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

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

Author information

1
Lymphocyte Cell Biology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
2
Translational Immunology Section, NIAMS, NIH, Bethesda, Maryland 20892, USA.
3
Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892, USA.
4
Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
5
The Jackson Laboratory for Genomic Medicine and Department of Genetic and Development Biology, University of Connecticut, Farmington, Connecticut 06030, USA.
6
Laboratory of Muscle Stem Cells and Gene Regulation, NIAMS, NIH, Bethesda, Maryland 20892, USA.

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.

PMID:
25686607
PMCID:
PMC4409450
DOI:
10.1038/nature14154
[Indexed for MEDLINE]
Free PMC Article

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