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

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

Published on:

July 4, 2024

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.