Abstract

Enhancers regulate spatiotemporal gene expression and impart cell-specific transcriptional outputs that drive cell identity1. 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 disease2,3,4,5,6. 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 lineages7. 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.

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Accessions

Primary accessions

Gene Expression Omnibus

Data deposits

All ChIP- and RNA-sequencing data sets have been deposited in the Gene Expression Omnibus under accession number GSE60482.

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Acknowledgements

The authors thank B. Afzali, A. Nussenzweig, A. Poholek, S. Canna, A. Richard and E. Mathe for critically reading this manuscript. We are grateful to R. Faryabi, H.-Y. Shih, W. Resch, M. Ombrello, Z. Deng and E. Remmers for their contributions to experimental and analytical components of this study. We also thank H. Sun, G. Gutierrez-Cruz, J. Simone, J. Lay and K. Tinsley for their excellent technical support. This study used the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health. R.R. is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant number 105663/Z/14/Z). This work was supported by the Intramural Research Program of NIAMS and by NCI grant R01 CA186714.

Author information

Author notes

    • Stephen C. J. Parker

    Present address: Departments of Computational Medicine & Bioinformatics and Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.

Affiliations

  1. Lymphocyte Cell Biology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA

    • Golnaz Vahedi
    • , Yuka Kanno
    • , Kan Jiang
    •  & John J. O’Shea
  2. Translational Immunology Section, NIAMS, NIH, Bethesda, Maryland 20892, USA

    • Yasuko Furumoto
    •  & Massimo Gadina
  3. Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892, USA

    • Stephen C. J. Parker
    • , Michael R. Erdos
    •  & Francis S. Collins
  4. Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA

    • Sean R. Davis
    • , Rahul Roychoudhuri
    •  & Nicholas P. Restifo
  5. The Jackson Laboratory for Genomic Medicine and Department of Genetic and Development Biology, University of Connecticut, Farmington, Connecticut 06030, USA

    • Zhonghui Tang
    •  & Yijun Ruan
  6. Laboratory of Muscle Stem Cells and Gene Regulation, NIAMS, NIH, Bethesda, Maryland 20892, USA

    • Vittorio Sartorelli

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Contributions

G.V., V.S., F.S.C. and J.J.O’S. participated in the study design. Y.K., Y.F. and K.J. performed sequencing experiments. Z.T. and Y.R. supervised and performed sequencing experiments. Y.F. and M.G. performed tofacitinib-related experiments. G.V. performed computational analysis. S.C.J.P., M.R.E. and S.R.D. participated in statistical analysis relevant to human genetics. R.R. and N.P.R. supervised and performed experiments involving Bach2-deficient cells. Y.K., Y.F. and S.R.D. participated in writing of the methodology. G.V., V.S. and J.J.O’S. wrote the manuscript and all authors reviewed it. J.J.O’S. supervised the project.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Golnaz Vahedi or John J. O’Shea.

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DOI

https://doi.org/10.1038/nature14154

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