amagai M. “Skin barrier homeostasis by stratum
corneum and tight junction” Keystone Symposia Conference: Immunity in Skin Development, Homeostasis andDisease (Tahoe, USA) February–March, 2016
Amagai M. “Dissecting Skin Barrier Dysfunction as a
Cause of Dermatitis” Gordon Research Conferences on
Barrier Function of Mammalian Skin (Waterville Valley,
USA) August, 2015
Amagai M. “Skin Barrier Homeostasis in Stratum Corneum and Granulosum” Gordon Research Conferenceson Epithelial Defferentiation & Keratinization (Newry,USA) July, 2015
Amagai M. “Towards antigen-specific immune suppression in pemphigus” Inflammatory Skin Disease
Summit: The Translational Revolution (Vienna, Austria)
November, 2014
Amagai M. “Epidermal barrier function and its dysfunction in atopic diseases” Singapore International
Conference on Skin Biology (Singapore, Singapore)
March, 201424

S

kin is the place where immunity meets external antigens. Cutaneous sensitization has now been considered to the initial key step for many allergic
disorders, not only atopic dermatitis (AD), but also asthma, food allergy and anaphylaxis. Skin harbors several barriers to prevent easy penetration of external
antigens into the body; however, the exact molecular mechanisms by which theskin 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 to top, the epidermis is composedof the stratum basale, stratum spinosum, stratum granulosum (SG) and stratum
corneum (SC). Our group has been focusing on SC as an air-liquid barrier andtight junction (TJ) and as a liquid-liquid barrier formed between SG2 cells, among
many other skin barriers. There is a fundamental biophysical paradox regarding
the function of the epidermis, namely, how it can maintain the barrier, but still
constantly replace and shed cells.
Our group is trying to clarify how epidermal barrier homeostasis is maintained under normal conditions and how impaired barrier function occurs andaffects microenvironments of the skin in various disease conditions. We use comprehensive approaches combining molecular biology, biochemistry, ultrastructural anatomy, live imaging, microbiology, and systems biology. For example, wehave recently succeeded in isolating and culturing SG1 cells, which enables us toperform several unique experiments to understand SC homeostasis.
Another of our strengths is to be able to go back and forth between the basic
science findings in mice and those in clinical science in humans with various skindiseases. 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.

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Lab activities

Metabolic Homeostasis
Team Leader: Naoto Kubota

Figure: Mechanisms underlying the anti-diabetic
and anti-obesity effects of tofogliflozin

Recent Major Publications
Obata A, Kubota N, Kubota T, Iwamoto M, Sato H,
Sakurai Y, Takamoto I, Katsuyama H, Suzuki Y, Fukazawa M, Ikeda S, Iwayama K, Tokuyama K, Ueki K,
Kadowaki T. Tofogliflozin Improves Insulin Resistancein Skeletal Muscle and Accelerates Lipolysis in Adipose
Tissue in Male Mice. Endocrinology 157, 1029–1042(2016)
Hashimoto S, Kubota N, Sato H, Sasaki M, Takamoto
I, Kubota T, Nakaya K, Noda M, Ueki K, Kadowaki T.
Insulin receptor substrate-2 (Irs2) in endothelial cells
plays a crucial role in insulin secretion. Diabetes 64,
876–886 (2015)
Shibata S, Tada Y, Hau CS, Mitsui A, Kamata M, Asano
Y, Sugaya M, Kadono T, Masamoto Y, Kurokawa M,
Yamauchi T, Kubota N, Kadowaki T, Sato S. Adiponectin
regulates psoriasiform skin inflammation by suppressing IL-17 production from γδ-T cells. Nat Commun 6,7687 (2015)

Invited Presentations
Kubota N. “Insulin action and insulin resistance” The
53rd Annual Meeting of Kantokoshinetsu Association of
the Japan Diabetes Society (Yokohama, Japan) January,
2016.
Kubota N. “Clarification of molecular mechanisms oftype 2 diabetes using genetic engineering techniquesin mice” 7th AASD Scientific Meeting and Annual Scientific Meeting of the Hong Kong Society of Endocrinology, Metabolism and Reproduction (Hong Kong, China)
November, 2015
Kubota N. “Approach for diabetic complication via endothelial cells” The 30th Annual Meeting of the Japan
Society of Diabetic Complications (Nagoya, Japan)
November, 2015
Kubota T. “The regulation mechanisms of glucose homeostasis via endothelial insulin signaling” The 88th
Annual Meeting of the Japan Endocrine Society (Tokyo,
Japan) April, 2015
Kubota N. “Identification of molecular mechanisms oftype 2 diabetes and obesity by using genetically-engineering technology” The 29th Annual Meeting of theJapan Society of Experimental Diabetes and Obesity(Kyoto, Japan) February, 2015

I

n recent years, there has been a rapid growth in the incidence of type 2 diabetes inboth Western and Asian countries. However, the precise molecular mechanisms leading to the progression of type 2 diabetes remain poorly understand. The goal of our teamis to identify molecular mechanisms of insulin secretion and insulin resistance.
Molecular mechanism of insulin secretion
Impaired insulin secretion, which leads the development of type 2 diabetes, 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 beenreported to be associated with defective pancreatic islet function. However, the functional role of genes identified by GWAS remains unclear. To elucidate the physiological andpathophysiological role of these genes in vivo, we have generated genetically engineered
mice. Specifically, we are investigating common variants in a potassium channel KCNQl
and a ubiquitin conjugating enzyme UBE2E2, which confer the largest effect on the riskof type 2 diabetes in Asians.
Molecular mechanism of insulin resistanceObesity-induced insulin resistance plays a crucial role in 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 insulin binds to the insulin receptor, insulin receptor substrate (IRS)-1 and IRS-2 are activated, and mediate intracellular insulin signaling. We have been studying IRS-1 andIRS-2, which show ubiquitous expression patterns (Diabetes 2000, Circulation 2003, J
Clin Invest 2004, Cell Metab 2008, Cell Metab 2011, Cell 2012), to clarify their role in theunderlying mechanisms of insulin resistance.

25

Laboratory for

Lab activities

Immune Crosstalk
Team Leader: Hilde Cheroutre

Figure: Nuclear localization of Themis is essential for its function.
(A) Putative structure and mutant schemes of Themis.
Themis consists of two homologous parts (CABIT1 and
CABIT2), which contain a Nuclear Localization Signal(NLS) and a Proline Rich Sequence (PRS). Since deleting
the NLS caused Themis protein instability, the NLS(330-RHFLIPISYKGKFKRRPR-347) in CABIT2 was replaced with the homologous amino acids from CABIT1(75-KPFELPMNFPGLFKVMAD-92) to stabilize Themis
protein and inactivate the NLS. (B) Total thymocytes
were fractionated into cytoplasmic (C) and nuclear(N) fractions. ÁÁActin and SATB1 were used as loading
controls for the cytoplasmic and nuclear fractions,
respectively. (C) CD4 and CD8 expression pattern of the
R-NLS mutant thymocytes. (D) Percentage of CD4 single
positive (SP) cells and CD8SP cells in the thymus of an
R-NLS mutant mouse.

Recent Major Publications
Larange A, Cheroutre H. Retinoic Acid and Retinoic Acid
Receptors as Pleiotropic Modulators of the Immune
System. Annu Rev Immunol 34, 369–394 (2016)
Mayans S, Stepniak D, Palida SF, Larange A, Dreux J,
Arlian BM, Shinnakasu R, Kronenberg M,Cheroutre H,
Lambolez F. αβT cell receptors expressed by CD4(-)
CD8αβ(-) intraepithelial T cells drive their fate into a
unique lineage with unusual MHC reactivities. Immunity 41, 207–218 (2014)
Fu G, Casas J, Rigaud S, Rybakin V, Lambolez F, Brzostek J, Hoerter JA, Paster W, Acuto O,Cheroutre H, Sauer
K, Gascoigne NR. Themis sets the signal threshold for
positive and negative selection in T-cell development.
Nature 504, 441–445 (2013)

Invited Presentations
Cheroutre H. “How the Gut Primes the Immune System”
2014 Annual Scientific Meeting of the American College of Rheumatology (ACR). (Boston, USA) November,
2014
Cheroutre H. “Environmental and Cell-Intrinsic Factors
Governing the Immune Response” 2014 Pittsburgh Immunology Symposium (Pittsburgh, USA) May, 2014.
Cheroutre H. “Mucosal Immunity: Taking Strategic
Planning a Step Further” Dutch Society for Immunology
Annual Symposium (Lunteren, the Netherlands) April,2014
Cheroutre H. “New Emerging Transcription Factor andCytokine Networks at the Mucosal Interface of the Intestine” Keystone Symposium (J3) (Vancouver, Canada)
January, 2014
Cheroutre H. “Protective Immunity: It Takes More Than
Memory” Harvard Medical School (HMS) Immunology
Seminar Series (Boston, USA) October, 201326

W

ith our previous research we discovered that not all self-reactive thymocytes aredeleted during negative selection, but that many auto-reactive T cells instead arerescued during “agonist” selection and redirected in their functional fate to become beneficial specialized T cells. In collaboration with Dr. Taniuchi’s group (p17) we also showedthat the lineage commitment in the thymus is not fixed and that mature CD4 T helper
cells can functionally reprogram to cytotoxic T lymphocytes (CTL) in response to cognate
antigen. The factors and molecular mechanisms that control these decisive processes are
not understood and they form a major goal of our research.
By phenotype screening of ENU-induced mutant mice, we newly identified Themis
as an essential gene for T cell development. Themis functions by interacting with Grb2
and SHP1, thus reducing TCR signals and allowing positive selection of thymocytes thatfurther mature to naïve T cells. We found that although Themis deletion impaired conventional selection it did not affect agonist selection. By generating specific nuclear localization signal mutants we now find that the nuclear localization of Themis is critical andessential for its function. Therefore, in addition to its function in proximal TCR signaling,
Themis also plays a role in the nucleus to control gene expression. Since GWAS studies
identified Themis as associated with celiac disease and atopic dermatitis, and since
Themis was linked with inflammatory bowel disease, and furthermore, since Themis
is essential for pathogenesis of cerebral malaria and for protection against pulmonary
tuberculosis, it must also play central roles for peripheral T cells. We are therefore investigating Themis and linked nuclear factors for the functional fate of mature T cells
as well. In addition, we are trying to understand the role of Themis and other factors incontrolling and translating pre-TCR and TCR signal strength during thymic selection andfate decisions of mature T cells. We are using unique and novel loss-and gain–of-function
approaches, designed in collaboration with Dr. Taniuchi’s laboratory. These studies also
led to the milestone discovery that the nuclear retinoic acid receptor alpha functions as
a partner of ZAP70 and plays a critical role in the proximal TCR signaling complex. We
are now elucidating these pioneer findings using sophisticated new tools and approaches.

Laboratory for

Lab activities

Inflammatory Regulation
Team Leader: Takashi Tanaka

Figure: LIM proteins constitute a new family ofnegative regulators of NF-κB signaling.
PDLIM2 and PDLIM7 are ubiquitin E3 ligases for the
p65 subunit of NF-κB, form heterodimers and cooperatively promote p65 degradation. By contrast, PDLIM1
sequesters p65 in the cytoplasm and inhibits its nuclear
translocation, thereby also suppressing NF-κB signaling.

Recent Major Publications
Ono, R., Kaisho, T., Tanaka, T. PDLIM1 inhibits
NF-κB-mediated inflammatory signaling by sequestering the p65 subunit of NF-κB in the cytoplasm. Sci Rep
5, 18327 (2015)
Tanaka T, Shibazaki A, Ono R, Kaisho T. HSP70 mediates degradation of the p65 subunit of nuclear factorκB to inhibit inflammatory signaling. Sci Signal 7,
ra119 (2014)
Yamazaki C, Sugiyama M, Ohta T, Hemmi H, Hamada
E, Sasaki I, Fukuda Y, Yano T, Nobuoka M, Hirashima T,
Iizuka A, Sato K, Tanaka T, Hoshino K, Kaisho T. Criticalroles of a dendritic cell subset expressing a chemokine
receptor, XCR1. J Immunol 190, 6071–6082 (2013)

Invited Presentations
Tanaka T. “From Molecules to Diseases. Clarificationof the molecular mechanisms that negatively regulate
inflammatory responses and association analysis of
autoimmune diseases by GWAS” The 6th Rheumatology winter seminar in St Luke’s International Hospital(Tokyo, Japan) February, 2015
Tanaka T. “From Molecules to Diseases. Clarificationof the molecular mechanisms that negatively regulate
inflammatory responses and association analysis of
autoimmune diseases by GWAS.” The 3rd Akashi-cho
rheumatic collaborative seminar in St Luke’s International Hospital (Tokyo, Japan) October 2014
Tanaka T. “Negative regulation for inflammatory responses and its association with autoimmune diseases”
Monash Univ. & RIKEN IMS Workshop (Yokohama,Japan) August, 2014
Tanaka T. “Regulation of inflammatory responses by
LIM proteins” The 5th LJI-RCAI Workshop “New Horizonin Immune Regulation towards Disease Intervention”(Yokohama, Japan) October, 2013
Tanaka T. “Clarifying the molecular mechanisms that
regulate inflammatory responses” The Osaka Minami
Medical Center: Talk with the expert seminar (Osaka,
Japan) October, 2013T

he inflammatory response is an important host defense mechanism to sense andeliminate invading microbial pathogens, and is initiated and conducted by the cooperation of dendritic cells and T-helper cells. However, these inflammatory responses
must be terminated at the appropriate time point, otherwise excessive responses candamage normal tissue and may lead to autoimmune diseases. Our research goal is to
identify a series of key negative regulators of inflammation-related signal transduction
pathways and clarify the complete picture of the molecular mechanisms for regulating
inflammatory responses. We predict that dysfunction of these negative regulators might
be the cause of human autoimmune diseases.
We previously identified PDLIM2 (PDZ and LIM domain-containing protein-2), a
nuclear protein that belongs to a large family of LIM protein, as one of the key factors
negatively regulating inflammatory responses. PDLIM2 is a ubiquitin E3 ligase for the
STAT4 and STAT3 transcription factors in CD4+T cells, suppressing Th1 and Th17 celldifferentiation, and for the p65 subunit of NF-κB in dendritic cells, negatively regulating
NF-κB-mediated inflammation. We recently found that LIM proteins constitute a new
family that negatively regulates inflammatory responses through different mechanisms.
For example, PDLIM1 binds to and sequesters p65 in the cytoplasm, thereby inhibiting
NF-κB activation in dendritic cells, whereas PDLIM4, which is predominantly expressedin CD4+T cells, suppresses STAT3 signaling by recruiting PTPBL, a protein tyrosine
phosphatase, and facilitating dephosphorylation of a STAT3 tyrosine residue. Notably, asingle nucleotide polymorphism (SNP) in human PDLIM4 is associated with rheumatoid
arthritis susceptibility. We have also identified novel negative regulators of inflammatory
responses by isolating PDLIM2-associated proteins. Moreover, to elucidate the mechanisms by which initially helpful inflammation leads to pathogenic chronic inflammation,
we analyzed the regulation of in vivo inflammatory responses using PDLIM2-deficientmice. These studies should help clarify the pathogenesis of human autoimmune and inflammatory diseases and may lead to the development of new therapeutic tools for these
diseases.
27

Laboratory for

Lab activities

Cytokine Regulation
Team Leader: Masato Kubo

Figure: E4BP4 has a role in the development of
all subsets of ILCs by controlling Id2 expression
levels.

Recent Major Publications
Motomura Y, Morita H, Moro K, Nakae S, Artis D,
Koyasu S, Kubo M. Basophil-derived interleukin-4
controls the function of natural helper cells, a memberof ILC2s, in lung inflammation. Immunity 40, 758–771(2014)
Kurashima Y, Amiya T, Fujisawa K, Shibata N, Suzuki Y,
Kogure Y, Hashimoto E, Otsuka A, Kabashima K, Sato S,
Sato T, Kubo M, Akira S, Miyake K, Kunisawa J, Kiyono
H. The enzyme Cyp26b1-mediates Inhibition of mastcell activation by fibroblasts to maintain skin-barrier
homeostasis. Immunity 40, 530–541 (2014)
Noti M, Wojno ED, Kim BS, Siracusa MC, Giacomin
PR, Nair MG, Benitez AJ, Ruymann KR, Muir AB, Hill
DA, Chikwava KR, Moghaddam AE, Sattentau QJ,
Alex A, Zhou C, Yearley JH, Menard-Katcher P, Kubo
M, Obata-Ninomiya K, Karasuyama H, Comeau MR,
Brown-Whitehorn T, de Waal Malefyt R, Sleiman PM,
Hakonarson H, Cianferoni A, Falk GW, Wang ML,
Spergel JM, Artis D. Thymic stromal lymphopoietin-elicited basophil responses promote eosinophilicesophagitis. Nat Med 19, 1005–1013 (2013)

Invited Presentations
Kubo M. “Role of T follicular helper cells in influenza
virus protection” France-Japan Immunology meeting(Cassis, France) October, 2014
Kubo M “Notch regulates reciprocal expression of
CCR7 versus CXCR5 to control central memory T cell
generation” The 2nd Symposium of International Immunological Memory and Vaccine Forum (La Jolla, USA)
August, 2014
Kubo M. “Regulation of allergic airway inflammation bybasophil and innate lymphoind cells” The 79th Annual
Meeting of the Japanese Society of Interferon & Cytokine Research (Sapporo, Japan) June, 2014
Kubo M. “Understanding a role of cytokine signaling inhomeostatic skin regulation” Shanghai Immunodermatology Forum 2014 (Shanghai, China) May, 2014
Kubo M. “Regulation of allergic airway inflammation bybasophil and innate lymphoind cells” Dry-eye allergy
joint seminer (Tokyo, Japan) January, 201428

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. Cytokines are critical factors in the transmission of information from the receptor to the nucleus as well as in the establishmentof communication networks among cells. Our overall long-term goal is to understand how effector cytokine genes are epigenetically controlled during cell lineage
commitment and how cytokine networks control cell lineage commitment andpathogenic states.
We have focused on Th2 cytokines and generated a series of genetically targeted mice disrupting the cis-acting regularly elements in the Il13/Il4 locus to understand lineage-specific regulation. This mouse system provided evidence that a specific enhancer controlled IL-4 expression in T follicular helper (Tfh) cells, which
provide B cell help for humoral immunity. Recently, we found that Th2 cytokines
are also secreted from several innate immune cells, including mast cells, basophils,
eosinophils, and group 2 innate lymphoid cells (ILC2s). IL-4 production by innate
immune cells is controlled by a distinct enhancer in each different lineage, which
led us to investigate the precise role of cell type-specific IL-4 expression.

Laboratory for

Lab activities

Innate Immune Systems
Team Leader: Kazuyo Moro

Figure: Group 2 innate lymphoid cells and thecytokine network.
Group 2 innate lymphoid cells (ILC2s) are known to
induce type 2 immune responses during helminth
infection and allergic inflammation. ILC2s produce large
amounts of IL-5 and IL-13 in response to IL-25 or IL-33
and induce eosinophilia and goblet cell hyperplasiathat not only attacks the worm but also exacerbatesallergic symptoms. Recently, we found that TSLP
induces steroid resistance of ILC2s, and that IL-4 frombasophils is important for activation of ILC2s during
allergic inflammation such as in asthma. ILC2s aresuppressed by IFN and IL-27, which might be critical
for the conversion from an innate to an acquired type 2
immune response during helminth or fungal infection
and allergic inflammation.

Recent Major Publications*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) (*corresponding)*Moro K, Koyasu S. Innate lymphoid cells, possible interaction with microbiota. Semin Immunopathol 37,
27–37 (2015) (*corresponding)Motomura Y, Morita H, Moro K, Nakae S, Artis D,Takaho A. Endo, Kuroki Y, Ohara O, Koyasu S, Kubo M.
Basophil-derived interleukin-4 controls the function ofnatural helper cells, a member of ILC2s, in lung inflammation. Immunity 40, 758–771 (2014)

Invited Presentations
Moro K. “Interferon and IL-27 antagonize ILC2 function
and type 2 innate immune responses” Annual Meetingof the Japanese Society for Immunology (Sapporo, Japan) November, 2015O

ur team has been focused on group 2 innate lymphoid cells (ILC2s), which
we originally reported as natural helper cells. ILC2s localize to a variety oftissues such as fat, lung, intestine, liver and skin, and mediate immunity to helminth and fungal infections via strong type 2 cytokine production. Infection withhelminths or fungi induces IL-25 and IL-33 production from epithelial cells or
endothelial cells and activates ILC2s, leading to eosinophilia and goblet cell hyperplasia resulting from the production of IL-5 and IL-13, respectively. These immune responses are extremely important for defense against infection, but recent
studies have shown that ILC2s exacerbate allergic inflammation using the samemechanisms.
We think that it is particularly important to determine the activation andsuppression mechanisms of ILC2s during infection and inflammation in orderto develop effective treatments for ILC2-related allergic diseases. Recently, we
found that ILC2s are involved in obesity, which leads to a variety of metabolic
syndromes. Therefore, an additional goal of our research group is to demonstrate
the dynamics of ILC2s in obesity, and understand the role of ILC2s in adipose
tissue inflammation.

Moro K. “Innate lymphoid cells and inflammation” Annual Meeting of the Japanese Society for Immunology(Kyoto Japan) December, 2014
Moro K. “Natural Helper Cell-a new player in innate immune system-” Annual Meeting of the Japanese Society
for Immunology (Chiba, Japan) December, 201329

Core for
Precise Measuringand ModelingToward the ultimate goal of obtaining a comprehensive understandingof the pathogenesis of human diseases, the functions of the Core forPrecise Measuring and Modeling are three pronged: production of mousemodels, 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 ofquantitative data in order to build a computational and predictive networkof the disease process. As for the production of genetically engineered micethat 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, one focus in 2014
has been to enhance the power of metabolite analysis by the Laboratory for
Metabolomics. Together with mRNA/protein profiling by the Laboratory for
Integrative Genomics, the enhanced multiomics measurements and bio-imaging (Laboratory for Tissue Dynamics) will greatly contribute to explorationof the etiology of human diseases. After being processed by bioinformatics(Laboratory for Integrated Bioinformatics), the datasets are used for modeling (Laboratories for Disease Systems Modeling and Integrated Cellular Systems). As a leading IMS project, an atopic dermatitis model mouse, provided
by the Laboratory for Immunogenetics, has been extensively analyzed fromseveral 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: Protracted binding of NP95 to hemimethylated DNA disrupts transcriptional silencing.
The upper panel shows protracted binding of NP95
onto ectopic hemimethylated DNA. NP95 binding
inhibits chromatin-mediated transcriptional silencing,in particular, in the retrotransposon associated IAP(intracisternal A particles) loci. The lower panel shows
preferential binding of the epigenetic repressor SETDB1
to the same sites, leading to robust transcriptionalsilencing. In this case, although hemimethylated DNA
is present, NP95 is not, which allows SETDB1 to silence
these loci.

Recent Major Publications
Sharif J, Endo TA, Nakayama M, Karimi MM, Shimada
M, Katsuyama K, Goyal P, Brind’Amour J, Sun M-A, Sun
Z, Ishikura T, Mizutani-Koseki Y, Ohara O, Shinkai Y,
Nakanishi M, Xie H, Lorincz MC, Koseki H. Activation of
Endogenous Retroviruses in Dnmt1−/− ESCs Involves
Disruption of SETDB1-Mediated Repression by NP95
Binding to Hemimethylated DNA. Cell Stem Cells (inpress)
Kondo T, Isono K, Kondo K, Endo TA, Itohara S, Vidal
M, Koseki H. Polycomb potentiates meis2 activation in
midbrain by mediating interaction of the promoter witha tissue-specific enhancer. Dev Cell 28, 94–101 (2014)
Isono K, Endo TA, Ku M, Yamada D, Suzuki R, Sharif
J, Ishikura T, Toyoda T, Bernstein BE, Koseki H. SAM
Domain Polymerization Links Subnuclear Clustering of
PRC1 to Gene Silencing. Dev Cell 26, 565–577 (2013)

Invited Presentations
Koseki, H. “Protoracted NP95 binding to hemimethlated
1 DNA disrupts SETB1-mediated proviral silencing” International Sympojium on “Chromosome Orchestration
System,” Osaka University (Awajishima, Japan) March,
2016
Koseki, H. “Protracted NP95 binding to hemimethylated
DNA disrupts proviral silencing” BMB2015 Biochemistry
and Molecular Biology (Kobe, Japan) December, 2015
Koseki, H. “Visualization of genes and epigenetic information in cells” The 67th Annual Meeting of the Japan
Society for Cell Biology (Tokyo, Japan) July, 2015T

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) proteins andDNA methylation related proteins.
Repression of endogenous retroviruses (ERVs) in mammals involves several
epigenetic mechanisms. For example, acute loss of the maintenance methyltransferase Dnmt1 induces widespread DNA demethylation and transcriptional activation of ERVs, including CpG-rich IAP (intracisternal A particle) proviruses. We
have recently shown that this effect is not due simply to a loss of DNA methylation. Our conditional deletions experiments revealed that both Dnmt1 and Np95
are essential for maintenance DNA methylation. However, while IAPs are derepressed in Dnmt1-ablated embryos and embryonic stem cells (ESCs), these ERVs
remain silenced when Np95 is deleted alone or in combination with Dnmt1. This
paradoxical phenotype results from an ectopic interaction between NP95 andthe H3K9 methyltransferase SETDB1. Normally, SETDB1 maintains silencing of
IAPs, but in the absence of DNMT1, prolonged binding of NP95 to hemimethylated DNA transiently disrupts SETDB1-dependent H3K9me3 deposition. Thus,
our observations reveal an unexpected antagonistic interplay between two repressive pathways involved in retroviral silencing in mammalian cells.

Koseki, H. “iPS-mediated induction of human NKT cells
and their application for cancer therapy” The 35th Annual Meeting of the Japanese Society of Inflammation
and Regeneration (Okinawa, Japan) July, 2014
Koseki, H. “Activation of polycomb-repressed genes”
Mouse Molecular Genetics conference (Cambridge, UK)
September, 201331

Laboratory for

Lab activities

Integrative Genomics
Group Director: Osamu Ohara

Figure: High-Throughput pipeline for immune
repertoire analysis
This figure shows a method for high-throughput (HT)generation of a cell line that stably produces an Fabmolecule identified from a single B cell, on the cellsurface. After sequencing variable regions in heavy
and light chains of immunoglobulin genes, they arecloned into an expression module by a ligation-freehigh-throughput method. The resultant expression
module is then inserted into the genome of a host cellusing a high-throughput dual recombinase-mediatedcassette exchange method modified at the Kazusa DNA
Research Institute. Using this approach, the immune
repertoire on the original single B cell is eventually
recaptured on the recombinant cell. The functionality of
the recombinant Fab molecule will be examined using
a single-molecule analysis with an automated robotic
system developed at RIKEN Quantitative Biology Center(QBiC, Dr. M. Ueda).

Recent Major Publications
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)
Yakushiji-Kaminatsui N, Kondo T, Endo TA, Koseki Y,
Kondo K, Ohara O, Vidal M, Koseki H. RING1 proteins
contribute to early proximal-distal specification of thefore limb bud by restricting Meis2 expression. Development 143, 276–285 (2016)
Inoue T, Morita M, Hijikata A, Fukuda-Yuzawa Y, Adachi
S, Isono K, Ikawa T, Kawamoto H, Koseki H, Natsume
T, Fukao T, Ohara O, Yamamoto T, Kurosaki T. CNOT3
contributes to early B cell development by controlling
Igh rearrangement and p53 mRNA stability. J Exp Med
212, 1465–1479 (2015)
Oda H, Sato T, Kunishima S, Nakagawa K, Izawa K, Hiejima E, Kawai T, YasumiT, Doi H, Katamura K, Numabe
H, Okamoto S, Nakase H, Hijikata A, Ohara O, Suzuki H,
Morisaki H, Morisaki T, Nunoi H, Hattori S, Nishikomori
R, Heike T. Exon skipping causes atypical phenotypes
associated with a loss-of-function mutationin FLNA byrestoring its protein function. Eur J Hum Genet 24,
408–414 (2016)

Invited Presentations
Ohara O. “From genotype to phenotype: Mind the gap
in multiscale structure of the phenotype” 4th Sardinian
Summer SchoolÁFrom genome-wide association studies(GWAS) to function (Pula, Italy) June, 2015
Ohara O. “Advances in Clinical Sequencing Technologies
for Primary Immunodeficiency Diseases” The 11th
Congress of Asian Society for Pediatric Research (ASPR2015) (Osaka, Japan) April, 2015

32

A

basic mission of the Laboratory for Integrative Genomics is to function asa “Gateway” to genomics. To achieve this, we have taken a three-pronged
approach to our research activities: (1) central support activities; (2) strategic andcollaborative research activities; and (3) exploratory research activities aimed at
new technology development.
As for the central support activities in category (1), we have made every effort
to update new technologies with the least delay, but only after they become matureand robust enough. We believe that these activities will be a big help for medical
scientists.
We have made a special effort in category (2) because it is crucial to enhance
the research activities of the center as a whole. In the strategic research activities,
our group plays the role of “workhorse” to drive the measurement and bioinformatics pipelines of the center projects such as the Atopic Dermatitis project, theAutoimmune project, and the Metabolic disorder project, and so on. The primarybioinformatics analyses are done in our laboratory. As for the collaborative research activities, we have also participated in many intramural as well as extramural collaborations on a laboratory-to-laboratory basis.
As for research category (3), we are now focusing our efforts in the development of single-cell measurement technologies and their applications. In general,
there are two measurement types in analysis of population dynamics at the single-cell resolution - snapshot vs real-time monitoring. In our group, we have madea special effort to develop optofluidics methods to monitor individual cells in
real-time. This approach will provide us with indispensable lines of information tointerpret single-cell snapshot data from the viewpoint of systems biology.

Laboratory for

Lab activities

Disease Systems
Modeling
Group Director: Hiroaki Kitano

Figure: Comprehensive maps of the stress response pathways for the budding yeast.
Pathways were categorized into six groups and containmultiple layers of information, which are not included
in simple interaction networks such as protein-protein
interaction (PPI).

Recent Major Publications
Kawakami E, Nakaoka S, Tazro Ohta T, Kitano H.
Weighted enrichment method for prediction ofÁtranscription regulators from transcriptome andÁglobal
chromatin immunoprecipitation data. Nucleic Acids
Res 44, 5010–5021 (2016)
Kitano H. Artificial intelligence to win the Nobel Prizeand beyond: Creating the engine of scientific discovery.
AI Magazine 37, 39–49 (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
Systems Biology and Applications 2, 15018 (2016)

Invited Presentations
Kitano H. “Artificial Intelligence for Scientific Discovery
in Biomedical Sciences” GET Conference (Boston, USA)
April, 2016T

he Laboratory for Disease Systems Modeling (LDSM) aims at in-depth understanding of several biological processes relevant to disease systems, andpossible applications to clinical practice. There are three interrelated projects: (1)Skin Homeostasis, (2) Aging, and (3) Precision systems biology using budding
yeast. Skin homeostasis is linked with IMS’s center project on atopic dermatitis.
We are striving to create computational models combined with a rage of cell-based
experiments at LDSM together with mouse data from other IMS teams. Aging is
a new topic with long-range objectives to understand possible control of aging
process and uncovering molecular mechanisms behind it. We are focusing on theeffect of SIRT1 (mammalian) and Sir2 (budding yeast), and NMN as a chemical
substance to affect these genes. We are linking skin homeostasis and aging with
low-grade chronic inflammation as the common thread. Precision systems biology using budding yeast strengthens our understanding of key biological process
by providing deeper insights on detailed molecular processes with our original
gTOW genome-wide assay system.
In addition, the LDSM have has extensive involvement with the Medical Innovation Hub project in its feasibility study stage, but that will not be reported here.

Kitano H. “Cellular systems” The 3rd EMBO Conference
on Visualizing Biological Data (VIZBI 2016) (Heidelberg,
Germany) March, 2016
Kitano H. “Systems Biology and Applications” ICSB
2014-15th International Conference on Systems Biology(Melbourne, Australia) September, 2014
Kitano H. “Software platform for systems drug discovery” Workshop on Translational Knowledge Management in Pharmaceutical R&D, Innovative Medicines
Initiative (IMI) (Brussels, Belgium) July, 201333

Laboratory for

Lab activities

Immunogenetics
Team Leader: Hisahiro Yoshida

Figure: Dermatitis developmental steps in the
Spade mutant.

Recent Major Publications
Yasuda T, Fukada T, Nishida K, Nakayama M, Matsuda
M, Miura I, Dainichi T, Fukuda S, Kabashima K, Nakaoka
S, Bin BH, Kubo M, Ohno H, Hasegawa T, Ohara O, Koseki H, Wakana S, Yoshida H. Hyperactivation of JAK1
tyrosine kinase induces stepwise, progressive pruritic
dermatitis. J Clin Invest 126, 2064–2076 (2016)
Satoh R, Kakugawa K, Yasuda T, Yoshida H, Sibilia M,
Katsura Y, Levi B, Abramson J, Koseki Y, Koseki H, vanEwijk W, Hollander GA, Kawamoto H. Requirement of
Stat3 Signaling in the Postnatal Development of Thymic
Medullary Epithelial Cells. PLoS Genet 12, e1005776(2016)
Miyai T, Hojyo S, Ikawa T, Kawamura M, Irie T, Ogura
H, Hijikata A, Bin BH, Yasuda T, Kitamura H, Nakayama
M, Ohara O, Yoshida H, Koseki H, Mishima K, Fukada T.
Zinc transporter SLC39A10/ZIP10 facilitates antiapoptotic signaling during early B-cell development. Proc
Natl Acad Sci U S A 111, 11780–11785 (2014)

Invited Presentations
Yoshida H. “Genetic factors and atopic dermatitis disease model” The 10th Tokyo Scientific Forum for Atopic
Dermatitis and Psoriasis (Tokyo, Japan) December,
2014
Yoshida H. “Genetic factors and onset of atopic dermatitis in murine disease model” The 113th Annual Meeting of the Japanese Dermatological Association (Kyoto,
Japan) May, 201434

B

efore the onset of an inflammatory disease, there must be an accumulation of many
imperceptible pathogenic events in the human body as part of pre-symptomatic disease development under the influence of genetic and environmental factors. If one could
precisely monitor and understand these multiple pre-symptomatic longitudinal eventsoccurring in a healthy individual, it should be possible to predict the timing of disease
onset and to take measures to prevent it. This strategy will be beneficial for many individuals in the coming era, when everyone can know their own genome sequence information and genetic risk factors shortly after birth.
In our laboratory, we had been working to identify the genetic factors for allergic or
immune disease development by phenotype screening of a chemical mutagen [N-ethyl
N-nitrosourea (ENU)] -induced mutant mice on a C57BL/6J background. Among the
mutants identified, we have focused on a dermatitis model in which the disease develops
at approximately 8 weeks after birth, as detected by ear skin desquamation and subsequent scratching of the skin a few days after the initial symptoms. This phase is followed
by a Th2-biased immune response detected by elevated serum IgE, IgG1 and histaminelevels 3 weeks later. Then, 8 weeks after that, a Th1 immune biased response ensues, withelevated serum IgG2b and IgG2c. At this final stage, the pathological findings led to thediagnosis of a chronic inflammatory condition of the skin. These symptoms are in partcompatible with those of human atopic dermatitis; therefore we named this mutant Spade(Stepwise progressive atopic dermatitis).
This phenotype was induced by a gain of function point mutation (R878H) in the
JAK1 tyrosine kinase molecule, which is usually activated by several cytokines. As expected, this disease was prevented by painting a JAK inhibitor on the skin, however,
petrolatum painting also blocked the dermatitis onset even the presence of the JAK1
activated molecular event. Using this disease model, we have precisely analyzed thepre-symptomatic pathological events as shown in the figure. The accumulation of allthese events leads to the onset of dermatitis in the late stage.

Laboratory for

Lab activities

Integrated Bioinformatics
Team Leader: Todd D. Taylor

Figure: Overview of the Integrated Database
SystemData generated by participating labs for a variety of
wet-lab experimental types, including flow cytometrydata, immunohistochemistry images, skin water loss
measurements, blood profiles, RNA-Seq data, andothers, are automatically or manually imported into
the database. These data are then easily accessible fordownstream analysis.

Recent Major Publications
Lau N-S, Makita Y, Kawashima M, Taylor TD, Kondo S,
Othman AS, Shu-Chien AC, Matsui M. The rubber tree
genome shows expansion of gene family associatedwith rubber biosynthesis. Sci Rep 6, 28594 (2016)
Jinda W, Poungvarin N, Taylor TD, Suzuki Y, Thongnoppakhun W, Limwongse C, Lertrit P, Suriyaphol P,
Atchaneeyasakul L. A novel start codon mutation of
the MERTK gene in a patient with retinitis pigmentosa.
Mol Vis 22, 342–351 (2016)
Nishijima S, Suda W, Oshima K, Kim SW, Hirose Y,
Morita H, Hattori M. The gut microbiome of healthy
Japanese and its microbial and functional uniqueness.
DNA Res 23, 125–133 (2016)

Invited Presentations
Taylor TD. “Turning ‘big data’ into ‘small data’ throughcrowdsourced curation: integrating all types of medical
and scientific knowledge.” 3rd AIST-RIKEN Joint Bioinformatics Seminar (Yokohama, Japan) June, 2016
Taylor TD. “Introduction to metagenomics; Metadatamanagement, sampling considerations, experimental
approaches, workflow summary.” CCB-USM Workshop
on Metagenomics. Centre for Chemical Biology, Universiti Sains Malaysia (Penang, Malaysia) December, 2014
Kim SW. “Microbial community analysis using 16S
rRNA.” CCB-USM Workshop on Metagenomics. Centre for Chemical Biology, Universiti Sains Malaysia(Penang, Malaysia) December, 2014
Taylor TD. “Online resources: databases, tools andpipelines; Introduction to the human genome projectand metagenomics.” 1st Workshop in Bioinformatics.
School of Biological Sciences, University Sains Malaysia(Penang, Malaysia) December, 2013
Taylor TD. “Metagenomics and barcoding.” Poznan
Summer School of Bioinformatics: Molecular Evolution& Phylogenomics. Collegium Biologicum at Campus
UAM Morasko, Adam Mickiewicz University (Poznan,
Poland) August, 2013

Large volumes of many different types of data are being generated as part ofthe core projects being conducted in IMS, and our team provides the necessary bioinformatic support. We are developing an integrated database and sample-tracking system to handle both small-scale and large-scale datasets of various
types of experimental outputs. The system currently brings together a variety of
wet-lab experimental types being generated by various labs. We are establishingcommon protocols for transferring massive datasets from different data management systems. For data being generated on a smaller scale, modules are being developed for a database web interface so that researchers or technicians can directly
input their data by hand, or by some other simple means. As per user requests, weplan to provide a variety of integrated views of the data, automatically perform
calculations and generate graphs, charts and tables, and even assist in data analysis. Most critically, users and collaborators will be able to extract whatever data
they need, in the format they need, to perform downstream analyses. The ultimate
goal is to develop a flexible system that makes it easy to manage, access, analyze,
integrate, and visualize various data types as per user requirements.
In addition, our lab continues to 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. With the advent of high-throughput
next-generation sequencers and subsequent massive data output, we anticipate
the need for better means of visualizing and understanding the results, and ouroverall long-term goal is the integration of such tools to ease the analytical burdenof non-bioinformatician scientists.

35

Lab activities

Laboratory for

Tissue Dynamics
Team Leader: Takaharu Okada

Figure: Imaging Analysis of Antigen-SpecificCD8+ T Cells interacting with Xcr1+ Cross-Presenting DC Subsets Using the Photochromic Fluorescent Protein KikGR.
(Modified from Kitano et al. Proc Natl Acad Sci
USA 113, 1044–1049, 2016).
(A) Experimental design. Cross-presenting DCs thathave arrived in the lymph nodes after immunization are
visualized as KikR+ cells while the other cross-presenting DCs in the lymph nodes are visualized as KikG+KikR− cells. (B) Fluorescence image of half of an inguinal
LN sagittal slice from an Xcr1KikGR/+ mouse treated as
described in (A). A maximal projection image of six
confocal sections (35 µm depth) is shown. The dottedline demarcates the LN boundary. “c” and “m” indicate
the cortical and medullary sides, respectively (C) Demarcation of the KikG+KikR− area, KikR+ area, and OT-I
T cell-occupied area in the image shown in (B). (D)An intravital two-photon image of an inguinal LN of
an Xcr1KikGR/+ mouse treated as in (A). A 3D-rendered
fluorescence image is shown. Image depth: 100 µm.
(E) OT-I T cell tracks. Imaging duration: 30 min. (F) The
interaction partners of low-motility OT-I T cells (medianvelocity ≤ 4 µm). The colored dots were placed on
low-motility OT-I T cells interacting with the indicatedcells.

Recent Major Publications
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)
Daniels N., Hyde E, Ghosh S, Seo K, Price KM, Hoshino
K, Kaisho T, Okada T, Ronchese F. Antigen-specific cytotoxic T lymphocytes target airway CD103+ and CD11b+
dendritic cells to suppress allergic inflammation. Mucosal Immunol 9, 229–239 (2016)
Lin WW, Adams WC, Nish SA, Chen YH, Yen B, Rothman NJ, Kratchmarov R, Okada T, Klein U, Reiner SL.
Asymmetric PI3K signaling driving developmental andregenerative cell fate bifurcation. Cell Rep 13, 1–16
(2015)

Invited Presentations
Okada T. “Imaging of cellular dynamics shaping theadaptive immune system” The 44th Annual Meeting ofJapanese Society for Immunologists, GlaxoSmithKline
K. K. Clinical Seminar (Sapporo, Japan) November, 2015
Okada T. “Fluorescence imaging of immune cell dynamics in the immunological disease model” The 10th
Invited Immunologist Seminar at The Shonan ResearchCenter of Takeda Pharmaceutical Company (Fujisawa,
Japan) October, 2015
Okada T. “Imaging of Immune Cell Dynamics” The 65th
Annual Meeting of the Japan Society for Cell Biology(Tokyo, Japan) July, 2015

36

A

Xcr1KikGR/+ mice

B

C
KikG+KikR- cell area
KikR+ cell area
OT-I

Xcr1-KikG
Xcr1-KikR
DiD (OT-I)

DiD-labeled
OT-I transfer
24 hr
Skin illumination

2 hr

OVA+poly(I:C) s.c.
α-CD62L Ab i.v.

18-22 hrdraining lymph node
Imaging analysis

200 μmDE

60 μm
Xcr1-KikG Xcr1-KikR DiD (OT-I)

F

60
60 μm
μm
OT-I cell track(median velocity > 4 µm/min)
OT-I cell track(median velocity ≤ 4 µm/min)

T

60 μm
OT-I
interacting with

KikG+KikR- only
KikR+ only
both KikG+KikR- and KikR+
neither KikG+KikR- nor KikR+

he goal of the laboratory is to mechanistically understand the in vivo cellular dynamics that shape immune responses and inflammation. Currently,
we have limited understanding of how immunological memory and tolerance,
two central features of adaptive immunity, are controlled by dynamic interactions
among immune cells. As a strategy for tackling this problem, we use multi-dimensional fluorescent imaging, in particular two-photon microscopy, to analyze cellular migration and interactions in the tissues. This microscopy method has been
revealing the striking dynamics of immune cells in various organs, underlining
the importance of this approach to resolve the complexity of the immune system.
By applying this imaging strategy to relevant mouse models, we aim to reveal immune cell dynamics that are critical for generation of immunological memory andtolerance. For this aim, we have been developing and studying mouse strains, inwhich (1) dynamics of helper T cells specialized for B cell immune responses are
perturbed, (2) cross-presenting dendritic cells (DCs) are fluorescently labeled forin vivo imaging, and (3) dynamics and function of regulatory T (Treg) cell subsets
are perturbed to break peripheral tolerance of autoreactive B cells and CD8+ T
cells.
In addition, we have recently started projects to study the roles for the peripheral nervous system in modulation of inflammation. Particularly, we are interested in structural and functional changes in sensory neurons in dermatitis. In
this study as well, the imaging approaches are very powerful for deciphering thediversity and dynamics of cellular activities. Through this study, we aim to findstrategies to suppress chronic inflammation based on the modulation of neuronal
activities.

Laboratory for

Lab activities

Integrated Cellular
Systems
Team Leader: Mariko Okada

Figure: Negative feedback regulation of ErbB
receptor signaling by PHLDA1PHLDA1 is transcriptionally induced upon activationof Ras-ERK and PI3K-Akt pathways and suppresses
high-order oligomerization of the receptor complex.

Recent Major Publications
Mina M, Magi S, Jurman G, Itoh M, Kawaji H, Lassmann
T, Arner E, Forrest ARR, Carninci P, Hayashizaki Y, DaubCO, the FANTOM Consortium, Okada-Hatakeyama M*,
Furlanello C*. Promoter-level expression clustering
identifies time development of transcriptional regulatory cascades initiated by ErbB receptors in breast cancer
cells. Sci Rep 5, 11999 (2015) * Corresponding authors.
Nagashima T, Inoue N, Yumoto N, Saeki Y, Magi S,
Volinsky N, Sorkin A, Kholodenko BN and Okada-Hatakeyama M. Feedforward regulation of mRNA stability
by prolonged ERK activity. FEBS J. 282, 613–629 (2015)
Shinohara H, Behar M, Inoue K, Hiroshima M, Yasuda
T, Nagashima T, Kimura S, Sanjo H, Maeda S, Yumoto
N, Ki S, Akira S, Sako Y, Hoffmann A, Kurosaki T, Okada-Hatakeyama M. Positive feedback within a kinasesignaling complex functions as a switch mechanism
for nuclear factor-κB activation. Science 344, 760–764(2014)

Invited Presentations
Okada-Hatakeyama M. “Mechanisms of dynamics behaviors of NF-κB signaling in B cell” 16th International
Conference of Systems Biology (ICSB) 2015 (Singapore,
Singapore) November, 2015
Okada-Hatakeyama M. “Data-based modeling of
signal-transcription network for cell fate control” BioNetVista Workshop-ICSB2015 (Singapore, Singapore)
November, 2015
Okada-Hatakeyama M. “Data-based modeling of on/off
switch mechanism arising from biochemical network”
EquaDiff 2015 (Lyon, France) July, 2015T

he aims of the laboratory are to determine the general regulatory rules inthe dynamic behavior of signal transduction-transcriptional networks in cell
determination processes and to apply this knowledge of regulatory principles forunderstanding and treatment of human diseases. For this purpose, we perform
quantitative measurements of the target biological system using various experimental methods and then integrate these heterogeneous data using mathematicalmodels. A biological system is often dissected with its time, size and data derived
from each experimental platform, and integration of such heterogeneous datais only possible using informatics and mathematical modeling. In particular, wehave strength in developing data-driven kinetic models, and this approach is being applied to various biological phenomena related to different aspects of cell
regulation. In particular, we have been working on signaling and transcription
dynamics in proliferation and differentiation of cancer and immune cells in vitro
and applying these data acquisition strategies and data analysis methods to in vivo
mouse models. To understand the regulatory layers between signaling and transcription regulation, we have recently analyzed dynamics of epigenetic regulation.
We collaborate with single molecule imaging experts to identify the critical kinetic parameters in the regulation. We also develop computational and theoreticalmethods with collaborators in different research fields that can be applied for the
analysis of real biological data. These collaborative efforts are complementary to
our kinetic modeling approach and could uncover the regulatory relationships ofthe molecules in the network in an unbiased manner.

Okada-Hatakeyama M. “On/off switching mechanisms
in signaling network” cBio Meeting (Tsuruoka, Japan)
May, 2015
Okada-Hatakeyama M. “A switch in NF-kappaB immune
signaling” The first Q-Bio Winter Meeting (Hawaii, USA)
February, 2013

37

Laboratory for

Lab activities

Metabolomics
Team Leader: Makoto Arita

Figure: Anti-inflammatory mechanisms of Omega-3 PUFAs and their bioactive metabolites.
Genetic and lipidomic analyses identified 18-hydroxyeicosapentaenoic acid (18-HEPE) as a cardioprotective
and anti-fibrotic metabolite generated by macrophages
in the heart. We also identified 17,18-epoxyeicosatetraenoic acid (17,18-EpETE) as an anti-allergic
metabolite generated in the gut from dietary omega-3alpha-linolenic acid.

Recent Major Publications
Sakayori N, Kikkawa T, Tokuda H, Kiryu E, Yoshizaki K,
Kawashima H, Yamada T, Arai H, Kang JX, Katagiri H,
Shibata H, Innis SM, Arita M, *Osumi N. Maternal dietary balance between omega-6 and omega-3 polyunsaturated fatty acids impairs neocortical development
via epoxy metabolites. Stem Cells 34, 470–482 (2016)*Kunisawa J, *Arita M, Hayasaka T, Harada T, Iwamoto R, Nagasawa R, Shikata S, Nagatake T, Suzuki H,
Hashimoto E, Kurashima Y, Suzuki Y, Arai H, Setou M,
Kiyono H. Dietary Á3 fatty acid exerts anti-allergic effectthrough the conversion to 17,18-epoxyeicostetraenoic
acid in the gut. Sci Rep 5, 9750 (2015)
Masterson JC, McNamee EN, Fillon SA, Hosford L, Harris
R, Fernando SD, Jedlicka P, Iwamoto R, Jacobsen E,
Protheroe C, Eltzschig HK, Colgan SP, Arita M, Lee JJ,*Furuta GT. Eosinophil-mediated signaling attenuates
inflammatory responses in experimental colitis. Gut 64,
1236–1247 (2015)

Invited Presentations
Arita M. “Advanced lipidomics to understand the quality difference of fatty acids in biological systems” The96th Chemical Society of Japan Annual Meeting (Kyoto,
Japan) March, 2016
Arita M. “Quality of Lipids in Health and Disease” Academia Sinica IBMS-RIKEN IMS Joint Workshop (Yokohama, Japan) March, 2016
Arita M. “Lipidomic approach to uncover anti-inflammatory properties of omega-3 polyunsaturated fatty acids” 14th International Conference of Bioactive Lipids inCancer, Inflammation and Related Diseases (Budapest,
Hungary) July, 2015
Arita M. “Lipidomic approach to uncover anti-inflammatory properties of omega-3 polyunsaturated fatty
acids” IMS-JSI International Symposium on Immunology
2015 (Yokohama, Japan) June, 2015
Arita M. “Lipo-quality in biological systems” The 57th
Annual Meeting of Japanese Conference on the Biochemistry of Lipids (Tokyo, Japan) May, 2015

38

L

ipids are recognized as extremely diverse molecules. Precise determinationof each molecular species of lipid, namely Lipo-Quality (Quality of Lipids),
becomes a prerequisite not only to understand their biological functions in physiology 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.
Polyunsaturated fatty acid (PUFA)-derived mediators are formed by enzymatic oxidation through the action of cyclooxygenases (COX), lipoxygenases (LOX),
and cytochrome P450 monooxygenases (CYP). By using LC-MS/MS-based lipidomics, we provided new insights into the cellular and molecular mechanisms ofinflammatory resolution, especially the functional roles of 12/15-LOX-expressing
eosinophils and macrophages in controlling the resolution of inflammation. Our
research is also focused on understanding the function of omega-3 PUFAs using
genetic and lipidomic approaches, and has identified novel metabolic pathways
and bioactive metabolites that may link to omega-3 PUFA’s anti-inflammatory
actions. Identification of endogenous mediators with potent anti-inflammatory
activity could lead to the development of novel therapeutics for disease when sustained inflammation is suspected as a key component of pathogenesis.
We also put a lot of effort into development and application of targeted andnon-targeted lipidomics platforms to discover novel links between lipid metabolism and biological phenotypes. By taking advantage of Q-TOF (global lipid
screening) and TripleQ (quantitative analyses) mass spectrometers, our new approach has a strong potential to search for lipids of interest globally, or to identify
unknown lipid species in a non-biased fashion.

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 concept of
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 ismainly 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. These laboratories are in close communication with the research group ofpharmacogenomics (Laboratory for Pharmacogenomics and Laboratory forInternational 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 manyother collaborators worldwide for further analyses. In addition to this strategy, the Laboratory for Genome Sequencing Analysis is mainly working onwhole genome sequencing of cancer genomes to clarify the pathogenesis ofcarcinogenesis.

39

Laboratory for

Lab activities

Genotyping Development
Team Leader: Yukihide Momozawa

Figure: High throughput dispensing system necessary for large scale genomic analysis.

Recent Major Publications
Liu JZ, van Sommeren S, Huang H, Ng SC, Alberts R,
Takahashi A, Ripke S, Lee JC, Jostins L, Shah T, et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic
risk across populations. Nat Genet 47, 979–986 (2015)
Okada Y, Momozawa Y, Ashikawa K, Kanai M, Matsuda
K, Kamatani Y, Takahashi A, Kubo M. Construction of
a population-specific HLA imputation reference panel
and its application to Graves' disease risk in Japanese.
Nat Genet 47, 798–802 (2015)
Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day
FR, Powell C, Vedantam S, Buchkovich ML, Yang J, et al.
Genetic studies of body mass index yield new insights
for obesity biology. Nature 518, 197–206 (2015)

Invited Presentations
Kubo M. “The Biobank Japan project” 2013 Taiwan
Human Genetics Society Spring Symposium & Annual
Meeting: Taiwan-Japan Joint Symposium on BioBank
and Genomic Medicine (Taipei, Taiwan) May, 2013
Kubo M. “From genomic research to genomic medicine
and prevention” The 59th Annual Meeting of the Japan
Society of Human Genetics (Society award) (Tokyo,
Japan) November, 2014
Kubo M. “Cancer pharmacogenomics in the Biobank
Japan Project” UK-Japan Collaborative Meeting (Cambridg, UK) February, 2015
Kubo M. “Pharmacogenetics in the BioBank Japan
project” The 3rd Meeting of South East Asian Pharmacogenomics Research Network (SEAPharm) (Jakarta,
Indonesia) April, 2014
Kubo M. “Biobank Japan Project” Finland-Japan BioBank session (Tokyo, Japan) October, 2015
Momozawa Y. “BioBank Japan: future direction” The
6th International Workshop on Genomic Epidemiology(London, UK) May, 201540

T

he aims of the Laboratory for Genotyping Development from FY2013 toFY2016 are 1) to produce precise and large-scale genomic data to identify
genetic variants related to diseases susceptibility, outcomes, and drug responses intight collaboration with the Laboratory for Statistical Analysis and 2) to develop
methods and database useful for clinical sequencing.
For these purposes, we newly installed a high-throughput whole genome sequencing (WGS) method, a whole exome sequencing (WXS) method and a target
sequencing (TS) method, in addition to the genome wide SNP genotyping that wehave previously used. We applied these methods to different projects in collaboration with the BioBank Japan project, the PGRN-RIKEN IMS Global Alliance, andother researchers. In total, between FY2013 and FY2016, we performed genome
wide SNP genotyping of 215,446 individuals in 80 projects, WGS of 1,782 individuals in 10 projects, WXS of 644 individuals in seven projects, and TS of 122,472
individuals in 12 projects.
We also contributed to construction of a Japanese population-specific reference panel (n = 908) for human leukocyte antigen (HLA) alleles. We performed
high-resolution (four-digit) genotyping of three class I HLA genes and four classII HLA genes and the Laboratory for Statistical Analysis developed the reference
panel and applied this panel to genome-wide association study data for Graves’disease. We found that amino acid polymorphisms of multiple class I and class II
HLA genes independently contribute to disease risk.
We have published 117 papers between FY2013 and 2016. We will continue
these efforts to contribute to the implementation of personalized medicine.

Laboratory for

Lab activities

Genome Sequencing
Analysis
Team Leader: Hidewaki Nakagawa

Recent Major Publications
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 N,
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, and Nakagawa H (corresponding).
Whole genome mutational landscape and characterization of non-coding and structural mutations in livercancer. Nat Genet 48, 500–509 (2016)
Fujimoto A, Furuta M, Shiraishi Y, Gotoh K, Kawakami
Y, Arihiro K, Nakamura T, Ueno M, Ariizumi S, Hai
Nguyen H, Shigemizu D, Abe T, Boroevich KA, Nakano
K, Sasaki A, Kitada R, Maejima K, Yamamoto Y, Tanaka
H, Shibuya T, Shibata T, Ojima H, Shimada K, Hayami S,
Shigekawa Y, Aikata H, Ohdan H, Marubashi S, Yamada
T, Kubo K, Hirano S, Ishikawa O, Yamamoto M, Yamaue
H, Chayama K, Miyano S, Tsunoda T, Nakagawa H.
Whole-genome mutational landscape of liver cancers
displaying biliary phenotype reveals hepatitis impact
and molecular diversity. Nat Commun 6, 6120 (2015)
Ono A, Fujimoto A, Yamamoto Y, Akamatsu S, Hiraga
N, Imamura M, Kawaoka T, Tsuge M, Abe H, Hayes CN,
Miki D, Furuta M, Tsunoda T, Miyano S, Kubo M, Aikata
H, Ochi H, Kawakami Y, Nakagawa H (corresponding),
and Chayama K. Circulating tumor DNA analysis forliver cancers and its usefulness as a liquid biopsy. Cell
Mol Gastroenterol Hepatol 1, 516–534 (2015)

Invited Presentations
Nakagawa H. “Cancer whole genome and clinicalsequencing for precision medicine” Commemorative
Symposium for the opening of Personalized Cancer
Medicine Care, SNU Cancer Hospital (Seoul, Korea)
October, 2015
Nakagawa H. “Cancer genome profiling by NGS ofarchives and liquid biopsy samples” The 74th Annual
meeting of the Japanese Cancer Association (Nagoya,Japan) October 2015
Nakagawa H. “Whole genome sequencing analysis foriver cancer and genome medicine” (Sapporo, Japan)
June 2015

Figure: Number of samples with a SV breakpoint across chromosome (chr1-22, X).
Bins with STV breakpoints ≥3% frequency are shown in red. Significantly mutated genes (frequency ≥2%) are annotated. TERT was frequently affected by SVs and HBV integration.

C

ancer is essentially a “disease of the genome” which evolves with the accumulation of diverse mutations in the background of germline variants. We
now recognize just how diverse human cancer biology and its underlying genomicchanges are. Germline variants are biomarkers predisposing to cancer development and genetic analysis of certain specific genes, such as BRCA1/2, is commonly
performed for cancer risk. Somatic mutations of driver genes have been targeted
for cancer treatment, and genotype-based personalized cancer therapy is now areality. Understanding of and attention to the underlying genetic diversity in cancer is, therefore, likely to increase the success of new cancer treatment modalities.
Recent explosive advances in next-generation sequencing (NGS) and bioinformatics enable a systematic, genome-wide identification of all somatic abnormalities by whole genome sequencing (WGS), whole exome sequencing, and RNA
sequencing (RNA-Seq). It is important to analyze the likely implications of thehuge genome datasets from NGS and to reach a consensus about how to interpretthe biological and clinical aspects of somatic and germline variants. Our research
objectives are to understand the cancer genome, including germline and somatic
events, by utilizing NGS, to identify novel genomic biomarkers and to develop
analysis platforms that can be used in clinics for precision medicine.

Nakagawa H. “International collaboration for cancer
whole genome sequencing and super-computer”
Symposium of Supercomputer “KEI” and Life Science(Okayama, Japan) June 2015
Nakagawa H. “Decoding whole genomes of liver cancer
toward genomic medicine and impact of chronic inflammation to cancer genome” 2015 SNU Cancer ResearchInstitute Symposium (Jeollanam, Korea) April 201541

Laboratory for

Lab activities

Medical Science
Mathematics
Group Director: Tatsuhiko Tsunoda

Recent Major Publications
Fujimoto A+, Furuta M+, Totoki Y+, Tsunoda T+, Kato
M+ (+: co-first), 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
non-coding and structural mutations in liver cancer. Nat
Genet 48, 500–509 (2016)
Miya F, Kato M, Shiohama T, Okamoto N, Saitoh S,
Yamasaki M, Shigemizu D, Abe T, Morizono T, Boroevich
KA, Kosaki K, Kanemura Y, Tsunoda T. A combination oftargeted enrichment methodologies for whole-exome
sequencing reveals novel pathogenic mutations. Sci
Rep 5, 9331 (2015).

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)).

Fujimoto A, Furuta M, Shiraishi Y, Nguyen HH, Shigemizu D, Gotoh K, Kawakami Y, Nakamura T, Ueno M,
Ariizumi S, Shibata T, Abe T, Boroevich KA, Nakano K,
Sasaki A, Kitada R, Maejima K, Yamamoto Y, Tanaka H,
Shibuya T, Ojima H, Shimada K, Hayami S, Shigekawa
Y, Aikata H, Arihiro K, Ohdan H, Marubashi S, Yamada
T, Ishikawa O, Kubo M, Hirano S, Yamamoto M, Yamaue
H, Chayama K, Miyano S, Tsunoda T*, Nakagawa H*(*: co-last). Whole-genome mutational landscape ofliver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity. Nat Commun 6,
6120 (2015)

T

Invited Presentations
Tsunoda T. “Big data analysis frontiers personalized
medicine” Software Japan 2016, (Tokyo, Japan) February 2016
Tsunoda T. “Omics big data analysis and artificial
intelligence for personalized/preemptive medicine”
Biomedical workshop (Osaka, Japan) October, 2015
Tsunoda T. “Whole Genome Big Data Analysis for Complex Diseases” 3rd Global COE Workshop between BGIand University of Tokyo – Advances in Medical Genomics (Tokyo, Japan) March, 2014
Tsunoda T. “Whole Genome Approach Is Revolutionizing Medicine” The 10th International Workshop on
Advanced Genomics (Tokyo, Japan) May, 2013
Tsunoda T. “Whole genome sequencing and comprehensive mutation analysis of liver cancer” SNUCRI &SNUCH Cancer Symposium (Seogwipo, Korea) May,
2013.

42

he medical application of rapidly progressing omic profiling technologies
and, in particular, the promotion of personalized/precision/preventive medicine have recently become major goals of medical researchers. Traditional therapies do not adequately take into account the individuality of each patient. Ourlaboratory develops strategies to overcome such medical science issues 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, by applying data-mining methodologies, we explore etiologies of intractable diseases, e.g., cancer, common diseases, and neurodegenerative diseases. Next, we classify each disease into finer categories throughmolecular profiles, and clarify disease-causing mechanisms through a systems approach. In this way, we can develop knowledge of disease incidence and progression
based on clinical and omic data. Last, we apply mathematical methods, e.g, machine learning techniques, to optimize therapy prediction for each patient when
she/he visits a hospital/medical institute. We can also apply these methods todisease prevention based on an individual’s medical history. Our laboratory does
biomedical research and genomic medicine research driven by prediction throughcomplete utilization of advanced mathematics and computational sciences withthe goal of developing personalized/precision/preventive medicine strategies. Our
research topics include: (1) exploration of disease etiologies driven by integrative
analysis of clinical and omic data, (2) molecular classification of, and a systems
approach to, understanding disease based on omic profiling, (3) prediction for
personalized/precision/preventive medicine, and (4) the development of methodologies for the above goals.

Laboratory for

Lab activities

Statistical Analysis
Team Leader: Yoichiro Kamatani

Figure: Predictive power of Random Forestmodels.
We constructed prediction models for 43 BioBank Japandiseases by using the Random Forest method. The
predictive power was estimated by the Area Under theCurve (AUC), which was calculated by 10-fold cross-validation for each model. We observed the highest predictive power in rheumatoid arthritis; however, that was
still low and an improved model is required.

Recent Major Publications
Joshi PK, Esko T, Mattsson H, Eklund N, Gandin I, Nutile
T, Jackson AU, Schurmann C, Smith AV, Zhang W, Okada
Y, Stančáková A, Faul JD, Zhao W, Bartz TM, Concas MP,
Franceschini N, Enroth S, Vitart V, Trompet S, Guo X,
Chasman DI, O'Connel JR, Corre T, Nongmaithem SS,
Chen Y, Mangino M, Ruggiero D, Traglia M, Farmaki AE,…, Kamatani Y, et al. Directional dominance on statureand cognition in diverse human populations. Nature
523, 459–62 ( 2015)
Okada Y, Momozawa Y, Ashikawa K, Kanai M, Matsuda
K, Kamatani Y, Takahashi A, Kubo M. Construction of
a population-specific HLA imputation reference panel
and its application to Graves' disease risk in Japanese.
Nat Genet 47, 798–802 (2015)
Debette S, Kamatani Y, Metso TM, Kloss M, ChauhanG, Engelter ST, Pezzini A, Thijs V, Markus HS, Dichgans
M, Wolf C, Dittrich R, Touzé E, Southerland AM, Samson
Y, Abboud S, Béjot Y, Caso V, Bersano A, Gschwendtner
A, Sessa M, Cole J, Lamy C, Medeiros E, Beretta S,
Bonati LH, Grau AJ, Michel P, Majersik JJ, Sharma P, etal. Common variation in PHACTR1 is associated withsusceptibility to cervical artery dissection. Nat Genet47, 78–83 (2015)

Invited Presentations
Kamatani Y. “The largest Asian GWAS of ischemic
stroke” International Stroke Genetics Consortium 2016
(Boston, USA) May, 2016
Kamatani Y. “Finding disease susceptibility genes andgenome cohort study” NGS Field 4th meeting (Tsukuba,
Japan) June, 2015
Kamatani Y. “Statistical analyses used for gene mapping of human diseases” Tokyo Workshop on Statistically Sound Data Mining (Tokyo, Japan) February, 2015
Kamatani Y. “Missing heritability, and a premise inheritability estimates” The 3rd annual meeting of Informatics in Biology, Medicine and Pharmacology 2014
(Sendai, Japan) October, 2014.
Kamatani Y, “How genome cohort study could contribute to reveal disease susceptible genes?” The 58th
annual meeting of Japanese Society of Human Genetics(Tokyo, Japan) November, 2013.

O

ur laboratory aims at analyzing genomic data to identify disease susceptibility genes, as well as developing new statistical methods. Until now, wehave used genome-wide SNP array data and performed genome wide association
studies (GWAS) of dozens of traits including cancers, metabolic diseases, immunological diseases, psychiatric disorders, and so on. These findings will lead tofurther understanding of disease mechanisms, drug discovery, and the possibility to predict occurrences of complex diseases by using genetic information. We
are continuing GWAS of the samples from ~200,000 BioBank Japan subjects with
~30,000 population controls genotyped for nearly a million genetic variants.
We are also trying to address three key issues in this field; missing heritability,
a functional interpretation of the identified genetic variants, and the polygenic
nature of the diseases in question. Firstly, CGM began whole genome sequencing(WGS) of thousands of individuals. By using this data, we could evaluate risk effects of rare variants and structural variations, which are not covered well by SNP
array data and are possible sources of missing heritability. In 2016, three diseases
will be analyzed; myocardial infarction, type 2 diabetes, and gastric cancer.
Secondly, we will focus on the interpretation of GWAS signals. Since it is estimated that the majority of the susceptibility variants for complex diseases will bein gene regulatory regions, evaluation of amino acid changes is not enough, andexperimental validation is necessary. We will use public databases and eQTL dataof lymphocyte subtypes generated by the Laboratory for Autoimmune Diseases tohelp the functional impact of these variants.
Lastly, we plan to use machine- learning techniques to reveal non-additive effects of genomic variants, such as dominance or epistasis effects, which have notbeen investigated well in this field. The novel machine-learning techniques will
facilitate detecting such effects.

43

Laboratory for

Lab activities

Pharmacogenomics
Group Director: Taisei Mushiroda

Recent Major Publications
Mushiroda T, Yanai H, Yoshiyama T, Sasaki Y, Okumura
M, Ogata H, Tokunaga K. Development of a prediction
system for anti-tuberculosis drug-induced liver injury inJapanese patients. Hum Gen Var 3, 16014 (2016)
Saito T, Ikeda M, Mushiroda T, Ozeki T, Kondo K,
Shimasaki A, Kawase K, Hashimoto S, Yamamori H,
Yasuda Y, Fujimoto M, Ohi K, Takeda M, Kamatani Y,
Numata S, Ohmori T, Ueno SI, Makinodan M, Nishihata
Y, Kubota M, Kimura T, Kanahara N, Hashimoto N, Fujita K, Nemoto K, Fukao T, Suwa T, Noda T, Yada Y, Takaki
M, Kida N, Otsuru T, Murakami M, Takahashi A, Kubo
M, Hashimoto R, Iwata N. Pharmacogenomic Study of
Clozapine-Induced Agranulocytosis/Granulocytopenia
in a Japanese Population. Biol Psychiatry (2016) inpress
Low SK, Fukunaga K, Takahashi A, Matsuda K, Hongo
F, Nakanishi H, Kitamura H, Inoue T, Kato Y, Tomita Y,
Fukasawa S, Tanaka T, Nishimura K, Uemura H, Hara
I, Fujisawa M, Matsuyama H, Hashine K, Tatsugami K,
Enokida H, Kubo M, Miki T, Mushiroda, T. Association
Study of a Functional Variant on ABCG2 Gene with
Sunitinib-Induced Severe Adverse Drug Reaction. PLoS
One 11, e0148177 (2016).

Invited Presentations
Mushiroda T, “Pharmacogenomics-based individualization of drug therapy” The 89th Annual Meeting of The
Japanese Pharmacological Society (Yokohama, Japan)
March, 2016
Mushiroda T, “Identification of genomic biomarkers
associated with drug responses for individualization of
drug therapy” The 36th Annual Meeting of The JapaneseSociety of Clinical Pharmacology and Therapeutics (Tokyo, Japan) December, 2015
Mushiroda T, “Clinical utility of genetic testing to avoid
carbamazepine-induced skin rash” The 114th Annual
Meeting of the Japanese Dermatological Association(Yokohama, Japan) May, 2015
Mushiroda T, “Prediction of risk of severe adverse
drug reactions by genetic testing and validation of theclinical utility” The 32nd Annual Meeting of The Japaneseociety of Therapeutic Drug Monitoring (Matsumoto,Japan) May, 2015
Mushiroda T, “Individualization of anticancer therapeutics based on pharmacogenomics” The 2015 Golden
Helix Symposium “Next-generation Pharmacogenomics” (Kuala Lumpur, Malaysia) March, 2015

44

Figure: Scheme of reverse translational pharmacogenomics research for implementation of genetic tests in clinical practice.
We previously reported that carbamazepine-induced skin rash was strongly associated with the HLA-A*31:01 allele in Japanese patients. The GENCAT Study is being
conducted in order to validate a prediction system for risk of carbamazepine-induced
skin rash using a genetic test for HLA-A*31:01. The advanced genetic test for
HLA-A*31:01 should significantly reduce the incidence of carbamazepine-induced skinrash in Japanese, indicating its clinical utility.

Responses to drugs vary widely. Lack of drug efficacy can lead to inadequate
control of disease and is furthermore a waste of resources. Conversely, adverse drug reactions (ADRs) are frequent and often unpredictable. Many genetic
polymorphisms have been identified in genes that affect efficacy or ADR risk forvarious drugs. In the USA, information on germline genomic biomarkers is available on FDA-approved drug labels. In particular, the US FDA strongly recommends genotyping for polymorphisms in drug-metabolizing enzymes and HLA
alleles prior to administration of several drugs, such as eliglustat, nilotinib, pimozide, tetrabenazine, carbamazepine and lapatinib.
By using the samples from Biobank Japan, we are conducting pharmacogenomics (PGx) studies for the identification of genomic biomarkers useful for individualized therapeutics. However, it is difficult for individual countries acting
alone to collect a sufficient number of samples for PGx research. Thus, we areconducting two international PGx collaborations, the South East Asian Pharmacogenomics Research Network (SEAPharm) and US NIH PGRN-RIKEN IMS.
Since our mission is establishment of PGx-based individualization of drug therapy,
the advantages of genomic biomarkers need to be demonstrated with respect toclinical validity, clinical utility and pharmacoeconomics by prospective clinical
trials, leading to implementation of pharmacogenomics in clinical practice.

Laboratory for

Lab activities

Cardiovascular Diseases
Group Director: Toshihiro Tanaka

Figure: Immunohistochemistry of a coronary
artery.
a: expression of FLT1 in endothelial cells (ECs), single
staining, b: Co-localization of FLT1 (brown) and CD31
(blue) in ECs, double staining

Recent Major Publications
Onouchi Y, Fukazawa R, Yamamura K, Suzuki H, Kakimoto N, Suenaga T, Takeuchi T, Hamada H, Honda T,
Yasukawa K, Terai M, Ebata R, Higashi K, Saji T, Kemmotsu Y, Takatsuki S, Ouchi K, Kishi F, Yoshikawa T, Nagai T, Hamamoto K, Sato Y, Honda A, Kobayashi H, SatoJ, Shibuta S, Miyawaki M, Oishi K, Yamaga H, Aoyagi N,
Yoshiyama M, Miyashita R, Murata Y, Fujino A, Ozaki
K, Kawasaki T, Abe J, Seki M, Kobayashi T, Arakawa H,
Ogawa S, Hara T, Hata A, Tanaka T. Variations in ORAI1
gene associated with Kawasaki disease. PLoS One 11,
e0145486 (2016)
Konta A, Ozaki K, Sakata Y, Takahashi A, Morizono T,
Suna S, Onouchi Y, Tsunoda T, Kubo M, Komuro I, Eishi
Y, Tanaka T. A functional SNP in FLT1 increases risk ofcoronary artery disease in a Japanese population. J of
Hum Genet 61, 435–41 (2016)

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 discover the mechanisms underlying these
disorders. We have been using comprehensive genetic analyses of the Japanese
population followed by functional in vitro analyses, and have been among the firstresearchers to describe genetic background effects in myocardial infarction (MI),atrial fibrillation, Kawasaki disease, and peripheral artery disease. Our ultimate
goal is to provide novel diagnostic/therapeutic approaches for such patients. To
this end, we are expanding our research area from genetics to molecular biology,
including in vivo analyses of genetically engineered mice. Also, we are making
efforts to develop a new drug for MI that would elute from a coronary stent, which
would be a powerful tool for coronary angioplasty.

Matsukura M, Ozaki K, Takahashi A, Onouchi Y, Morizono T, Komai H, Shigematsu H, Kudo T, Inoue Y, Kimura
H, Hosaka A, Shigematsu K, Miyata T, Watanabe T,
Tsunoda T, Kubo M, Tanaka T. Genome-wide Association Study of Peripheral Arterial Disease in a Japanese
Population. PLoS One 10, e0139262, 2015

Invited Presentations
Tanaka T. “Pharmacogenomics in Cardiology” University
Seminar at Okayama University (Okayama, Japan) July,
2015
Tanaka T. “Genome Changes Medicine” Forum on Common Diseases and Cognitive Impairment (Kanazawa,
Japan) December, 2015
Onouchi Y. “Susceptibility genes for Kawasaki Disease
identified by genome-wide studies in Japan” 11th Congress of Asian Society for Pediatric Research (Osaka,
Japan) April, 2015

45

Laboratory for

Lab activities

Autoimmune Diseases
Team Leader: Kazuhiko Yamamoto

Figure: The strategy to predict cytokine pathway
activity based on a cell- specific eQTL database.
Left; We utilized upstream regulator analysis provide
by Ingenuity Pathway Analysis (IPA). Z case-control andcorresponding gene names were analyzed. When the
direction of change in candidate causal genes (Z case-control) is consistent with the activated state of the target
cytokine, this gene is identified as an activating gene.
The total effect of each gene on the target cytokine
activity was summarized and Z cytokine was calculated by
IPA. Right; Cell-type specific cytokine activity predicted
in rheumatoid arthritis. Positive Z cytokine score indicatesthat the assessed cytokine is upregulated in RA anda negative score indicates that it is downregulated(Z cytokine < -2 or > 2 correspond to p-value < 0.05).

Recent Major Publications
Sun C, Molineros EJ, Looger LL, Zhou X, Kim K, Okada
Y, Ma J, Qi Y, Kim-H X, Motghare P, Bhattarai K, Adler
A, Bang S-Y, Lee HS, Kim TH, Kang YM, Suh CH, Chung
WT, Park YB, Choe JY, Shim SC, Kochi Y, Suzuki A, Kubo
M, Sumida T, Yamamoto K, Lee SS, Kim YJ, Han BG,
Dozmorov M, Kaufman MK, Wren DJ, Harley BJ, Shen N,
Chua KH, Zhang H, Bae SC, Nath KS. High-density genotyping of immune-related loci identifies new SLE risk
variants in individuals with Asian ancestry. Nat Genet
48, 323–330 (2016)
Yamamoto K, Okada Y, Suzuki A, Kochi Y. Genetics ofrheumatoid arthritis in Asia—present and future. Nat
Rev Rheumatol 11, 375–379 (2015)
Okada Y, Wu D, Trynka G et al. Genetics of rheumatoid
arthritis contributes to biology and drug discovery.
Nature 506, 376–381 (2014)

Invited Presentations
Yamamoto K. “Patogeneses and novel treatments ofosteoporosis” Bangladesh Rheumatology Society (BRS)
Conference-2015 (Dahka, Bangladesh) October, 2015
Yamamoto K. “Genetics and Epigenetics of Rheumatoid
Arthritis” The 17th Asia Pacific League of Associations
for Rheumatology Congress (Chennai, India) September, 2015
Yamamoto K. “Regulatory T cells in human disease”
11th International Congress on Systemic Lupus Erythematosus (Vienna, Austria) September, 2015
Yamamoto K. “A novel regulatory T cell subset controlling B cell functions: a combination of therapeutic
cytokines” 7th International Forum on Rheumatoid
Arthritis (IFRA) (Beijing, China) September, 2015
Yamamoto K. “From human immunology to next generation rheumatology” 59th Japan College of Rheumatology (Nagoya, Japan) April 2015

46

M

ost autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus and Graves’ disease, are multifactorial diseases involving both
genetic and environmental factors. The aim of our laboratory is to elucidate the
etiology of these autoimmune diseases by dissecting their genetic contributions.
Furthermore, through functional analyses of disease-associated variants andgenes together with epigenetic studies, we also clarify the mechanisms of disease
pathogenesis. The majority of disease risk variants of complex traits and diseases
are expression quantitative trait loci (eQTLs) and these eQTLs are working mostly
in a cell type-specific manner. Therefore, subpopulations of immune related cells,such as T cells, B cells, dendritic cells, macrophages and others should be isolated
and investigated. One advantage of research on immune mediated diseases is that
we can relatively easily obtain such immune related cells from human subjects.
Through genetic as well as informatics analyses on these samples, we are investigating the gene expression and functions of each subset of immune related cells
and will dissect their roles in the global immune systems and in several autoimmune diseases.

Laboratory for

Lab activities

Digestive Diseases
Team Leader: Kazuaki Chayama

Figure: Monitoring of serial circulating tumor
DNA (ctDNA) levels.
The ctDNA was quantified by real-time qPCR in sera
serially sampled before and after surgery from a patientwith positive ctDNA (case H1). The figure shows thetime course of serum levels of ctDNA, alpha-fetoprotein(AFP), and des-gamma carboxy prothrombin (DCP) withclinical events and treatments. Levels of ctDNA are
expressed as a ratio relative to levels of those obtainedusing DNA extracted from tumor tissue.

Recent Major Publications
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 N,
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, and Nakagawa H (corresponding).
Whole genome mutational landscape and characterization of non-coding and structural mutations in livercancer. Nat Genet 48, 500–509 (2016)
Fujimoto A, Furuta M, Shiraishi Y, Gotoh K, Kawakami Y,
Arihiro K, Nakamura T, Ueno M, Ariizumi S, Nguyen HH,
Shigemizu D, Abe T, Boroevich KA, Nakano K, Sasaki A,
Kitada R, Maejima K, Yamamoto Y, Tanaka H, Shibuya
T, Shibata T, Ojima H, Shimada K, Hayami S, Shigekawa
Y, Aikata H, Ohdan H, Marubashi S, Yamada T, Kubo M,
Hirano S, Ishikawa O, Yamamoto M, Yamaue H, Chayama K, Miyano S, Tsunoda T, Nakagawa H. Whole-genome mutational landscape of liver cancers displaying
biliary phenotype reveals hepatitis impact and molecular diversity. Nat Commun 6, 6120 (2015)
Akamatsu S, Hayes CN, Ochi H, Uchida T, Kan H, Murakami E, Abe H, Tsuge M, Miki D, Akiyama R, Hiraga N,
Imamura M, Aikata H, Kawaoka T, Kawakami Y, Chayama K. Association between variants in the interferon
lambda 4 locus and substitutions in the hepatitis C
virus non-structural protein 5A. J Hepatol 63, 554–563(2015)

Invited Presentations
Chayama K. “HCV Treatment Update-a New Era of Alloral HCV Treatment” The 46th Annual Meeting of GEST
and The 25th Annual Meeting of DEST (Taipei, Taiwan)
March, 2016
Chayama K. “DAA/PR therapy in Asian HCV patients”
Asian Pacific Digestive Week (Taipei, Taiwan) December, 2015
Chayama K. “All Oral Direct Acting Antiviral Therapy for
Chronic Hepatitis C” Asia-Pacific Congress of Medical
Virology (APCMV) (Taipei, Taiwan) October, 2015

U

sing a GWAS approach, our laboratory has primarily focused on investigating hostgenetic factors for various liver diseases, such as chronic HBV and HCV infection,
HCV-induced liver cirrhosis and cancer, and responsiveness to therapy, including response to interferon therapy and ribavirin-induced anemia.
We have also participated in whole-genome sequencing analyses that have identified several recurrently mutated genes/pathways, HBV integration events, mutations in
non-coding regions, and structural variations associated with liver cancer. By using WGS
data, we analyzed circulating tumor DNA (ctDNA) to develop a non-invasive liquidbiopsy in liver cancer. We found that ctDNA reflects tumor progression and that detection of ctDNA can predict microscopic vascular invasion of the portal vein and cancer
recurrence.
We have now intensively investigated and verified how to apply this genetic information to clinical practice. We demonstrated that ribavirin dose reduction during telaprevir/
ribavirin/peg-interferon triple therapy for genotype 1 chronic hepatitis C is able to overcome the risk of ribavirin-induced anemia in individuals with the ITPA polymorphism.
We also found that polymorphism in the IFNL4 locus predicts the outcome of simeprevir/ribavirin/peg-interferon triple therapy, a more recent treatment for chronic HCV, andthat the ITPA polymorphism influences the decrease of hemoglobin during treatment.
We have studied not only the human genome but also the genome of the hepatitis C
virus to predict and improve treatment response using in vitro and in vivo infection models. We found that the host IFNL4 polymorphism was strongly associated with the HCV
NS5A-Y93H resistance-associated variant, which confers drug resistance to the NS5A
inhibitor class of direct-acting antiviral agents.
In addition, because our GWAS results highlight the importance of the immune
system in the etiology of hepatitis B and C infection, we are currently investigating thehost immune response to viral infection to elucidate the mechanism of hepatitis andcarcinogenesis.

47

Laboratory for

Lab activities

Bone and Joint Diseases
Team Leader: Shiro Ikegawa

Recent Major Publications
Guo L, Yamashita H, Kou I, Takimoto A, Meguro-Horike
M, Horike S, Sakuma T, Miura S, Adachi T, Yamamoto T,
Ikegawa S, Hiraki Y, Shukunami C. Functional investigation of a non-coding variant associated with adolescentidiopathic scoliosis in zebrafish: elevated expression of
the ladybird homeobox gene causes body axis deformation. PLoS Genet 12, e1005802 (2016)
Ogura Y, Kou I, Miura S, Takahashi A, Xu L, Takeda K,
Takahashi Y, Kono K, Kawakami N, Uno K, Ito M, Minami S, Yonezawa I, Yanagida H, Taneichi H, Zhu Z, Tsuji T, Suzuki T, Sudo H, Kotani T, Watanabe K, Hosogane
N, Okada E, Iida A, Nakajima M, Sudo A, Chiba K, Hiraki
Y, Toyama Y, Qiu Y, Shukunami C, Kamatani Y, Kubo M,
Matsumoto M, Ikegawa S. A functional SNP in BNC2 isassociated with adolescent idiopathic scoliosis. Am J
Hum Genet 97, 337–42 (2015)
Sharma S, Londono D, Eckalbar WL, Gao X, Zhang D,
Mauldin K, Kou I, Takahashi A, Matsumoto M, Kamiya
N, Murphy KK, Cornelia R; TSRHC Scoliosis ClinicalGroup; Japan Scoliosis Clinical Research Group, Herring
JA, Burns D, Ahituv N, Ikegawa S, Gordon D, Wise CA.
A PAX1 enhancer locus is associated with susceptibility
to idiopathic scoliosis in females. Nat Commun 6,
6452 (2015)

Invited Presentations
Ikegawa S. “How to identify disease genes in skeletal
dysplasias” Third Scandinavian Skeletal Dysplasia
Workshop (Oslo, Norway) March, 2016
Ikegawa S. “Genome study of bone and joint diseases”
10th International Congress of Chinese Orthopedic Association (Chongqing, China) November, 2015
Ikegawa S. “Genetic study of common bone and joint
disease” 2015 Annual Meeting of Chinese Joint Surgery(Xi'an, China) September, 2015
Ikegawa S. “Combined genetics for rare and commonbone and joint diseases” 12th International Skeletal
Dysplasia Society Meeting (ISDS) (Istanbul,
Turkey) July, 2015
Ikegawa S. “Rare disorders and common problems in
the age of deep sequencing” 9th Annual Introductory
Course on Skeletal Dysplasias (Lausanne, Switzerland)
July, 201548

Figure: Over-expression of BNC2 in zebrafish embryos.
a) Embryos (24 hpf) over-expressing EGFP (control) and BNC2 by tol2-mediated transgenesis. Ubiquitous transgene
expression was confirmed by green fluorescence (left). The BNC2 transgenic embryos exhibit severe body curvatureand malformation of the somite. Scale bars, 1 mm. b) Quantification of phenotypes of embryos over-expressing EGFP
(control) or BNC2. The percentage of the number of embryos that died by 24 hpf (lethal), that had the deformed somites with body curvature (abnormal somite), and that had no apparent abnormality in the somites (normal somite).
c) Zebrafish embryos injected with increasing doses of BNC2 mRNA. The mRNA injection caused body curvature andsevere malformation of the somites in a dose-dependent manner. Arrowhead: delayed pigmentation of the embryo
injected with the mRNA at the higher doses (100 and 200 pg). Scale bars, 500 µm. d) Quantification of phenotypes ofembryos injected with BNC2 mRNAW

e are working on genetic diseases of bone and joints, both common polygenic
and rare monogenic diseases.
1) Genomic Study of Common Diseases
Common bone and joint diseases have become serious concerns for the world health andeconomy, as exemplified by the WHO initiative “Bone and Joint Decade” (2000–2010).
We are searching for susceptibility genes for common (polygenic) bone and joint diseases
including osteoarthritis (OA), lumbar disc disease (LDD)/herniation (LDH), osteoporosis, avascular necrosis of the femoral head (ANF), scoliosis, and ossification of the posterior longitudinal ligament of the spine (OPLL).
Through genome-wide association studies (GWASs) and next-generation sequencing approaches, we identify and characterize susceptibility genes, and clarify their disease-causing mechanism at the molecular level. Using the genome information obtainedby these studies, we will realize our final goal, “order-made medicine”. GWASs for OA,
LDD/LDH, adolescent idiopathic scoliosis (AIS), OPLL, and ANF are in progress, andsome of them have already succeeded in identification of susceptibility genes. Functional
studies of the genes in vitro and using animal model are underway.
2) 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 so many patients are waiting for treatment. We are engaging in the clinicaland basic study of these difficult diseases. By large-scale mutation screening, includingexome sequencing, we are identifying the disease genes.
Though 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 diseases (‘nan-byo’). 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: Shiro Maeda

Figure: Results of GWAS meta-analysis for type 2
diabetes in the Japanese population (15,463 patients with type 2 diabetes vs. 26,183 controls).
Previously identified loci are in black and the sevennovel loci identified in this study are shown in red.

Recent Major Publications
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
RCW, 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 CHT, Hirose H,
Maegawa H, Ito C, Kaku K, Watada H, Tanaka Y, Tobe
K, Kawamori R, Kubo M, Cho YS, Chan JCN, Sanghera
D, Frossard P, Park KS, Shu X-O, Kim B-J, Florez JC,
Tusié-Luna T, Jia W, Tai ES, Pedersen O, Saleheen D,
Maeda S and Kadowaki T. Genome-wide association
studies in the Japanese population identify seven novelloci for type 2 diabetes. Nat Commun 7, 10531 (2016)
Hara K, Fujita H, Johnson TA, Yamauchi T, Yasuda K,
Horikoshi M, Peng C, Hu C, Ma RC, Imamura M, Iwata
M, Tsunoda T, Morizono T, Shojima N, So WY, Leung TF,
Kwan P, Zhang R, Wang J, Yu W, Maegawa H, Hirose H;
DIAGRAM consortium, Kaku K, Ito C, Watada H, Tanaka
Y, Tobe K, Kashiwagi A, Kawamori R, Jia W, Chan JC,
Teo YY, Shyong TE, Kamatani N, Kubo M, Maeda S,
Kadowaki T. Genome-Wide Association Study Identifies
Three Novel Loci for Type 2 Diabetes. Hum Mol Genet23, 239–246 (2014)
Imamura M, Shigemizu D, Tsunoda T, Iwata M, Maegawa H, Watada H, Hirose H, Tanaka Y, Tobe K, Kaku
K, Kashiwagi A, Kawamori R and Maeda S. Assessing
the clinical utility of a genetic risk score constructedusing 49 susceptibility alleles for type 2 diabetes in a
Japanese population. J Clin Endocrinol Metab 98,
E1667–1673 (2013)

Invited Presentations
Maeda S. “Genetic Study of type 2 diabetes in Japan”
2016 International Biomedecal Interface Symposium(Taipei, Taiwan) March, 2016
Imamura M. 58th Annual Meeting of Japan Diabetes
Society (Shimonoseki, Japan) May, 2015T

he total number of individuals with diabetes mellitus is estimated to be over 422
million worldwide, and its prevalence continues to increase in many countries, including Japan. The increasing incidence of diabetic microvascular complications suchas nephropathy and retinopathy, especially among patients with type 2 diabetes, which
accounts for over 90 % of patients with diabetes, is also a serious worldwide concern
in terms of both poor prognosis and medical costs. Although the precise mechanisms
underlying the development and progression of type 2 diabetes or diabetic microvascularcomplications have not been elucidated, it is thought that genetic factors play an important role in the pathogenesis. Introduction of genome-wide association studies (GWAS)
has brought a significant breakthrough in genetic studies of several common diseases,
and over susceptibility 50 loci for type 2 diabetes have been identified as of 2012. However, integration of this genetic information can explain only ~10 % of disease susceptibility,
and thus most of the heritability of type 2 diabetes still remains unidentified. GWAS for
diabetic nephropathy or retinopathy have also been performed by several groups, including ours, but worldwide efforts to identify susceptibility to these diabetic complications
have not met with clear success. Therefore, we have been attempting to expanded GWAS
for type 2 diabetes, diabetic nephropathy and diabetic retinopathy to identify additional
susceptibility loci.
Autosomal dominant polycystic kidney disease (ADPKD) is a common hereditarykidney disease, and most of its heritability can be explained by mutations in PKD1 and
PKD2. The prevalence of ADPKD in patients undergoing chronic renal replacement therapy is between 3.4 and 12.2 %, and the prevalence of clinically diagnosed ADPKD is 1
per 1000~4033. It has been suggested that genetic factors are a powerful indicator of
renal prognosis in patients with ADPKD. However, most of the available findings on themolecular basis of ADPKD have been obtained from studies of European and American
populations, and there are limited data on ADPKD in East Asian populations, including
Japanese. To investigate the genotypic and phenotypic characteristics of ADPKD in Japanese patients, we performed a comprehensive search for PKD1 and PKD2 mutations inJapanese ADPKD patients.
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Laboratory for

Lab activities

Respiratory and Allergic
Diseases
Team Leader: Mayumi Tamari

Figure: Manhattan plot of the multi-ancestry
MANTRA analysis of atopic dermatitis.
Arrows indicate variants not associated in the European-only analysis. The dotted horizontal line shows
the significance threshold for this study, log10 (Bayes
factor) = 6.1.

Recent Major Publications
EArly Genetics and Lifecourse Epidemiology (EAGLE)
Eczema Consortium. Multi-ancestry genome-wide
association study of 21,000 cases and 95,000 controls
identifies new risk loci for atopic dermatitis. Nat Genet
47, 1449–1456 (2015)
Tomita K, Sakashita M, Hirota T, Tanaka S, Masuyama
K, Yamada T, Fujieda S, Miyatake A, Hizawa N, Kubo M,
Nakamura Y, Tamari M. Variants in the 17q21 asthma
susceptibility locus are associated with allergic rhinitis
in the Japanese population. Allergy 68, 92–100 (2013)
Ellinghaus D, Baurecht H, Esparza-Gordillo J, Rodríguez
E, Matanovic A, Marenholz I, Hübner N, Schaarschmidt
H, Novak N, Michel S, Maintz L, Werfel T, Meyer-Hoffert U, Hotze M, Prokisch H, Heim K, Herder C, Hirota
T, Tamari M, Kubo M, Takahashi A, Nakamura Y, Tsoi
LC, Stuart P, Elder JT, Sun L, Zuo X, Yang S, Zhang X,
Hoffmann P, Nöthen MM, Fölster-Holst R, Winkelmann
J, Illig T, Boehm BO, Duerr RH, Büning C, Brand S, Glas
J, McAleer MA, Fahy CM, Kabesch M, Brown S, McLean
WH, Irvine AD, Schreiber S, Lee YA, Franke A, Weidinger
S. High-density genotyping study identifies four new
susceptibility loci for atopic dermatitis. Nat Genet 45,
808–812 (2013)

Invited Presentations
Tamari M. “The Most Important Cause of Asthma inChildren” WAC XXIV World Allergy Congress (Seoul,
Korea) October, 2015Á
Tamari M. Genome-Wide Association Study of Allergic
Diseases, Plenary Lecture, The Annual Meeting of the50th Japanese Society of Pediatric Allergy and Clinical
Immunology (Kanagawa Japan) October, 2013
Tamari M. “Genomics in Allergic Disease” Symposium
24 World Allergy Forum, Omics in Allergic Disease,
European Academy of Allergy and Clinical Immunology& World Allergy Organization World Allergy & Asthma
Congress (Milan, Italy) June, 2013
Tamari M. “Genome-Wide Association Study of Allergic
Diseases” 8th RCAI-JSI International Symposium on
Immunology 2013, Interface between Immune System
and Environment (Kanagawa, Japan) June, 2013
Tamari M. “Genetic Study of Allergic Diseases” Taiwan-Japan Joint Symposium on BioBank and Genomic
Medicine in Academia Sinica (Taipei, Taiwan) May,
2013

50

T

he aim of our project is to explore genetic components of respiratory and allergic diseases. Genome-wide association study (GWAS) is a hypothesis-freemethod to comprehensively assess genes underlying susceptibility to human diseases. Through GWAS and functional analyses, we have identified several genetic
factors for bronchial asthma and atopic dermatitis, and the findings of these studies improve our understanding of the complex heterogeneity of allergic diseases. We participate in the global consortium for meta-analysis of GWASs of atopic
dermatitis (AD). In 2015, a multi-ancestry AD GWAS of 21,000 cases and 95,000
controls including our Japanese data set has been reported. The study identified
a total of 10 new risk loci for AD in Europeans, and six of the 10 loci (PPP2R3C,
ETS1, C1orf51/MRPS21, MIR5708/ABTB10, IL15RA/IL2RA and PUS10) reachedgenome-wide significance across studies of all ancestry groups. With these newones, a total of 31 AD risk loci have been identified. Interestingly, the 3q13.2(CCDC80) and 11p15.4 (OR10A3/NLRP10) loci are likely to be Japanese-specificsignals. Candidate genes at the new loci suggest roles for regulation of innate hostdefenses and T cell functions in the pathogenesis of AD. We also participate in
the Global Alliance between the U.S. NIH Pharmacogenetics Research Network(PGRN) and RIKEN IMS. In this international collaboration, we have conducted pharmacogenomics GWASs and identified several loci that are associated withtreatment responses in subjects with asthma or pulmonary arterial hypertension.
To contribute to the development of better treatment and preventive strategies, wewill conduct further cross-disciplinary studies combining genetics, immunology
and clinical epidemiology for translation of our research into clinical practice.

Program for
Medical Innovations
Six original projects for clinical applications have been performed in 2013:
1) A biochemical drug using a PEGylated Cryj-1/2 fusion recombinant
protein for Cedar Pollinosis has been developed by the Torii pharmaceutical company and IMS and introduced to the Japanese market. 2) A chemical compound recently developed using the α-galactosylceramide (α-GalCer)
analog, RCAI-X, selectively induces apoptosis of IgE but not IgG B cells andpreferentially suppresses IgE production. It therefore potentially could be applied to any type of allergic disorder, such as pollinosis, food allergy, as well
as allergic asthma. 3) NKT cell-targeted therapy for head and neck tumors has
been done in collaboration with Chiba University, and was authorized by theJapanese government as Advanced Medical Treatment B in 2013. 4) The artificial adjuvant vector cell as an anti-tumor vaccine project has been acceptedby 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. 5) 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 Research Center Network for Realization of Regenerative Medicine, Japan in 2013. 6) 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.

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Laboratory for

Lab activities

Immune Regulation
Group Director: Masaru Taniguchi

Figure: Generation of novel Traj18-deficient micelacking Vα14 NKT cells with an undisturbed TCRαchain repertoire.
(A) Newly generated Traj18-deficient mice lack Vα14
NKT cells by flow cytometry analysis. Numbers indicate
percentage of αGC/CD1d dimer+ TCRβ+ NKT cells.
(B) Undisturbed Jα gene usage in newly generated
Traj18-deficient mice as revealed by next generation
sequencing. Bars indicate the percentage of productive
Traj gene transcripts in Cd1d-/- (red bars) and Traj18-/(blue bars) CD4+CD8+ thymocytes. The blue arrow indicates the exclusive absence of Traj18 gene expression
in the Traj18-/- mice.

Recent Major Publications
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 VÁ14 Natural Killer T Cells with an Undisturbed
T Cell Receptor Á-Chain Repertoire. Plos One 11,
e0153347 (2016)
Taniguchi M, Harada M, Dashtsoodol N, Kojo S. Discovery of NKT cells and development of NKT cell-targetedanti-tumor immunotherapy. Proc Jpn Acad Ser B Phys
Biol Sci 91, 292–304 (2015)
Fujii S, Shimizu K, Okamoto Y, Kunii N, Nakayama T,
Motohashi S, Taniguchi M. NKT Cells as an Ideal Anti-Tumor Immunotherapeutic. Front Immunol 4, 409(2013)

Invited Presentations
Taniguchi M. “Alternative developmental pathway ofa Va14+ NKT cell subset bypassing CD4+CD8+ double
positive stage” 2015 CD1-MR1 (Lorne, Australia) November, 2015
Taniguchi M. “NKT cell -mediated adjuvant cell therapy
on lung cancer and head and neck cancer” FOCIS 2014
(Chicago, USA) June, 2014
Taniguchi M. “Discovery of NKT cells and their clinicalapplication” 12th International Symposium on Sjögren’s
Syndrome (Kyoto, Japan) October, 2013
Taniguchi M. “Characterization of the cell with NKT
cell potential in DN1 thymic fraction” 7th International
Symposium on CD1 and NKT Cell (Tours, France) September, 2013
Taniguchi M. “NKT cells as an ideal target for anti-tumor immunotherapy” 15th International Congress of
Immunology (Milan, Italy) August, 2013

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KT cells are characterized by their expression of an invariant T cell receptor(TCR) α chain encoded by Vα14Jα18 in mouse and Vα24Jα18 in humans,
which recognizes glycolipid antigens in association with the non-classical MHC
I, CD1d molecule. In order to achieve highly effective immune responses, NKT
cell-mediated adjuvant activity is essential. In our laboratory, we had been working to clarify the mechanisms of NKT cell development and function, and also toestablish novel NKT cell-targeted immunotherapy for the treatment of any type ofcancers.
Based on current models of NKT cell development, NKT cells are derived
from DP thymocytes similar to conventional T cells. However, we identified a novel NKT cell developmental pathway originating from late DN stage precursors thatbypasses the DP stage, as judged by the following: 1) RORγt, which is essential
for maintenance of NKT cells at DP stage, was not necessary for DN NKT cell
development. 2) Conditional deletion of the Rag2 gene controlled by DP-specific
E8III-Cre resulted in the loss of Vα14-Jα18 mRNA in DP stage cells but not in DN
stage cells, suggesting that NKT cells detected in Rag2-cKO mice are derived from
DN stage precursors. 3) Fate-mapping studies using ROSA26-YFP controlled by
DP-specific E8III-Cre revealed the presence of YFP-negative NKT cells, suggesting that these NKT cells developed directly from the DN stage bypassing the DP
stage. 4) The out-of-frame Vα14-Jα18 sequences were significantly detected in the
DN fraction of RAG2-cKO mice.
NKT cells mediate adjuvant activity and can activate both CD8 cytotoxic T cells
to kill MHC-class I positive tumor cells and also NK cells to eliminate MHC-negative tumors at the same time. The project on the development of an immunotherapy using a novel NKT ligand was approved in 2015 as a Translational Research
Network Program. We generated and selected a novel glycolipid, RK-X, which
induces strong NKT-mediated adjuvant activity and tumor rejection in mice.

Laboratory for

Lab activities

Immunotherapy
Team Leader: Shin-ichiro Fujii

Figure: Secondary response of memory T cells in
aAVC vaccinated mice.
C57BL/6 mice were vaccinated with aAVC-OVA (α-GalCer loaded, CD1d-expressing NIH3T3 cells transfectedwith OVA mRNA)(1st). Antigen-specific CD8+T cells
were maintained in aAVC-OVA vaccinated mice 6month later. Mice were challenged with aAVC-OVA or
DC pulsed with OVA peptide (DC/pep) and robust expansion of antigen-specific T cells was observed.

Recent Major Publications
Shimizu K, Yamasaki S, Shinga J, Sato Y, Watanabe T,
Ohara O, Kuzushima K, Yagita H, Komuro Y, Asakura M,
Fujii S*. Systemic and potent DC activation modulates
the tumor microenvironment and shapes the long-lived
tumor specific memory CD8+ T cells. Cancer Res (inpress)
Sato Y, Shimizu K, Shinga J, Hidaka M, Kawano F, Kakimi K, Yamasaki S, Asakura M, Fujii S*. Characterizationof the myeloid-derived suppressor cell subset regulated
by NK cells in malignant lymphoma. Oncoimmunol 4,
e995541 (2014)
Shimizu K, Sato Y, Shinga J, Watanabe T, Endo T, Asakura M, Yamasaki S, Kawahara K, Kinjo Y, Kitamura H,
Watarai H, Ishii Y, Tsuji M, Taniguchi M, Ohara O, Fujii
S*. KLRG+ invariant natural killer T cells are long-lived
effectors. Proc Natl Acad Sci U S A 111, 12474–12479(2014)

Invited Presentations
Fujii S. “Development of new type of cancer vaccine forestablishment of immune surveillance against cancer”
Scientific seminar for RIKEN centennial anniversary offoundation (Tokyo, Japan) November, 2015
Fujii S. “Development of Novel Type of Cancer Vaccine“aAVC” in RIKEN Drug Discovery and Medical Technology Platforms” The 74th Annual Meeting of The Japanese Cancer Association (Nagoya, Japan) October, 2015
Fujii S. “Immunological memory and antitumor immunity elicited by artificial adjuvant vector cells for cancer
immunotherapy.” The 43rd Annual Meeting of theJapanese Society for Immunology (JSI) (Kyoto, Japan)
December, 2014
Fujii S. ”Development of new type of tumor immunotherapy utilizing NKT-licensed dendritic cells “artificial
adjuvant vector cells. The 6th Society of Immunotherapy for Hematological Disorders (Kyoto, Japan)
September, 2014
Fujii S. “Development of a Novel Type of Cancer Vaccine
Linking Innate and Adaptive immunity.” The 22ndInternational Symposium on Molecular Cell Biology of
Macrophages (MMCB2014) (Kobe, JAPAN) June, 2014T

he aims of the laboratory are to extend basic studies for advancing immunotherapy
and translational research, from basic studies back and forth to the bedside in thefield of cancer and the control of other diseases. For this purpose, we have been focusing
on the following 5 projects related to NKT cells. The synthetic glycolipid, α-galactosylceramide (α-GalCer) as an NKT cell ligand is presented by CD1d molecules to invariant
NKT lymphocytes. When NKT cells were activated in this way, they showed unique immunostimulatory features for innate immunity. First, as a basic study, we have recently
identified memory like KLRG1+NKT cells and have been characterizing them in termsof intrinsic and extrinsic factors (project 1). Additionally, we have been developing translational research projects to establish therapeutic strategies to generate strong antitumor
immunity. We previously reported the full maturation of DCs soon after the activation of
NKT cells in vivo. Based on this observation, we have developed and established artificial
adjuvant vector cells (aAVC) as a new type of drug delivery system composed of NKT
cell ligand and tumor-associated antigen. We have been elucidating the mechanisms bywhich aAVC can augment antitumor effects (project 2). Since this project has also been
accepted by the RIKEN Translational Program and Translational Research center program at Tokyo University, we are making efforts in translational research toward eventual
clinical trials (project 3). As project 4, we work toward the establishment of iPS-NKT cells
to develop an iPS-NKT cell transfer strategy, in a collaborative study with the RIKEN
iPS-group. In this project, our group plays a role in the preparation of primary NKT cells
as starting material for generating NKT cell-derived iPS cells, and analyzing the functionof the iPS-derived NKT cells. As a final project (project 5), we have been working on a
joint clinical phase I /IIa study of NKT cell therapy for early stage post-operative lungcancer patients with the National Hospital Organization (NHO). In this study, our role isthe analyses of immune cells in the trial and also, in collaboration with the RIKEN IMSGenomic Medicine, SNP analysis of responder and poor-responder groups to find suitable biomarkers.

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Laboratory for

Lab activities

Vaccine Design
Team Leader: Yasuyuki Ishii

Figure: Effects of liposomal RK-141 (RK-569) andDexamethasone on airway hyperresponsiveness(AHR) and infiltration of inflammatory cells in
bronchoalveolar lavage fluid (BALF) inducedby ovalbumin (OVA) inhalation challenge in
OVA-sensitized mice.
BALB/c mice were intraperitoneally immunized with
OVA/alum three times weekly. The mice were randomized by serum IgE antibody titers at 7 days after the
final immunization and then treated with two rounds
of intravenous injection of RK-569 at the indicateddoses or with Dexamethasone one day before challenge with six consecutive OVA inhalation treatments.
AHR and the number of cells in BALF were assessed
one day after the last challenge. (A) Airway resistanceafter methacholine (MCh) inhalation was measured
by double chamber plethysmography. Data are themean±SE of 6 mice. Student’s t-test was performed
to compare the non-challenge group with the control
group (†p<0.05, ‡p<0.01) Dunnett’s test was performed
to compare the control group with the RK-569 groups(*p<0.05, **p<0.01) Student’s t-test was performed
to compare the control group with the dexamethasonegroup ( p<0.01) (B) The total volume of each BALF
suspension was adjusted to 1 mL with saline, and cellnumbers/µL were calculated. Data are the mean±SEof 5 or 6 mice. Student’s/Aspin-Welch’s t-test was
performed to compare the non-challenge group withthe control group (†p<0.05) Dunnett’s/Steel’s test was
performed to compare the control group with the RK569 groups (*p<0.05) Student’s/Aspin-Welch’s t-test
was performed to compare the control group with thedexamethasone group ( p<0.05)

Recent Major Publications
Hirai T, Ishii R, Miyairi S, Ikemiyagi M, Omoto K, Ishii Y,
Tanabe K. Clonal Deletion Established via Invariant NKTCell Activation and Costimulatory Blockade Requires In
Vivo Expansion of Regulatory T Cells. Am J Transplant
16, 426–439 (2016)
Hirai T, Ishii Y, Ikemiyagi M, Fukuda E, Omoto K, Namiki
M, Taniguchi M, Tanabe K. A Novel approach inducing
transplant tolerance by activated invariant natural killer
T cells with costimulatory blockade. Am J Transplant
14, 554–567 (2014)
Shimizu K, Sato Y, Shinga J, Watanabe T, Endo T, Asakura M, Yamasaki S, Kawahara K, Kinjo Y, Kitamura H,
Watarai H, Ishii Y, Tsuji M, Taniguchi M, Ohara O, Fujii
S. KLRG+ invariant natural killer T cells are long-lived
effectors. Proc Natl Acad Sci U S A 111,12474–12479(2014)

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atural killer T (NKT) cells play important immunoregulatory roles, such as
suppression of IgE responses, as well as having immuno-stimulatory adjuvant effects in host defense. Although the mechanisms of immune activation by
NKT cells are fairly well understood, those mediating immune suppression haveremained unclear. In our previous studies, we showed that a liposome formulation of α-galactosylceramide (α-GalCer), the prototypical NKT cell ligand, waspreferentially delivered to a splenic B220-positive cell subset. As this subset included IgE-expressing B cells, IL-21 derived from NKT cells was involved in the
induction of B cell-specific apoptosis and, ultimately, IgE isotype-specific suppression. To develop α-GalCer into an IgE-suppressive drug, we screened analogues
and formulations by assessing IL-21 expression by NKT cells from mice injected intravenously with liposomal derivatives. An optimized liposomal α-GalCer
analogue designated RK-141 was screened and assessed for in vivo efficacy andsafety in a mouse experimental asthma model. An intravenous RK-141 injection
just one day before a course of antigen-challenge resulted in the suppression ofserum chemokines and pro-inflammatory cytokines such as eotaxin, keratinocyte-derived chemokine (KC), IL-5 and IL-13. After the full course of challenge,
both airway hyperresponsiveness (AHR) and eosinophil/neutrophil infiltration in
bronchoalveolar lavage fluid (BALF) were significantly suppressed (Figure). Surprisingly, after the antigen challenges, the IgE antibody level in BAL fluid, rather
than in serum, was significantly suppressed, suggesting that systemic administration of liposomal RK-141 might preferentially suppress regional IgE production
in antigen-exposed local organs, a highly beneficial pharmacological outcome.
Liposomal RK-141 is now being developed as a project of the RIKEN Program for
Drug Discovery and Medical Technology Platforms.

Laboratory for

Lab activities

Allergic Disease
Team Leader: Toshiaki Kawakami

Figure: Pathogenic mechanisms for the hypothetical AD-Myeloproliferative Neoplasm (MPN)
Syndrome.
Keratinocyte-derived TSLP together with an impaired
skin barrier seem to play a critical role in dendritic
cell-dependent Th2 responses to offending allergens
or injury. Th2 cytokines predominantly cause an acuteinflammation and activation of several types of cells,
including dermal fibroblasts. Th2 cytokine-stimulated
fibroblasts secrete periostin, an αv integrin-interacting
matricellular protein, which in turn stimulates keratinocytes to secrete TSLP. TSLP also stimulates mast cells
to secrete Th2 and other cytokines. Periostin secretionfrom dermal fibroblasts depends on Th2 cytokines andmast cells, forming at least two positive feedback loops(indicated by thick and thin circular loops). Keratinocyte-derived G-CSF is important for MPN developmentin certain mutant mice. Expression of genes coding for
G-CSF and TSLP is under control of the c-Fos/AP-1 transcription factor, which is positively regulated by EGFR
and negatively regulated by Notch signaling and JunB.
The proliferative and survival properties of hematopoietic stem cells (HSCs) are positively regulated by Stat5,
whose constitutive activation can lead to MPN. PLC-β3
negatively regulates TSLP production in keratinocytes,
periostin production in fibroblasts, and Stat5 activity in
HSCs, mast cells, and Th2 cells. DC, dendritic cell; NICD,
Notch intracellular domain; RBPj, recombination signal
binding protein for immunoglobulin kappa region.

Recent Major Publications
Draber P, Halova I, Polakovicova I, Kawakami T. Signaltransduction and chemotaxis in mast cells. Eur J Pharmacol 778, 11–23 (2016)
Carroll-Portillo A, Cannon JL, te Riet J, Holmes A, Kawakami Y, Kawakami T, Cambi A, Lidke DS. Mast cells
and dendritic cells form synapses that facilitate antigentransfer for T cell activation. J Cell Biol 210, 851–864(2015)
Kawakami T, Ando T, Kawakami Y. Hypothetical atopic
dermatitis-myeloproliferative neoplasm syndrome.
Front Immunol 6, 434 (2015)

Invited Presentations
Kawakami T. National Jewish Heath, University of Colorado (Denver, USA) March, 2016
Kawakami T. The 7 EMBRN International Mast Celland Basophil Meeting, Keynote Speaker (Marseille,
France) October, 2015th

Kawakami T. SPC-NUS Workshop (Paris, France) October, 2015
Kawakami T. University of Pittsburgh (Pittsburgh, USA)
September, 2015
Kawakami T. IMMUNOLOGY 2015, Block Symposium:
Mast cell biology (New Orleans, USA) May, 2015

Role of histamine-releasing factor (HRF) in allergic diseases
HRF is a cytokine-like protein that can stimulate histamine release and cytokine(IL-4 and IL-13) production/secretion from IgE-sensitized basophils and mast
cells. HRF activities are found in bodily fluids during the late phase of allergic
reactions. We demonstrated that some, but not all, IgE and IgG molecules interact
with HRF with low affinity. By mapping the binding sites on both HRF and IgE/
IgG molecules, we developed competitive inhibitors of HRF-IgE (or IgG) interactions. Using these inhibitors, we showed that HRF promotes allergic inflammation in mouse models of anaphylaxis and asthma (Kashiwakura et al., 2012).
These findings could be explained by a model where the FcεRI (high-affinity IgE
receptor) on mast cells/basophils is cross-linked by receptor-bound IgE and HRF
dimers, resulting in release of histamine and other allergic mediators. For the past
three years, we have been studying the role of HRF in food allergy. Using an ovalbumin-induced food allergy model, we showed that HRF is involved in the promotion of allergic reactions including diarrhea (unpublished). These and humanimmunotherapy results support the efficacy of the HRF inhibitors as potential
therapeutics for food allergy.
Pathogenic mechanisms of atopic dermatitis (AD)AD is a chronic pruritic inflammatory skin disease. As part of the AD project,
we have been studying its cellular and molecular mechanisms using our previously established in vivo AD induction model and the spontaneously occurring
AD-like skin lesions in phospholipase C (PLC)-β3-deficient mice. We showed theimportance of PLC-β3-mediated Stat5 regulation in mast cells in causing AD andthe crucial role of FcεRI in allergen-induced AD (Ando et al., 2014). Althoughbasophils express the αβγ2-type FcεRI, similar to mast cells, basophils seem dispensable in allergen-induced AD (Ando et al., unpublished).

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Lab activities

Drug Discovery
Antibody Platform Unit
Unit Leader: Toshitada Takemori

Figure: A possible mechanism of direct killing of
B cell lymphomas by HLA-DR engagement.
As a member of the tetraspan family of integral
membrane proteins is highly enriched in MHC class
II-containing compartment (MIICs), we are analyzing
the possibility that a tetraspanin (X) forms a complex
with HLA-DR upon stimulation with L243 mAbs andmediates the non-apoptotic killing signal, indepently of
the HLA-DR cytoplasmic domains.

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)
Takemori T, Kaji T, Takahashi Y, Shimoda M, Rajewsky K.
Generation of memory B cells inside and outside germinal centers. Eur J Immunol 44, 1258–1264 (2014)
Takemori T. Generation of memory B cells. In: Alt F,
Honjo T, Radbruch A, Reth M. (eds.), Molecular Biology of B cells 2nd edition, London, UK: Academic Press/
Elsevier, pp. 227–230 (2014)

Invited Presentations
Takemori T. “Antibody Drugs on Cancer” A basic lecture,
Sanofi Ltd. (Tokyo, Japan), July (2015)
Takemori T. “CD4 memory T cells develop and acquire
functional competence by sequential cognate interactions and stepwise gene regulations.” Symposiumon the International Leibniz Research Cluster ImmunoMemory (Berlin, Germany) November, (2014)
Takemori T. “CD4 memory T cell development islicensed by Bcl6 and accomplished by expression ofa group of genes mediated by cognate B cell interactions.” The 36th annual meeting of the Molecular Biology of Japan (Kobe, Japan) November (2013)56

T

his laboratory creates monoclonal antibodies (mAbs) that are candidates for
antibody drugs to meet medical needs. In this context, we developed a systemthat allows for rapid selection of clones secreting antibodies that have high physiological activity from a number of clones during hybridoma cultivation. In thisLaboratory, mAbs prepared by hybridoma technology are then generally modified to produce human chimeric or sometimes humanized mAbs. In addition, theLaboratory is now developing new systems to prepare human mAbs directly fromtarget antigen-specific human B cells in peripheral blood or by utilizing the Ribosomal Display System, in collaboration with the Laboratory for Cell-Free Protein
Synthesis at the RIKEN Quantitative Biology Center.
We are now trying to establish mAbs that will be candidate drugs for AML andfor blocking HBV infection and are analyzing the mechanism of direct killing of a
B cell lymphoma cell line by an anti-HLA-DR mAb.
The HLA-DRα/β heterodimer is highly expressed on B cell lymphomas, andthe engagement by mAbs, such as L243, directly kills the cells via a non-apoptotic
cell death, although HLA-DR molecules do not possesses any known signaling
motifs in their cytoplasmic and transmembrane domains. The ability of such antiHLA-DR mAbs may present a clinical advantage over conventional therapeuticmAbs for leukemia/lymphoma.
To understand the killing mechanism, we have established a mutant B cell lymphoma cell line that is deficient in HLA-DRα expression as a result of genomic
manipulation using the CRISPR-Cas9 system. To identify which HLA-DRα region
was responsible for mediating the killing activity upon stimulation with the L243
mAb, the HLA-DRα mutant cell line was transfected with chimeric HLA-DRαmutants, followed by L243 stimulation. The results suggest that HLA-DRα is not
the element responsible for transducing the killing activity upon L243 stimulation.

YCI program

YCI Laboratory for

Stem Cell Competency
Young Chief Investigator: Hayato Kaneda

A

Figure: Restoration of muscle repair capacity by upregulation of GDF6 in old(24 month) mice.
Mesenchymal stem/stromal cells (MSCs) are well known to secrete a variety of homeostatic factors; however no critical factors had been identified yet. We identified GDF6
and investigated its effects on age-related disorders by lentiviral transduction into old
mice. We found that GDF6 exerted positive effects in vivo on aging-associated pathologies such as reduced lymphopoiesis, insufficient muscle repair, reduced numbers ofneural progenitors in the brain, and chronic inflammation.

dult tissue stem cells (TSCs) become functionally impaired withage. TSC dysfunction and decreased regenerative capacity are involved, at least in part, in age-associated disturbances of tissue homeostasis, e.g., inefficient muscle repair, reduced bone mass, neurodegenerative
diseases, and dysregulation of hematopoiesis. Therefore, the restorationof TSC functions is expected to contribute to recovery of tissue homeostasis and improvements in our health.
Previously, we identified the “competence change”, which is responsible for the responsiveness of neural stem/progenitor cells (NSPCs) to
extrinsic signals (Naka et al., Nat Neurosci, 2008). Moreover, further investigation revealed that competence regulation enabled us to control theneurogenic-to-gliogenic transition and restore neurogenic potential indevelopmentally-progressed gliogenic NSPCs (Naka-Kaneda et al., Proc
Natl Acad Sci USA, 2014). Based on these findings, we have been investigating stem cell aging. Competence regulation is also involved in the
aging of other TSCs, such as the decline in differentiation potential inhematopoietic stem cells and mesenchymal stem/stromal cells. We also
found that restoration of stem cell functions may improve geriatric disorders (Figure, Hisamatsu et al., Aging, 2016). We aim to elucidate thecentral molecular machinery of stem cell aging and its influence on tissue
homeostasis and, in turn, to develop a method for functional recovery ofaged stem cells and restoration/maintenance of tissue homeostasis.

YCI Laboratory for

Immune Regeneration
Young Chief Investigator: Tomokatsu Ikawa

T

Figure: Genome-wide gene
expression profiles during
B lineage commitment.
(A) Scheme for sample
collection. The induced
Leukocyte Stem (iLS) cells
were induced to differentiate
into B lineage cells by
withdrawing 4-OHT. The cells
at the indicated time points
were harvested, the RNA was
purified and RNA-seq analysis
was performed. (B) Expression
profiles of differentiallyexpressed genes. Gene
expression was separated
into ten clusters (I-X) basedon expression pattern andkinetics. Representative genes
are shown in every cluster
and transcription factors arehighlighted in red.

, B and NK lymphocytes are generated from pluripotent hematopoietic stem cells (HSCs) through a successive series of lineage restriction process. Transcription factors (TFs) play a key role in regulating
lineage-associated gene programs. Although many essential TFs, such as
PU.1, Ikaros, GATA3, TCF-1, Bcl11b, E2A, EBF1 and Pax5 have been implicated in regulating the cell fate choice of lymphoid lineages, molecularmechanisms underlying the generation of these patterns during cell fate
determination remain unexplored because of the lack of suitable experimental systems.
We have recently established stable multipotent progenitor cells,
termed induced Leukocyte Stem (iLS) cells, that can be used to examine gene regulatory networks during lymphoid lineage specification from
HSCs (Figure, Ikawa et al. Stem Cell Reports, 2015). This novel systemenabled the analysis of a large set of regulatory molecules that control
the generation of T and B lymphocytes. It can also be applied for ex vivo
expansion of human hematopoietic stem/progenitors, which will be required for immune cell therapy or transplantation of HSCs. Thus, theaims of our study are 1) from a basic science perspective, to elucidate themechanisms that orchestrate cell fate specification, commitment and differentiation during lymphocyte development and 2) from a clinical medicine perspective, to establish a novel method to expand human hematopoietic stem/progenitors for the development of HSC transplantation asa clinical strategy.

57

YCI program

YCI Laboratory for

Quantitative Omics
Young Chief Investigator : Katsuyuki Shiroguchi

Figure: Digital RNA Sequencing(JSI Newsletter vol.24-2, p21)

Quantitative Omics at the Single Cell and Single Molecule
Level for Biological and Medical Sciences
In order to understand biological systems and contribute to
medical sciences, we have been developing quantitative methods
for system-wide genomic analyses. We established a platform for
digital RNA sequencing (dRNA-Seq) including cell collection,
cDNA library preparation, sequencing, and computational analysis,
which provides results of genome-wide gene expression profiling inthree days. Using this platform, we established numerous collaborations with researchers inside and outside of IMS, for example, in theanalysis of limited numbers of immunologically-related cells. We
also have been developing a novel method to measure many cells
simultaneously to observe cell-number distributions with single
cell resolution. This high throughput and high resolution analysis
enables us to identify the state of biological systems based on cell
heterogeneity. Using these methods, we are developing applications
to contribute to medical sciences as well. I think that understanding
cell heterogeneity within a population is important for understanding overall population function. Therefore, the accurate measurement of cell heterogeneity will allow linkage of different biologicallayers, from cells to tissues to organisms.

YCI Laboratory for

Cellular Bioenergetic Network
Young Chief Investigator : Toshimori KitamiT

he central goal of our laboratory is to understand the role ofcellular metabolism in the pathogenesis of complex diseases.
Research over the past decades has shown that monogenic mutations in metabolic pathways cause a large number of humandiseases. However, more recent studies have highlighted therole of cellular metabolism in the development of a wide varietyof complex human diseases. Our laboratory in particular has been
studying the function of mitochondrial energy metabolism, whichis associated with neurodegeneration, cardiovascular disease, type 2
diabetes, and aging. We use genetic and chemical screens to identify
novel pathways that restore or improve mitochondrial function andplan to examine their potential therapeutic value using geneticallyFigure: Chemical dissection of the NLRP3 inflammasome pathway
We have identified a handful of chemicals involved inmodifying NLRP3 inflammasome activation. We hope to
use these chemical tools to dissect the role of mitochondria in complex disease pathways.

58

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 a variety of complex diseases. The
NLRP3 inflammasome is activated by changes in cell physiology,
including mitochondrial damage, although the molecular players
involved have not been fully elucidated. We hope to leverage ourexpertise in high-throughput screens to systematically identify
genes and pathways involved in NLRP3 inflammasome activationand to place mitochondria in the context of this important disease
pathway.

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 Lab provides a range of support for flow cytometry andcell sorting, techniques that are essential for nearly all immunological experiments. The FACS Lab has upgraded all FACS Arias and added
an Aria Fusion. In addition to FACS machines, the lab installed ImageStreamX, a device that combines flow cytometry with the visual detailof microscopy in a single platform, and upgraded CyTOF2, a mass-spectrometry-based cytometer that has the potential for analyzing more than
30 markers simultaneously with metal-labeled antibodies.
In 2015, 1611 analytical and 1963 sorting experiments were performed in the lab. For the users of the FACS machines (cell analyzers
and cell sorters), two staff members offer various services: (1) Technicalsupport and training: In 2015, the facility offered 11 technical courses (7for cell sorting and 4 for cell analysis). Courses were held at 3 different
levels, Calibur basic, Canto II and Aria basic. A total of 60 researchers
took the courses in 2015. (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 2015, thelab provided 205 such operation services. Special cell sorting techniques,
such as single cell sorting, have also been performed. (3) Management/

maintenance of FACS machines: FACS machines are available for registered users 24 hours a day and reservations are accepted up to one monthin advance through 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 in the FACS Lab.
Machine types

Machines# of machines

FACS cell analyzer

Calibur
Canto II

4
2

FACS cell sorter

Aria II
Aria III
Aria Fusion

3
2
1

Mass-cytometer

CyTOF2

1

Imaging flow cytometer

ImageStreamX

1

Confocal LaboratoryThe Confocal Lab. provides equipment for cell and tissue imaging, and coordinates technical support. There are sevenlaser-scanning fluorescence microscopes and a super-resolution
microscope available to researchers at IMS.
1. IInverted Leica SP2 system with visible lasers for single-photon
excitation and a femtosecond Ti:Sa laser for two-photon excitation.
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 SP5 system with visible lasers for single-photon
excitation including a 405 violet laser.
4. Upright Leica SP2 system with visible and UV lasers for single-photon excitation.
5. Inverted Leica SP8 system with visible lasers for single-photon
excitation. SP8 is Leica’s newest system with improved optics.
6. Upright Leica SP5 system with two femtosecond Ti:Sa lasers for
two-photon excitation. This system utilizes resonant scanners

Photo: Upright SP5 two-photon microscope (#6)

that enable high-speed acquisition of large z-stacks for live tissue
imaging.
7. Inverted Leica SP8 system with two femtosecond Ti:Sa lasers for
two-photon 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.
8. Inverted Nikon N-SIM/N-STORM super-resolution microscopefor dual color imaging.

59

Central Facilities

Genomics LaboratoryWe are a technical support service lab that provides genomeand proteome-wide analysis for research groups in theCenter for Integrative Medical Sciences (IMS). We offer a variety ofservices to suit the needs of different labs. These include DNA sequencing, proteomics analysis, multiplex suspension array, cDNA/
Genomic clone distribution, and Primer/labeled probe distribution for qRT-PCR analysis of immune cells (TABLE). Supplying
advanced technologies on demand, we provide comprehensive interrogation of the nucleic-acid based information in a cell at single-base resolution with the Illumina HiSeq1500 and as well as proteomic approaches using the AB SCIEX TripleTOF 5600. Using thisunbiased sequencing approach, we have interrogated: transcription
units, mapping/genome annotation, alternative splice sites, andtranscription factor binding sites. Our mass spectrometry system
will make it possible to use quantitative proteomic approaches invarious 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 2015
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

1,086
277
413

31
7
10

# of samples# of teams

1
2,708

1
6

# of samples# of teams

36cm capillary
50cm capillary

5,313
3,602

16
15

cDNA clone delivery# of samples# of teams

34
Primer/labeled probe delivery# of samples
173# of teams
1

Animal FacilityWe maintain over 50,000 mice in the SPF (specific pathogenfree) area and 1,500 mice in the isolated area. In addition,
the SPF area contains 550 germ-free or gnotobiotic mice maintainedin vinyl isolator rooms, and in vinyl isolator bio-bubble rooms. The
former is used by several IMS research groups, in particular the
mucosal immunologists; while the latter is used for maintenance of“humanized mice”.
We introduce mouse lines into the SPF area by a combinationof in vitro fertilization (IVF) and embryo transfer techniques. We
have also generated cryo(frozen)-stocks of genetic resources for 713
lines. At the same time, we maintain relatively large colonies of several commonly used strains such as NOD/SCID/common γ chain
KO (NSG) mice, Rag1 KO mice and Cre delete mice; and provide
them to users on demand.
We also provide technical assistance to generate knockout andtransgenic mice (57 lines already established). Furthermore, we
made 121 KO and KI mouse lines using the CRISPR/Cas technique,and have created 13 lines of germ-free mice.
We have recently launched a new activity to improve the efficacy of transplantation of human hematopoietic stem cells into NSG
mice (see above), by enhancing the degree of “humanization” ofthe host strain. For this purpose, we have introduced large genomic fragments containing human genes encoding MHC, cytokines,
adhesion molecules, virus receptors and others, into the NSG mice.
We maintain transgenic mice and six knock-in mice with confirmed
expression of human genes on a C57BL/6 background; and have

60

started backcrossing these mice into the NSG background, using
the speed-congenic method.

Photo: Creation of germ-free mouseAward winners 2015

Award winners

Name of the awardee

Name of the award

Date of theannouncement

Kazuhiko Yamamoto,Team Leader, Laboratory for Autoimmune Diseases

Carol Nachman Award

May, 2015

Toshitada Takemori,
Unit Leader, Drug Discovery Antibody Platform Unit

The Order of the Sacred Treasure, Gold Rays with RosetteApr, 2015

Kenya Honda,
Team Leader, Laboratory for Gut Homeostasis

The 18th Japanese Society for Immunology (JSI) Award

Nov, 2015

Masayuki Amagai,
Team Leader, Laboratory for Skin Homeostasis

Authur Rook Oration from British Association of Dermatologists

Jul, 2015

Masayuki Amagai,
Team Leader, Laboratory for Skin Homeostasis

Honorary Membership of the European Society for Dermatological ResearchSep, 2015

Masayuki Amagai,
Team Leader, Laboratory for Skin Homeostasis

Honorary Membership of the German Society of Dermatology

Nov, 2015

Naoto Kubota,
Team Leader, Laboratory for Metabolic Homeostasis

The Masato Kasuga Award for Outstanding Scientific Achievement, The Asian
Association for the Study of Diabetes

Nov, 2015

Naoto Kubota,
Team Leader, Laboratory for Metabolic Homeostasis

Outstanding Scientific Achievement Award of the Japan Society of Experimental
Diabetes and ObesityFeb, 2015

Masato Kubo
Team Leader, Laboratory for Cytokine Regulation

Tokyo University of Science Outstanding Scientist of the Year 2014

May, 2015

Yuuki Obata,
Graduate Student, Laboratory for Intestinal Ecosystem

JSPS (Japan Society for the Promotion of Science) Ikushi Prize

Mar, 2015

Yuuki Obata,
Graduate Student, Laboratory for Intestinal Ecosystem

Chiba University President Award for Research Excellence

Mar, 2015

Yuuki Obata,
Graduate Student, Laboratory for Intestinal Ecosystem

Chiba University Dean of the Graduate School of Medical and Pharmaceutical
Sciences Award for Research Excellence

Mar, 2015

Ikuyo Inaba,
Senior Scientist, Laboratory for Bone and Joint Diseases

Young Investigator Award, Japanese Society of Human Genetics

Oct, 2015

Ikuyo Inaba,
Senior Scientist, Laboratory for Bone and Joint Diseases

The 6th RIKEN Researcher Incentive Award

Mar, 2015

Takashi Kanaya,
Research Scientist, Laboratory for Intestinal Ecosystem

The 6th RIKEN Researcher Incentive Award

Mar, 2015

Tomomitsu Hirota,
Research Scientist, Laboratory for Respiratory and Allergic Diseases

Letter of Appreciation from the President of RIKEN

Jan, 2015

Kazuyo Moro,
Senior Scientist, Laboratory for Immune Cell System

World Immune Regulation Meeting IX, Best Workshop Presentation Award

Feb, 2015

Akihiro Fujimoto
Deputy Team Leader, Laboratory for Genome Sequencing Analysis

Best Paper Award in the Annual Meeting of the Genetics Society of Japan

Nov, 2015

Yoji Ogura, Visiting Scientist and Shiro Ikegawa, Team Leader,
Laboratory for Bone and Joint Diseases

The John H. Moe Award, Scoliosis Research Society

Oct, 2015

Tomomitsu Hirota,
Research Scientist, Laboratory for Respiratory and Allergic Diseases

Travel grant, XXIV World Allergy Congress (WAC2015)

Oct, 2015

Rumiko Ono,
Junior Research Associate, Laboratory for Inflammatory Regulation

Ursula and Fritz Melchers Travel Award (Japanese Society of Immunology)

Dec, 2015

Kentaro Inoue,
Postdoctoral Researcher, Laboratory for Integrated Cellular Systems

Research Incentive Award (Japanese Society for Bioinformatics 2015)

Oct, 2015

Chikako Shimokawa,Research Scientist, Laboratory for Intestinal Ecosystem

Tadamitsu Kishimoto International Travel Award

Apr, 2015

Takayuki Imanishi,
Research Scientist, Laboratory for Cell Signaling

Tadamitsu Kishimoto International Travel Award

Sep, 2015

Miho Tanaka,
Technical Staff, Drug Discovery Antibody Platform Unit

DMP Achievement Award

Mar, 2015

Akiko Ishige-Sugimoto,Technical Staff, Drug Discovery Antibody Platform Unit

DMP Achievement Award

Mar, 2015

61

RIKEN International Program Associate
(IPA)

I

MS accepted four international students as RIKEN International Program Associates (IPA). Under this IPA program, IMS
lab heads host international students from collaborating graduate
schools and supervise their Ph.D. program as Joint Supervisors. The
students receive a daily living allowance and housing costs for up toa maximum of three years.
The IPA students who studied at IMS in 2015 were
Krutula Nair (Graduate School of Frontier Biosciences, Osaka Uni-

Other programs

versity) from India studied in the Laboratory for Transcriptional
Regulation.
Tsermpini Evangelia (University of Patras, Greece) studied in the
Laboratory for International Alliance on Genomic Research.
Kong Mei Suen (University of Science, Malaysia) studied in the
Laboratory for Cell Signaling.
Chanyoung Shin (Tokyo Institute of Technology) from Korea studied in the Laboratory for Inflammatory Regulation.

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 2015, three young researchers studied at IMS as RIKEN FPRs.

Wooseok Seo studied in the Laboratory for Transcriptional
Regulation.
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, 21 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)
Ryohei Aoyagi (Laboratory for Metabolomics)
Yuki Furuichi (Laboratory for Skin Homeostasis)

Tadashi Takeuchi (Laboratory for Intestinal Ecosystem)
Rintaro Ono (Laboratory for Human Disease Models)
Rumiko Ono (Laboratory for Inflammatory Regulation)
Takaharu Sasaki (Laboratory for Immune Cell Systems)
Tomohiro Miyai (Laboratory for Immune Cell Systems)
Yujiro Yamamoto (Laboratory for Genotyping Development)
Yurina Miyajima (Laboratory for Innate Immune Systems)
Takato Kobayashi (Laboratory for Innate Immune Systems)
Toshihiro Morita (Laboratory for Gut Homeostasis)
Takaaki Kawaguchi (Laboratory for Gut Homeostasis)
Kensuke Yamaguchi (Laboratory for Autoimmune Diseases)
Keiichi Masaki (Laboratory for Digestive Diseases)
Yuma Sakamoto (Laboratory for Bone and Joint Diseases)
Hirotsugu Oda (Laboratory for Integrative Genomics)
Ye Liu (Laboratory for International Alliance on Genomic Research)

RIKEN Special Postdoctoral Researcher (SPDR) Program

R

IIKEN’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, five postdocs conducted their research at IMS through62

the SPDR program.
Guillermo Juan Betancur Medina (Laboratory for Developmental
Genetics)
Takeshi Tanoue (Laboratory for Gut Homeostasis)
Jun Miyata (Laboratory for Metabolomics)
Yosuke Isobe (Laboratory for Metabolomics)
Motomura Yasutaka (Laboratory for Innate Immune Systems)

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 and to thedevelopment of therapeutics. On a collaborative basis with individual 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 focused on establishing a robust protocol
to prepare functional human Vα24+iNKT cells through iPSCs (iPS-

ProjectVα24+iNKT). Indeed, they confirmed that such iPS-Vα24+iNKT
cells can be activated by ligand-pulsed dendritic cells (DCs) andcan produce a large amount of interferon-γ upon activation, as
much as the parental Vα24+iNKT cells. Moreover, iPS-Vα24+iNKT
cells showed much more potent cytotoxic activity against tumor celllines than that of the parental Vα24+iNKT cells. These results arevery encouraging for potential clinical application of human iPSVα24+iNKT cells for tumor immunotherapy. A CPC (Cell Processing Center) has been constructed in IMS (named IMS CMU: Cell
Manufacturing Unit). The facility has started the operation of IMS
CMU to prepare iPS-Vα24+iNKT cells under GMP (Good Manufacturing Practice)/GCTP (Good Gene, Cellular, and Tissue-based
Products Manufacturing Practice) guidelines to apply them to preclinical studies.

Figure: Preparation of functional human iPS-Va24+iNKT cells.
(A) Identification of rearranged TCRα and TCRβ chain gene segments in established
Va24+iNKT-iPSCs. (B) Comparison of global gene expression by RNA-seq analysis
of human iPS-Va24+iNKT cells and a Va24+iNKT line upon stimulation with murine
DC/Gal for 6h. (C) IFN-γ production by a Va24+iNKT line (left) or iPS-Va24+iNKT cells(right). The cells were co-cultured with murine DC, DC/Gal or nothing for 24 h. IFN-γ
production was measured by ELISA. (D) Cytotoxic activity of a Va24+iNKT cell line or
iPS-Va24+iNKT cells against a panel of tumor cell lines. Va24+iNKT cells (upper) and
iPS-Va24+iNKT cells (lower) were prepared as effector cells. Cells were mixed with thetumor cell lines (K562, NCI-H460, A549, HT-29, COLO 205 and Detroit 562) at ratios of
5:1 or 10:1 and incubated for 6 h, then cytotoxicity was assessed by an LDH assay.

Modeling skin diseases

Human immune-mediated diseases develop and progress throughhighly complex processes in which various types of immune cells
sequentially infiltrate into the sites of inflammation, interact with resident non-immune cells and induce a series of inflammatory mediators,
finally causing pathological symptoms and tissue damage. To tackle
such complexity, IMS has constructed center-wide projects to clarify
the pathogenesis of human diseases, including atopic dermatitis (AD).
In each project, multiple research groups work interactively and synergistically to understand the molecular and cellular networks leading todisease development.
In the atopic dermatitis project, we take advantage of AD mousemodels, including Spade, a mutant mouse line established in RIKENIMS (J. Clin. Invest. 2016, 126: 2064-2076), and STAT3-deficient mice.
Drs. Yoshida and Kubo investigate the RNA-seq-based gene expression
profiles of pre-symptomatic events occurring in skin from birth to theonset of dermatitis at ~ 12 weeks. Using their samples, Dr. Ohara’s grouphas conducted transcriptome analysis, and Drs. M. Okada and Kitano’s
groups have established an integrated feedback model of AD progression.
Dr. T. Okada examines the nerve fiber structure in skin by confocal fluorescence microscopy. Drs. Amagai and Tsunoda have been working to

Figure: Pre-symptomatic RNA-seq analysis of skin in the Spade AD mousemodel
Using novel prediction methods, we elucidate dynamic changes in transcriptional
regulation during the development of dermatitis by transcript profiling of the Spademice at high temporal resolution using RNA-seq. FDR; false discovery rate.

64

connect the findings in mouse and human AD to discover any common
mechanisms of disease onset.
Moreover, Dr. Taylor’s group has developed an integrated databasefor various types of experimental data, including flow cytometry data,
immunohistochemistry images, blood profiles, RNA-seq data. They arecooperating with the experimental labs led by Drs. Yoshida, Kubo, T.
Okada and Amagai, and the computational analysis/modeling labs led
by Drs. M. Okada, Kitano, Ohara and Tsunoda.

Project

Impact of host-gut microbiome interactions
on the pathogenesis of diabetesR

ecent studies of the gut microbiome indicate that changes in
its composition and the loss of microbial diversity, or dysbiosis, are not the consequence but rather the cause of various diseases (Figure). Type 2 diabetes (T2D) is one such disease. As an IMS
Center project, we are using our comprehensive multiple omics
approach to determine the impact of host-gut microbiome interactions on the pathogenesis of type 2 diabetes. The project is a collaboration with Professors Takashi Kadowaki and Tsutomu Yamazaki
from the University of Tokyo Hospital and Professor Masahira Hattori from Waseda University. From RIKEN IMS, the Laboratories
for Metabolic Homeostasis, Intestinal Ecosystem, Metabolomics,
Integrative Genomics, and Integrated Bioinformatics are mainly
involved in this project. Fecal metagenomic, metatranscriptomic
and metabolomic data, as well as plasma and urine metabolomic

data will be obtained from three groups of volunteers undergoinga 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, or blood glucose after a meal ≥ 140 mg/dl, HbA1c 6.0%).
In addition, exomes and SNPs of T2D susceptibility genes will beanalyzed. The goal is to identify T2D risk factors, such as certain
bacteria and/or their metabolites, by analyzing the meta data fromthe comprehensive multiple omics analyses, combined with clinical and genetic datasets. 100 volunteers have already been recruitedfor Group 1, and 50 each have participated so far in the other twogroups.

Figure: The contribution of dysbiosis to pathogenesis.
In healthy individuals, the gut microbiota is robust and resistant to perturbations caused by antibiotics and bacterial/viral
infections, for example, and can quickly recover and maintainits composition within a normal range to sustain homeostasis, or symbiosis. However, in susceptible individuals, genetic
predispositions may make it difficult to maintain homeostasis
once the composition of their microbiome is perturbed andthe change becomes irreversible. The resultant abnormal
microbiota, or dysbiosis, has a causative role in disease by
evoking a chronic inflammatory state.

Humanized mouseTo understand the biology of normal and diseased human hematopoiesis and immunity, we have developed a humanizedmouse model. To overcome limitations of this model due to species barriers between human cells and the mouse environment, wehave been creating immune-compromised mouse strains expressing human cytokines, HLA, and adhesion molecules. In FY2015,
we assessed the potential usefulness of HLA-expressing humanized
mice in vaccination and gene therapy. In this study, we chose thetumor antigen Wilms tumor protein (WT1) as a model antigen toelicit specific human immune responses in vivo. In an experimenttesting gene therapy, we transduced WT1-specific T cell receptor

genes into human hematopoietic stem cells. By doing transplantation experiments, we found that the transduced human hematopoietic stem cells can generate WT1-specific T cells in the bonemarrow and spleen. The WT1-specific T cells were functional incytokine production and cytotoxicity against WT1-expressing
HLA-matched target cells. In the future, we will create next-generation humanized mice with an even more “humanized” environment
to better reconstitute human immunity and then use these mice in
pre-clinical testing for molecular targeting drugs or immune-targeting therapies.

Figure: Skewed TCR repertoire among human CD8+ T
cells developed in a humanized mouse from WT1 TCR
gene transduced HSC.
Human CD8+ T cells were purified from a humanized mousetransplanted with WT1-specific TCR transduced human HSCs
and from control mice engrafted with non-transduced human
HSCs. Pie charts depict the major TCR repertoire greater than
1%.

65

NKT cell projects

N

KT cells have the capacity to either enhance or suppress immune responses. The medical innovation groups in IMS havelaunched projects aimed at application of NKT cell therapy to cancer and allergic disease as translational research. When an NKT cell
ligand is loaded on CD1d+ cells, such as dendritic cells (DCs) orCD1d transfectants, NKT cells can produce IFN-γ. On the other
hand, when the ligand is incorporated into a liposomal compound,
NKT cells can produce IL-21 and suppress B cell function. Here we
introduce five NKT cell-related projects.
First, we have begun a collaboration with 15 National Hospital Organization (NHO) hospitals involving clinical therapeuticstudies using the NKT glycolipid, α-galactosylceramide (α-GalCer) pulsed autologous DCs (DC/Gal) in a randomized phase IIa
trial in early stage lung cancer (Figure). In our part of this study,
we perform immunological analyses of the DC/Gal-treated andcontrol cancer patients. Second, IMS was selected as part of theresearch center network for realization of regenerative medicine
and we have successfully established human iPS-NKT cells. After
stimulation with DC/Gal, the iPS-NKT cells produced more IFN-γ
than parental NKT cells and had strong antitumor effects in vivo.
This iPS-NKT cell project has been planned as a clinical application research project. Third, as a new type of cancer vaccine, weestablished artificial adjuvant vector cells, which contain tumor
antigen mRNA and α-GalCer, leading to activation of both innate
and adaptive immunity. We have almost completed the preclinical

Project

studies through discussions with the Pharmaceuticals and Medical
Devices Agency (PMDA). Forth, we developed several new NKT
cell ligand candidates and have been investigating the function of
one of them. We have been examining its efficacy in preclinicalstudies for next generation NKT cell ligand cancer immunotherapy. The three preclinical projects have been supported by the Japan
Agency for Medical Research and Development (AMED). As a fifth
study, we have developed a new chemical liposomal compound that
includes a new NKT cell ligand that can be selectively delivered to
B cells, resulting in the preferential suppression of IgE production.
This drug could be applicable for asthma, pollinosis or food allergy.
These four projects (iPS-NKT, new ligand, aAVC therapy and liposomal compound) are also supported by the RIKEN Drug Discovery
and Medical Technology Platforms (DMP).

Figure: NKT translational study and clinical projects in IMS.
We have been collaborating with 15 National Hospital Organization (NHO) hospitals
for a randomized phase IIa trial of NKT cell therapy in early stage lung cancer patients.

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.
The DMP was founded in RIKEN in 2010 in order to support allphases of development of new therapeutics, from the discovery ofpromising targets to the identification of potential lead compounds,
such as small molecules and antibodies, and the acquisition of intellectual property rights to drugs and technologies that can thenbe brought to the development phase. The implementation of drug
discovery requires a different technology, thus DMP establishedseveral medical technology platforms that promote research andFigure: IMS links to the DMP project66

development. IMS contributes to this effort in several ways, including by setting up a facility for development of antibody drugs.
IMS now has five programs in association with DMP, including
Artificial adjuvant vector cells (Shin-ichiro Fujii), Leukemia treatment drugs targeting leukemic stem cells (Fumihiko Ishikawa),
Cancer treatment with NKT cells (Haruhiko Koseki), Drugs for allergic diseases (Yasushi Ishii), and a monoclonal antibody for HBV
prevention (Daiki Miki). The Artificial adjuvant vector cells projectfor cancer therapy is now at the preclinical stage of drug development.

PGRN-RIKEN projectT

he U.S. NIH Pharmacogenomics Research Network (PGRN) is
a consortium of research groups funded as individual cooperative agreements by the NIH. PGRN investigators are top researchers from U.S. academic institutions and conduct studies of variationin human genes relevant to drug metabolism, pharmacokinetics
and pharmacodynamics, and the relationship of these genetic variation to drug responses. Principal investigators of the PGRN and
RIKEN Center for Genomic Medicine (now RIKEN IMS Core for
Genomic Medicine: CGM) held a series of discussions on the needto accelerate discoveries in pharmacogenomics (PGx) and launched
the Global Alliance of Pharmacogenetics (GAP) in 2008. Currently, the PGRN-RIKEN Project is conducted under a PGRN-Hub, anewly-formed resource established to enhance scientific exchange
between the PGRN and the scientific community at large.
In this international collaboration, the PGRN has been successfully assembling a very large collection of DNA samples from

Project

well-phenotyped patients receiving specific drugs and drug combinations in clinical trials conducted in the U.S. The CGM focuses onhigh-throughput genome-wide SNP scans and targeted sequencing of selected genes or regions using next generation sequencing(NGS). We also provide technological and methodological expertise to identify genetic factors associated with drug responses, riskof severe adverse drug reactions and non-response to medications.
Together, the PGRN-RIKEN Project capitalizes on these strengths
to advance discoveries in PGx research. To date, we have initiated
41 collaborative projects and have 43 publications and over 55,000
DNA samples genotyped through this collaboration, which willlead to development of better and safer medications and realize the
dream of global precision medicine.

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

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 inEast Asian and Southeast Asian populations, and several genetic
factors 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 for Han
Chinese and other Asian populations with a high prevalence of
HLA-B*15:02 prior to the administration of carbamazepine, due
to the risk of ADR associated with this allele. To tackle this problem regionally, in 2012 we established the South East Asian Pharmacogenomics Research Network (SEAPharm) together with six
other Asian countries (Korea, Indonesia, Malaysia, Singapore, Taiwan, and Thailand). The aim of the collaborative efforts is to identify significant ADRs in the region so that we can identify genomic
biomarkers associated with their risk, information that could leadto a reduction in severe ADRs. We are now focusing on the iden-tification of genomic biomarkers associated with cutaneous ADRs
induced by the anticonvulsant phenytoin and the antibiotic co-trimoxazole, as well as with hepatic injury induced by anti-tuberculosis agents. In addition, we also aim to understand how the identified
genomic biomarkers lead to the ADRs by performing functional
studies. It is hoped that the discoveries from our collaborative efforts will identify useful biomarkers that can be used to predict therisk of ADRs, leading to the establishment of “stratified medicine”
based on pharmacogenomic-guided drug therapeutics.

Figure: South East Asian Pharmacogenomics Research Network (SEAPharm).

67

Project

International Cancer Genome Consortium (ICGC)
Laboratory for Genome Sequencing Analysis

Laboratory for Medical Science Mathematics

The ICGC has been organized to launch and coordinate a large number of research projects that have the common aim of comprehensively elucidating the genomic changes present in many types of cancers.
Its primary goals are to generate comprehensive catalogues of genomic
abnormalities in different cancer types and to make the data available tothe entire research community with minimal restrictions. At the end of
2015, 78 cancer genome projects across 16 countries and the EU were ongoing, and the ICGC released the genomic data from 14,767 cancer samples as Release 20 (November, 2015). The RIKEN group has been involved
with virus-related liver cancer, which is one of the most common anddeadly cancers worldwide, especially in Japan and Asia. We performed
whole genome sequencing (WGS) and RNA-Seq for 270 liver cancer samples and called their somatic mutations by using our in-house pipeline.
We deposited the WGS data from all 270 liver cancers and released them.
As an ICGC verification/validation working group, we were involved withbenchmark comparison studies, where eleven genome centers analyzed
exactly the same raw sequence data or the same DNA by each of theirpipelines or platforms to compare their results in somatic mutation identification. Under this pipeline comparison, we released the guidelines
for WGS analysis (Nature Communications 2015). ICGC also launched a“pan-cancer” whole genome project (PCAWG) in 2014, where 2834 can-Laboratory for Digestive Diseases

cer WGS data +RNA-Seq are analyzed in the uniform pipelines within
the same computational environment. Approximately 1000 researchers
and technical staff are involved world-wide in 16 theme working groups(Figure). We are contributing to this ambitious project as a member of atechnical working group arranging ten “cloud” data centers worldwide,
PI and researchers for driver gene analysis, mutational signatures, immunogenomics, and mitochondrial genomics, as well as by providing
270 WGS data to the PCAWG (10% contribution 270/2834), which is themost productive within ICGC/TCGA (Figure). In 2015, we completed thealignment and mutation calls by the Sanger pipeline and we establishedand validated certain pipelines for immunogenomic profiling from WGS
and RNA-Seq, such as HLA genotyping, HLA mutation, and neo-antigen
prediction, which was performed in collaboration with the group of The
University of Tokyo.

Figure: Overview of the PCAWG2015 (“Pan-CAncer” Whole Genome project)in ICGC/The Cancer Genome Atlas (TCGA).
The ICGC is organizing ten synchronized cloud data centers worldwide, including
Amazon clouds, each with 1 petabyte (PB) of storage capacity, where ~3000 WGS
pair datasets are analyzed in the same computational environment and by three
uniform pipelines (Sanger, Broad, and DKFZ/EMBL pipelines). RIKEN is involved with
the Tokyo Data Center, where we performed WGS alignment and mutation calls by
Sanger pipeline for 2834 PCAWG donors. There are 16 working groups (WG) including
those analyzing signatures, genomic structural variations (SV), cis-regulatory elements,
non-coding RNA, pathogens, and immunogenomics.

Commissioned Research

The Biobank Japan projectI

n 2013, the Japanese government started a new initiative forlife sciences called Healthcare and Medical Strategy. Thisinitiative consists of nine top priority research fields: 1) Drugdevelopment, 2) Development of medical devices, 3) Translational research, 4) Regenerative medicine, 5) Genomic medicine, 6) Cancer, 7) Brain science, 8) Infectious diseases, and 9)
Rare diseases. For the genomic medicine research field, in 2015
the government decided to promote rapid and publically visible clinical applications of genomic research findings in parallelwith strengthening of the basic infrastructure of human genome
research. Based on this concept, the government is planning toestablish a network of existing biobanks [Biobank Japan (BBJ),
Tohoku Medical Megabank (Tohoku MMB), and National
Center Biobank Network (NCBN)]. The government also established priority disease areas in 2015. Rare (hereditary) diseases,
cancer, dementia, infectious diseases and pharmacogenomics
were selected as the first priority disease areas because these diseases are thought to be very close to implementation of genomic
information for actual medical practice Common multifactorialdiseases such as diabetes and cardiovascular diseases are posi-68

tioned as the second priority disease area, which needs further
basic genomic research to precisely elucidate the relationships
between genetic variations and disease.
The Biobank Japan project was started as a MEXT-commissioned project in 2003, and the final goal of this project is theimplementation of personalized medicine. To pursue this aim,
the project constructed a large disease biobank, named Biobank
Japan, in the Institute of Medical Science, University of Tokyo.
This biobank has already collected DNA and clinical information from 230,000 patients suffering from 51 target diseases.
The Core for Genomic Medicine has been working as the main
infrastructure of genomic research for this project since thebeginning. Since the primary area of this project is common
multifactorial disease, we are performing large-scale genomic
research including GWAS and whole-genome sequencing-based
association studies using BBJ samples. We are also collaboratingwith various international research groups using this importantresource.

Part 4
Events

Events

RIKEN
IMS
Summer
Program (RISP)
2015

The IMS-JSIInternational
Symposium on
Immunology
2015

I

T

MS was delighted to again successfully organize the 10th RISP
(RIKEN IMS Summer Program). RISP began as the RCAI International Summer Program (RISP) in 2006 and has been continued by
IMS, beginning two years ago. The aim of this activity is to provide
networking opportunities on a broad international 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 2015 program was expanded to include
topics in genomic studies to understand human diseases, in addition
to its original focus on immunology. The internship program, in which
the participants perform research in IMS laboratories, has also been
maintained. RISP 2015 was co-organized by the Chiba University
Leading Graduate School Program.
Due to financial constraints, IMS was unfortunately unable to cover travel expenses for all RISP students for RISP 2015. However, wewere pleased to welcome fifty-four graduate students and postdoctoral
fellows from twenty-one countries, together with ten students from
Chiba University, who gathered at Yokohama from June 12th to 19th. It
is noteworthy that the percentage of students in M.D/Ph.D programs
increased this year. RISP began with a tour of IMS research facilities,
which include advanced two-photon microscopes, a HILO microscopefor single molecule imaging and a CyTOF cell sorting instrument. The
scientific sessions included 12 lectures by distinguished senior scientists. RISP students also presented their research in both oral and poster sessions. The RISP program ended with participation in a two day
International Symposium on Immunology, co-organized by IMS and
the Japanese Society for Immunology.
RISP2015 was again a success; we received very nice feedback comments in the evaluation survey and all students indicated that theywould recommend this program to colleagues. From the other perspective, many lecturers commented on how impressed they were with
the quality of the RISP students. IMS will again organize RISP in 2016,
shifting to include broader topics as necessary to keep pace with recent
developments in this rapidly moving life science field.

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 on June 18–19 at the Pacifico Yokohama conference center. The symposium, entitled “Infection and Immunity”,
included 20 internationally-recognized speakers presenting theircutting-edged research and attracted close to 400 participants.
There were four sessions: (1) RNA and immune responses, (2)Infection and inflammation, (3) Vaccine development, and (4)Metabolism and immune regulation. The “RNA and immune
responses” session posed the intriguing question of how translational regulation contributes to immune responses. Recent
findings about mRNA modifying molecules have revealed theimportance of quantitative control of mRNA levels in immune
responses. In the “Infection and inflammation” session, besides
pathogens infecting the host, the host-pathogen interactions
cause dynamic changes in local immune cell integrity, which canoften can lead to development of various diseases. Mechanisms
controlling this outcome need to be understood. The “Vaccine
development” session provided insight into how next-generation
vaccines are being designed and developed. Merging structural
biology, bioinformatics, and human immunology is a key to thisend. In the “Metabolism and immune regulation” session, various metabolites are now being identified using mass spectroscopy and shown to play important roles in the immune system.
Using metabolomics, undescribed or as yet unidentified small
molecules will give clues to solve many questions in immunology.
Of note, the symposium this year attracted more young researchers, and this added value to the event.

Events

12th
PGRN-RIKEN
Strategic
Alliance
Meeting

The 2nd
IMS
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 started in 2008, with the objective of identifying therelationship between genetic variants and individual responses to drugs, including efficacy and side effects. PGRN-RIKEN
strategic alliance meetings, held alternately in Japan and United States, allow for face-to-face discussions about the progressof ongoing projects and future directions for the PGRN-RIKEN
collaboration.
On September 9–10, 2015, IMS hosted the 12th PGRN-RIKEN Strategic Alliance Meeting at the TKP Garden City Premiumof the Landmark Tower Yokohama, in Yokohama, Japan. It started with an introduction to PGRN’s structural reform as of July 1,2015 from Prof. Kathy Giacomini, Program Leader of the PGRN,
followed by two presentations by PGRN PIs on the current situation regarding clinical implementation of pharmacogenomics
in the US. From the RIKEN side, Dr. Taisei Mushiroda, Group
Director of IMS, presented data on the clinical utility of genomic
biomarkers for warfarin sensitivity and carbamazepine-induced
skin rash.
In addition to these formal presentations, all 35 participants
had in-depth discussions about the four ongoing collaborative
activities: “Genetic Determinants of Clinical Cardiovascular
Events in Patients Receiving Statins”, “Genetic Basis of Variability in VEGF Plasma Levels”, “African Ancestry Pharmacogenomics” and “Targeted Resequencing of Candidate Genes fromCALGB 40101”.
Participants also explored three new research proposals fromPGRN and finally decided to adopt two of them as additional
collaboration projects, then the meeting concluded successfully.

n May 28, 2015, the RIKEN Center for Integrative Medical
Sciences (IMS) held its second public symposium on new
medical sciences for the advancement of personalized and preventive medicine at Station Conference Tokyo.
The symposium was attended by 114 participants, including
researchers from universities, various research institutes, andpharmaceutical and medical companies.
After the opening greetings by Mr. Hiroshi Tsuboi, Deputy
Director-General of the Office of Healthcare Policy in the Cabinet Secretariat and Mr. Yoshiaki Ando, Deputy Director-General, Research Promotion Bureau in the Ministry of Education,
Culture, Sports, Science and Technology (MEXT), seven IMS
investigators from the center’s different research sections spoke
about their frontline research activities to advance personalized
and preventive medicine in terms of predicting disease in the individual and the development of preventive methods and treatments tailored to the individual.
The keynote lectures were delivered by Dr. Makoto Suematsu, President of the Japan Agency for Medical Research and Development (AMED) and Dr. Masahira Hattori, Professor of the
School of Advanced Science and Engineering at Waseda University. Dr. Suematsu spoke about the mission and prospects of
AMED, while Dr. Hattori described the present and future of human microbiome research.

71

Events

Harvard
SummerSchool2015

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 the IMS laboratories, have basic biomedical sciences lectures by IMS PIs and attend a Japanese language course. They also participate in the RIKEN IMS Summer
Program (RISP) and the RIKEN IMS-JSI International Symposium on Immunology. The participants receive a letter grade from
IMS and course credit from Harvard. In 2015 from June 1 to August 10, there were three students from Harvard University, Sam
Murphy, Larry Zhang, and Lucy Nam.
Mr. Murphy conducted his research project in the Laboratory for Transcriptional Regulation (Dr. Taniuchi), Mr. Zhang in
the Laboratory for Medical Science Mathematics (Dr. Tsunoda)
and Ms. Nam in the Laboratory for Developmental Genetics (Dr.
Koseki). 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.
In addition, they visited Yokohama Science Frontier HighSchool and met with students who want to become scientists. On
this occasion, they also experienced Japanese culture and learned
Sado (tea ceremony) from the local high school students.

72

MS collaborates with and accepts graduate students from 8
domestic university graduate schools. There are now a totalof 30 adjunct professors/associate professors in IMS (Table), and55 students studied at IMS in 2015. On August 29, IMS held abriefing session on adjunct graduate school programs. Thirty
students participated from Hokkaido, Miyagi, Tokyo, Kanagawa,
Osaka, Tokushima and Fukuoka prefectures. The session provided an opportunity for students to visit and talk directly with lab
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 Associate Professor),
Yasuyuki Ishii (Visiting Associate
Professor), Fumihiko Ishikawa (Visiting
Associate Professor)

School of Biomedical Science,
Tokyo Medical and Dental University

Takashi Saito (Visiting Professor)

Graduate School of Medicine,
Yokohama City University

Michiaki Kubo (Visiting Professor),
Shiro Ikegawa (Visiting Professor),
Mayumi Tamari (Visiting Professor),
Tatsuhiko Tsunoda (Visiting Professor),
Hidewaki Nakagawa (Visiting Professor), Taisei Mushiroda (Visiting Professor), Yukihide Momozawa (Visiting
Associate Professor), Yoichiro Kamatani(Visiting Associate Professor)

Graduate School of Medical Life
Science, Yokohama City University

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

Research Institute of Biological Sciences, Tokyo University of Science

Masato Kubo (Professor), Shohei Hori
(Visiting Associate 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)

Part 5
Data andStatistics

Publlications 2015

1. Adachi, Y., T. Onodera, Y. Yamada, R. Daio, M. Tsuiji, T. Inoue, K. Kobayashi, T. Kurosaki, M.
Ato, and Y. Takahashi. 2015. Distinct germinal center selection at local sites shapes memory
B cell response to viral escape. Journal of Experimental Medicine 212: 1709–1723.
2. Aiba, Y., K. Yamazaki, N. Nishida, M. Kawashima, Y. Hitomi, A. Komori, M. Kubo, K. Tokunaga, and M. Nakamura. 2015. Shared disease-susceptibility genes between primary biliary
cirrhosis and Crohn’s disease in the japanese population. Journal of Hepatology 62:
S790–S791.

Table: IMS Publlications Jan-Dec, 2015

3. Aiba, Y., K. Yamazaki, N. Nishida, M. Kawashima, Y. Hitomi, H. Nakamura, A. Komori, Y.
Fuyuno, A. Takahashi, T. Kawaguchi, M. Takazoe, Y. Suzuki, S. Motoya, T. Matsui, M. Esaki,
T. Matsumoto, M. Kubo, K. Tokunaga, and M. Nakamura. 2015. Disease susceptibility genes
shared by primary biliary cirrhosis and Crohn's disease in the Japanese population. Journalof Human Genetics 60: 525–531.

JournalIF (2014)

Nature41.5

2Nature Reviews Immunology

35.0

1

Science

33.6

2

Cell

32.2

2

Nature Genetics

29.4

8

Immunity

21.6

2

Nature Immunology

20.0

5

Journal of Clinical Oncology

18.4

1

Cell Metabolism

17.6

1

BMJ-British Medical Journal

17.4

1

Science Translational Medicine

15.8

1

Gut

14.7

1

Genome Research

14.6

1

American Journal of Respiratory and Critical Care
Medicine

13.0

1

Journal of Experimental Medicine

12.5

7

Cell Host & Microbe

12.3

1

Journal of Allergy and Clinical Immunology

11.5

3

Nature Communications

11.5

11

Journal of Hepatology

11.3

2

Hepatology

11.1

7

American Journal of Human Genetics

10.9

3

Blood

10.5

3

Leukemia

10.4

1

Trends in Immunology

10.4

1

Annals of the Rheumatic Diseases

10.4

2

Biological Psychiatry

10.3

1

Nature Reviews Rheumatology

9.8

1

Journal of Cell Biology

9.8

1

Proceedings of the National Academy of Sciencesof the United States of America

9.7

4

Nature Protocols

9.7

1

Journal of the American Society of Nephrology

9.3

1

eLIFE

9.3

1

Clinical Cancer Research

8.7

1

Oncogene

8.5

1

Cell Reports

8.4

3

Diabetes

8.1

2

BMC Biology

8.0

1

Clinical Pharmacology & Therapeutics

7.9

2

12. Arai, Y., C. M. Martin-Ruiz, M. Takayama, Y. Abe, T. Takebayashi, S. Koyasu, M. Suematsu,
N. Hirose, and T. von Zglinicki. 2015. Inflammation, But Not Telomere Length, Predicts
Successful Ageing at Extreme Old Age: A Longitudinal Study of Semi-supercentenarians.
EBioMedicine 2: 1549–1558.

Seminars in Immunopathology

7.7

3

13.

PLoS Pathogens

7.6

1

PLoS Genetics

7.5

1

Current Opinion in Immunology

7.52

Mucosal Immunology

7.4

1

Journal of Investigative Dermatology

7.2

2

Journal of Bone and Mineral Research

6.8

1

Diabetologia

6.7

1

Molecular Ecology

6.5

1

Human Molecular Genetics

6.4

4

Science Signaling

6.3

1

Oncoimmunology

6.3

1

Journal of Clinical Endocrinology & Metabolism

6.2

1

Allergy

6.0

2

Arteriosclerosis Thrombosis and Vascular Biology

6.0

1

Others

6.0

166

TOTAL

74

Number ofPapers 2015279

4. Aitken, S., S. Magi, A. M. N. Alhendi, M. Itoh, H. Kawaji, T. Lassmann, C. O. Daub, E. Arner,
P. Carninci, A. R. R. Forrest, Y. Hayashizaki, L. M. Khachigian, M. Okada-Hatakeyama, C.
A. Semple, and F. Consortium. 2015. Transcriptional Dynamics Reveal Critical Roles for
Non-coding RNAs in the Immediate-Early Response. Plos Computational Biology 11:
e1004217.
5. Akamatsu, S., C. N. Hayes, H. Ochi, T. Uchida, H. Kan, E. Murakami, H. Abe, M. Tsuge, D.
Miki, R. Akiyama, N. Hiraga, M. Imamura, H. Aikata, T. Kawaoka, Y. Kawakami, and K. Chayama. 2015. Association between variants in the interferon lambda 4 locus and substitutionsin the hepatitis C virus non-structural protein 5A. Journal of Hepatology 63: 554–563.
6. Akamatsu, S., C. N. Hayes, M. Tsuge, D. Miki, R. Akiyama, H. Abe, H. Ochi, N. Hiraga, M.
Imamura, S. Takahashi, H. Aikata, T. Kawaoka, Y. Kawakami, W. Ohishi, and K. Chayama.
2015. Differences in serum microRNA profiles in hepatitis B and C virus infection. Journalof Infection 70: 273–287.
7. Akamatsu, S., C. N. Hayes, M. Tsuge, E. Murakami, N. Hiraga, H. Abe, D. Miki, M. Imamura,
H. Ochi, K. Chayama, and G. Hiroshima Liver Study. 2015. Ribavirin dose reduction during
telaprevir/ribavirin/peg-interferon therapy overcomes the effect of the ITPA gene polymorphism. Journal of Viral Hepatitis 22: 166–174.
8. Alioto, T. S., I. Buchhalter, S. Derdak, B. Hutter, M. D. Eldridge, E. Hovig, L. E. Heisler, T. A.
Beck, J. T. Simpson, L. Tonon, A. S. Sertier, A. M. Patch, N. Jager, P. Ginsbach, R. Drews,
N. Paramasivam, R. Kabbe, S. Chotewutmontri, N. Diessl, C. Previti, S. Schmidt, B. Brors,
L. Feuerbach, M. Heinold, S. Grobner, A. Korshunov, P. S. Tarpey, A. P. Butler, J. Hinton, D.
Jones, A. Menzies, K. Raine, R. Shepherd, L. Stebbings, J. W. Teague, P. Ribeca, F. C. Giner,
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Guest lectures 2015
Table: Guest Lectures Jan–Dec, 2015
Date

Speaker

Affiliation

Country

Title

14-Jan-15

Dr. Matteo Barberis

Synthetic Systems Biology, Swammerdam Institute forLife Sciences, University of Amsterdam

The Netherlands

A systems biology approach to the tuning of cell cycling and chromatin dynamics

23-Jan-15

Dr. Taro Tsujimura

Department of Advanced Nephrology and Regenerative Medicine, University of Tokyo HospitalJapan

Enhancer allocation and chromatin conformation:
topological and regulatory autonomy of the adjacentTfap2c and Bmp7 genes in mice

23-Jan-15

Dr. Wojciech Makalowski

Institute of Bioinformatics, University of Münster

Germany

Nanopore sequencing for genotyping pathogens oftropical diseases

9-Feb-15

Dr. Hisashi Arase

Laboratory of Immunochemistry, WPI Immunology
Frontier Research Center and Department of Immunochemistry, Research Institute for Microbial Diseases,
Osaka University

Japan

Cellular misfolded proteins rescued from protein
degradation by MHC class II molecules are targets for
autoimmune diseases

13-Feb-15

Dr. Daniel K. Nomura

Department of Nutritional Science and Toxicology,
University of California Berkeley

USA

Chemoproteomic and metabolomic strategies for
drug discovery and toxicology

25-Feb-15

Dr. Gabriel D. Victora

Whitehead Institute for Biomedical Research

USA

Cellular and clonal dynamics in germinal centers

26-Feb-15

Dr. Yeonseok Chung

College of Pharmacy, Seoul National University

Korea

Th17 and Tfh cells at the cross-road of atherosclerosis
and autoimmunity

6-Mar-15

Dr. Yibo Wu

Institute of Molecular Systems Biology, ETH Zurich

Switzerland

Multilayered genetic & omics dissection - A new age
for biomedical researches

14-May-15

Prof. Susan M. Gasser

Friedrich Miescher Institute for Biomedical Research

Switzerland

Gene and repeat repression during development: arole for histone H3K9 methylation

16-May-15

Dr. Shigeru Kondo

Laboratory of Pattern Formation, Graduate School of
Frontier Biosciences Osaka University

Japan

Turing pattern formation without diffusion

22-May-15

Dr. Masashi Watanabe

Experimental Immunology Branch, National Cancer
Institute, NIH

USA

The role of tumor suppressor p53 in CD4 T cell function and homeostasis

23-Jul-15

Dr. Richard A. Flavell

Department of Immunobiology, Howard Hughes Medical Institute, Yale School of Medicine

USA

Regulation and resolution of immune response

24-Jul-15

Dr. Melita Vidaković

Department of Molecular Biology, Institute for Biological Research

SerbiaThe role of epigenetics mechanisms in diabetes
mellitus

28-Jul-15

Dr. Yun-Cai Lui

Division of Cell Biology, La Jolla Institute for Allergy
and Immunology

USA

Control of Treg stability and function by O2 sensor

1-Sep-15

Dr. Yasushi Matsumura

Department of Integrated Medicine, Osaka University
Graduate School of Medicine

Japan

Toward construction of new clinical research platform

25-Sep-15

Dr. Ichio Aoki

Magnetic Resonance Molecular Imaging Team, National Institute of Radiological Sciences

Japan

Magnetic resonance microimaging and functional“smart” contrast agents

20-Oct-15

Dr. Gregory F. Sonnenberg

Department of Microbiology and Immunology, Weill
Cornell Medical College, Cornell University

USA

Immune regulation of intestinal health and disease

21-Oct-15

Dr. Julie Stacey

Chief Editor of EBioMedicine

USA

EBioMedicine: Translating science to improve health29-Oct-15

Dr. Hajime Karasuyama

Department of Immune Regulation, Graduate Schoolof Medical and Dental Sciences, Tokyo Medical and
Dental University

Japan

Basophils have emerged as a key player in immunity:a neglected minority gains new respect

30-Oct-15

Dr. Yutaka Suzuki

Department of Computational Biology and Medical
Sciences, the University of Tokyo

Japan

Single cell analysis of lung cancer cell lines

2-Nov-15

Mr. Tony Z. Jia

Department of Molecular Biology, and Center for
Computational and Integrative Biology, Massachusetts General Hospital
Department of Chemistry and Chemical Biology,
Harvard University

USA

Peptide-assisted nonenzymatic RNA replication

13-Nov-15

Dr. Matthew C. Lorincz

Department of Medical Genetics, University of British
Columbia

CanadaImpact of LTR retrotransposons on the methylome,
imprintome and transcriptome in mouse oocytes

17-Nov-15

Dr. Mark Shlomchik

Department of Immunology, University of Pittsburgh
School of Medicine

USA

How autoimmunity gets started

11-Dec-15

Dr. Yoshihiro Ogawa

Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences,
Tokyo Medical and Dental University

Japan

Tissue remodeling in metabolic diseases

14-Dec-15

Dr. Yoshiko Takahashi

Department of Zoology, Graduate School of Science,
Kyoto University

Japan

The biology of the tail: An organ that is a characteristic feature of the vertebrates but remains poorly
understood

25-Dec-15

Dr. Reiko Tanaka

Department of Bioengineering, Imperial College ofLondonUK“Double switch” in mathematical models of atopic
dermatitis reveals underlying mechanisms of diseaseprogression

83Budget, personnel and patents

IMS Budget FY2015

Personnel FY2015
JPY Million

IMS Budget FY2015

Category

NumberGovernment funding for operations

3,011

Director

1

Commissioned research

1,266

Senior Advisor

2

Deputy Director

2Group Director

10Team Leader

26

Coordinator

2

Partnership-Promotion Coordinator

1

Deputy Team Leader

4

Senior Scientist

20

Research Scientist

40

Postdoctoral Researcher

13

Special Postdoctoral Researcher

5

Foreign Postdoctoral Researcher

3

Research Fellow

7

Senior Technical Scientist

2Technical Scientist

11

Technical Staff I

55

Technical Staff II

69

International Program Associate

4

Research Associate

7

Junior Research Associate

19

Student Trainee

91

Assistant

29

Part-time Administrative Staff

10

Part-time Research Staff

4

Part-time Technical Staff

17

Research Consultant

2

Consultant

12

Senior Visiting Scientist

8External competitive funding

977

Total

5,254

Patents
There were 25 patents filed from January to December in 2015.
Patents

Total

International
patents (PCT)

Domestic patents(Japan)

2013

32

20

12

2014

32

24

8

2015

25

16

9

Visiting Scientist

177

Visiting Technical Scientist

33

Visiting Researcher

3

Temporary Staffing

9

Total

84

698

RIKEN Center for Integrative Medical Sciences
Organization Chart

Access to RIKEN Yokohama Campus

Local Access

RIKEN President
Hiroshi Matsumoto

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.

Director
Shigeo Koyasu(until September)
Tadashi Yamamoto(from October)

Integrative
Medical Sciences
Planning Office

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

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

Senior Advisor

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

Masaru Taniguchi
Shizuo Akira

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

Max Cooper (chair)Mark Lathrop (vice chair)
Ronald N. Germain
Paul W. Kincade
Bernard Malissen
William E. Paul
Dale Umetsu
Arthur WeissJohn O’Shea
Fiona Powrie
Peter Sorger
Rudi Balling
Kiyoshi Takatsu
Hajime Karasuyama
Yutaka Kawakami
Michel Georges
Edison Tak-Bun Liu
Katsushi Tokunaga
Hiroyuki Aburatani

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.

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