Scientists discover new T cells and genes related to immune disorders

Good news! Amazing stuff!

"Researchers ... have discovered several rare types of helper T cells that are associated with immune disorders such as multiple sclerosis, rheumatoid arthritis, and even asthma. ... the discoveries were made possible by a newly developed technology they call ReapTEC, which identified genetic enhancers in rare T cell subtypes that are linked to specific immune disorders. The new T cell atlas is publicly available and should help in the development of new drug therapies for immune-mediated diseases. ..."

From the editor's summary and abstract:

"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. ...

Structured Abstract

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-accessible chromatin using sequencing (snATAC-seq) to a total of ~1 million single human CD4+ T cells and constructed a CD4+ T cell type–resolved multimodal atlas to pinpoint genetic and cellular causes of immune-mediated diseases.

RESULTS

By using ReapTEC, we accurately mapped the transcription start sites of mRNAs, long noncoding RNAs, and eRNAs in single cells, which allowed us to study the expression of not only genes but also bidirectionally transcribed candidate enhancers (btcEnhs). We characterized rare and uncharacterized cell types, including GPR25-expressing regulatory T cells, along with the expression profiles of ~130 surface proteins. We identified 62,803 btcEnhs and 218,508 accessible chromatin regions active across diverse CD4+ T cells. We found higher cell type specificity for RNA transcription than for chromatin accessibility both at promoters and enhancers. We also showed that the heritability of immune-mediated diseases was enriched more in btcEnhs than in open chromatin regions. Using our CD4+ T cell type–resolved atlas of btcEnhs, we systematically interpreted genetic variants associated with a range of immune-mediated diseases. We found that btcEnhs harboring disease SNPs were often active in specific subsets of CD4+ T cells; generally, they were conserved across mammals but in some cases were primate specific. We investigated the target genes of disease-relevant btcEnhs by generating fine-scale chromatin contact maps derived from ultradeep Micro-C data; we further performed CRISPR activation of selected disease-relevant btcEnhs to validate their target genes.

CONCLUSION

Our study establishes a platform for integrating and elucidating CD4+ T cell diversity and genetic risk of immune-mediated diseases. Although 3′ scRNA-seq is widely used as a major tool for single-cell gene expression analysis, our study demonstrates the strength of 5′ scRNA-seq. We anticipate the utility of our multimodal atlas in addressing variant-to-function challenges."

Scientists discover new T cells and genes related to immune disorders

Scientists discover new T cells and genes related to immune disorders (original news release)

An atlas of transcribed enhancers across helper T cell diversity for decoding human diseases (no public access)

CD4+ T cell type–resolved atlas of btcEnhs for systematic interpretation of the genetic basis of immune-mediated diseases.