Super-enhancers delineate disease-associated regulatory nodes in T cells

Nature. 2015 Apr 23;520(7548):558-62. doi: 10.1038/nature14154. Epub 2015 Feb 16.

Abstract

Enhancers regulate spatiotemporal gene expression and impart cell-specific transcriptional outputs that drive cell identity. Super-enhancers (SEs), also known as stretch-enhancers, are a subset of enhancers especially important for genes associated with cell identity and genetic risk of disease. CD4(+) T cells are critical for host defence and autoimmunity. Here we analysed maps of mouse T-cell SEs as a non-biased means of identifying key regulatory nodes involved in cell specification. We found that cytokines and cytokine receptors were the dominant class of genes exhibiting SE architecture in T cells. Nonetheless, the locus encoding Bach2, a key negative regulator of effector differentiation, emerged as the most prominent T-cell SE, revealing a network in which SE-associated genes critical for T-cell biology are repressed by BACH2. Disease-associated single-nucleotide polymorphisms for immune-mediated disorders, including rheumatoid arthritis, were highly enriched for T-cell SEs versus typical enhancers or SEs in other cell lineages. Intriguingly, treatment of T cells with the Janus kinase (JAK) inhibitor tofacitinib disproportionately altered the expression of rheumatoid arthritis risk genes with SE structures. Together, these results indicate that genes with SE architecture in T cells encompass a variety of cytokines and cytokine receptors but are controlled by a 'guardian' transcription factor, itself endowed with an SE. Thus, enumeration of SEs allows the unbiased determination of key regulatory nodes in T cells, which are preferentially modulated by pharmacological intervention.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Rheumatoid / genetics*
  • Arthritis, Rheumatoid / immunology
  • Arthritis, Rheumatoid / pathology
  • Basic-Leucine Zipper Transcription Factors / metabolism
  • Cell Differentiation / genetics
  • Cell Lineage / genetics
  • Enhancer Elements, Genetic / genetics*
  • Gene Expression Regulation / genetics
  • Genetic Predisposition to Disease / genetics
  • Janus Kinase 3 / antagonists & inhibitors
  • Mice
  • Mice, Inbred C57BL
  • Piperidines / pharmacology
  • Pyrimidines / pharmacology
  • Pyrroles / pharmacology
  • RNA, Untranslated / genetics
  • T-Lymphocytes, Helper-Inducer / immunology
  • T-Lymphocytes, Helper-Inducer / metabolism*
  • T-Lymphocytes, Helper-Inducer / pathology*
  • Transcription, Genetic / genetics
  • p300-CBP Transcription Factors / metabolism

Substances

  • Bach2 protein, mouse
  • Basic-Leucine Zipper Transcription Factors
  • Piperidines
  • Pyrimidines
  • Pyrroles
  • RNA, Untranslated
  • tofacitinib
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor
  • Janus Kinase 3

Associated data

  • GEO/GSE60482