. 2024 Jul 5;385(6704):eadd8394.

doi: 10.1126/science.add8394. Epub 2024 Jul 5.

An atlas of transcribed enhancers across helper T cell diversity for decoding human diseases

Akiko Oguchi^#^{1

2

3}, Akari Suzuki^#⁴, Shuichiro Komatsu^#^{1

5}, Hiroyuki Yoshitomi^{2

6}, Shruti Bhagat², Raku Son^{1

2

3}, Raoul Jean Pierre Bonnal⁵, Shohei Kojima⁷, Masaru Koido^{8

9

10}, Kazuhiro Takeuchi^{1

2

11}, Keiko Myouzen⁴, Gyo Inoue⁴, Tomoya Hirai^{1

12}, Hiromi Sano¹, Yujiro Takegami¹³, Ai Kanemaru¹³, Itaru Yamaguchi¹³, Yuki Ishikawa¹⁰, Nao Tanaka¹⁰, Shigeki Hirabayashi^{1

14

15}, Riyo Konishi¹⁶, Sho Sekito^{2

17}, Takahiro Inoue¹⁷, Juha Kere^{18

19

20}, Shunichi Takeda^{21

22}, Akifumi Takaori-Kondo¹⁴, Itaru Endo¹², Shinpei Kawaoka^{16

23}, Hideya Kawaji^{24

25

26}, Kazuyoshi Ishigaki²⁷, Hideki Ueno^{2

6}, Yoshihide Hayashizaki^{13

26}, Massimiliano Pagani^{5

28}, Piero Carninci^{29

30}, Motoko Yanagita^{2

3}; ITEC Consortium‡; Nicholas Parrish⁷, Chikashi Terao^{10

31

32}, Kazuhiko Yamamoto⁴, Yasuhiro Murakawa^{1

2

5

11}; ITEC Consortium Members

Collaborators, Affiliations

Collaborators

Matteo Guerrini, Hiroaki Hatano, Kazuyoshi Ishigaki, Yuki Ishikawa, Shuichiro Komatsu, Michihiro Kono, Yasuhiro Murakawa, Masahiro Nakano, Akiko Oguchi, Raku Son, Akari Suzuki, Kazuhiro Takeuchi, Nao Tanaka, Chikashi Terao, Kohei Tomizuka, Kazuhiko Yamamoto, Soichiro Yoshino

Affiliations

¹ RIKEN-IFOM Joint Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
² Institute for the Advanced Study of Human Biology, Kyoto University, Kyoto, Japan.
³ Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
⁴ Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁵ IFOM ETS - the AIRC Institute of Molecular Oncology, Milan, Italy.
⁶ Department of Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
⁷ Genome Immunobiology RIKEN Hakubi Research Team, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁸ Division of Molecular Pathology, Department of Cancer Biology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁹ Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
¹⁰ Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
¹¹ Department of Medical Systems Genomics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
¹² Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
¹³ K.K. DNAFORM, Yokohama, Japan.
¹⁴ Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
¹⁵ Division of Precision Medicine, Kyushu University Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
¹⁶ Inter-Organ Communication Research Team, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan.
¹⁷ Department of Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine, Mie University, Tsu, Japan.
¹⁸ Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
¹⁹ Stem Cells and Metabolism Research Program, University of Helsinki, Helsinki, Finland.
²⁰ Folkhalsan Research Center, Helsinki, Finland.
²¹ Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
²² Shenzhen University School of Medicine, Shenzhen, Guangdong, China.
²³ Department of Integrative Bioanalytics, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
²⁴ Research Center for Genome & Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
²⁵ Preventive Medicine and Applied Genomics Unit, RIKEN Center for Integrative Medical Science, Yokohama, Japan.
²⁶ RIKEN Preventive Medicine and Diagnosis Innovation Program, Wako, Japan.
²⁷ Laboratory for Human Immunogenetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
²⁸ Department of Medical Biotechnology and Translational Medicine, Università degli Studi, Milan, Italy.
²⁹ Laboratory for Transcriptome Technology, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
³⁰ Human Technopole, Milan, Italy.
³¹ Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan.
³² Department of Applied Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.

^# Contributed equally.

PMID: 38963856
DOI: 10.1126/science.add8394

An atlas of transcribed enhancers across helper T cell diversity for decoding human diseases

Akiko Oguchi et al. Science. 2024.

. 2024 Jul 5;385(6704):eadd8394.

doi: 10.1126/science.add8394. Epub 2024 Jul 5.

Authors

Collaborators

Matteo Guerrini, Hiroaki Hatano, Kazuyoshi Ishigaki, Yuki Ishikawa, Shuichiro Komatsu, Michihiro Kono, Yasuhiro Murakawa, Masahiro Nakano, Akiko Oguchi, Raku Son, Akari Suzuki, Kazuhiro Takeuchi, Nao Tanaka, Chikashi Terao, Kohei Tomizuka, Kazuhiko Yamamoto, Soichiro Yoshino

Affiliations

¹ RIKEN-IFOM Joint Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
² Institute for the Advanced Study of Human Biology, Kyoto University, Kyoto, Japan.
³ Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
⁴ Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁵ IFOM ETS - the AIRC Institute of Molecular Oncology, Milan, Italy.
⁶ Department of Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
⁷ Genome Immunobiology RIKEN Hakubi Research Team, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁸ Division of Molecular Pathology, Department of Cancer Biology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁹ Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
¹⁰ Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
¹¹ Department of Medical Systems Genomics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
¹² Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
¹³ K.K. DNAFORM, Yokohama, Japan.
¹⁴ Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
¹⁵ Division of Precision Medicine, Kyushu University Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
¹⁶ Inter-Organ Communication Research Team, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan.
¹⁷ Department of Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine, Mie University, Tsu, Japan.
¹⁸ Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
¹⁹ Stem Cells and Metabolism Research Program, University of Helsinki, Helsinki, Finland.
²⁰ Folkhalsan Research Center, Helsinki, Finland.
²¹ Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
²² Shenzhen University School of Medicine, Shenzhen, Guangdong, China.
²³ Department of Integrative Bioanalytics, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
²⁴ Research Center for Genome & Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
²⁵ Preventive Medicine and Applied Genomics Unit, RIKEN Center for Integrative Medical Science, Yokohama, Japan.
²⁶ RIKEN Preventive Medicine and Diagnosis Innovation Program, Wako, Japan.
²⁷ Laboratory for Human Immunogenetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
²⁸ Department of Medical Biotechnology and Translational Medicine, Università degli Studi, Milan, Italy.
²⁹ Laboratory for Transcriptome Technology, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
³⁰ Human Technopole, Milan, Italy.
³¹ Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan.
³² Department of Applied Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.

^# Contributed equally.

PMID: 38963856
DOI: 10.1126/science.add8394

Abstract

Transcribed enhancer maps can reveal nuclear interactions underpinning each cell type and connect specific cell types to diseases. Using a 5' single-cell RNA sequencing approach, we defined transcription start sites of enhancer RNAs and other classes of coding and noncoding RNAs in human CD4⁺ T cells, revealing cellular heterogeneity and differentiation trajectories. Integration of these datasets with single-cell chromatin profiles showed that active enhancers with bidirectional RNA transcription are highly cell type-specific and that disease heritability is strongly enriched in these enhancers. The resulting cell type-resolved multimodal atlas of bidirectionally transcribed enhancers, which we linked with promoters using fine-scale chromatin contact maps, enabled us to systematically interpret genetic variants associated with a range of immune-mediated diseases.

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An atlas of transcribed enhancers across helper T cell diversity for decoding human diseases

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An atlas of transcribed enhancers across helper T cell diversity for decoding human diseases

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