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

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 cel...

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Published in:Science (American Association for the Advancement of Science) 2024-07, Vol.385 (6704), p.eadd8394
Main Authors: Oguchi, Akiko, Suzuki, Akari, Komatsu, Shuichiro, Yoshitomi, Hiroyuki, Bhagat, Shruti, Son, Raku, Bonnal, Raoul Jean Pierre, Kojima, Shohei, Koido, Masaru, Takeuchi, Kazuhiro, Myouzen, Keiko, Inoue, Gyo, Hirai, Tomoya, Sano, Hiromi, Takegami, Yujiro, Kanemaru, Ai, Yamaguchi, Itaru, Ishikawa, Yuki, Tanaka, Nao, Hirabayashi, Shigeki, Konishi, Riyo, Sekito, Sho, Inoue, Takahiro, Kere, Juha, Takeda, Shunichi, Takaori-Kondo, Akifumi, Endo, Itaru, Kawaoka, Shinpei, Kawaji, Hideya, Ishigaki, Kazuyoshi, Ueno, Hideki, Hayashizaki, Yoshihide, Pagani, Massimiliano, Carninci, Piero, Yanagita, Motoko, Parrish, Nicholas, Terao, Chikashi, Yamamoto, Kazuhiko, Murakawa, Yasuhiro, Guerrini, Matteo, Hatano, Hiroaki, Kono, Michihiro, Nakano, Masahiro, Tomizuka, Kohei, Yoshino, Soichiro
Format: Article
Language:English
Subjects:
Accessibility
CD4 antigen
Cell activation
Cell surface
Chromatin
CRISPR
Disease
Enhancers
Gene expression
Gene mapping
Gene regulation
Gene sequencing
Genes
Genetic diversity
Genetic variance
Genetics
Heritability
Immunoregulation
Lymphocytes
Lymphocytes T
Nucleotides
Rare diseases
Regulatory sequences
Ribonucleic acid
RNA
Single-nucleotide polymorphism
Transcription
Transcription activation
Transposase
Citations: Items that this one cites
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Summary: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. Editor’s summary Currently, 3′ single-cell RNA sequencing is widely used as a tool for single-cell gene expression analysis. By leveraging a distinctive “cap signature” derived from the 5′-end cap, Oguchi et al . introduced a technique to investigate the precise position of the RNA 5′-ends in single cells, enabling simultaneous profiling of gene expression and enhancer activity. The authors constructed a CD4 + T cell–type resolved multimodal atlas to integrate and elucidate CD4 + T cell diversity and genetic risk of immune-mediated diseases. They also identified rare, uncharacterized CD4 + T cell types that might contribute to the pathology of immune-mediated diseases. —Di Jiang INTRODUCTION Enhancers are distal cis-regulatory elements that increase the expression of target genes. Active enhancers produce bidirectional enhancer RNAs (eRNAs). Transcription of eRNAs can be used to measure enhancer activity and to delineate enhancer architecture at nucleotide resolution. Profiling of transcribed enhancers in single human cells can provide insights into cell type–specific gene regulation and genetic predisposition to diseases. However, comprehensive maps of eRNAs in cell types relevant to diseases are still lacking. RATIONALE The 5′ cap is added to the first nucleotide of an RNA molecule. By leveraging a specific “cap signature,” we developed read-level prefiltering and transcribed enhancer call (ReapTEC), a method for simultaneously profiling gene expression and enhancer activity by using 5′-end single-cell RNA sequencing (5′ scRNA-seq). We applied ReapTEC and single-nucleus assay for transposase-ac
ISSN:0036-8075
1095-9203
1095-9203
DOI:10.1126/science.add8394