Abstract

Over 90% of genetic variants associated with complex human traits map to non-coding regions, but little is understood about how they modulate gene regulation in health and disease. One possible mechanism is that genetic variants affect the activity of one or more cis-regulatory elements leading to gene expression variation in specific cell types. To identify such cases, we analyzed ATAC-seq and RNA-seq profiles from stimulated primary CD4+ T cells in up to 105 healthy donors. We found that regions of accessible chromatin (ATAC-peaks) are co-accessible at kilobase and megabase resolution, consistent with the three-dimensional chromatin organization measured by in situ Hi-C in T cells. Fifteen percent of genetic variants located within ATAC-peaks affected the accessibility of the corresponding peak (local-ATAC-QTLs). Local-ATAC-QTLs have the largest effects on co-accessible peaks, are associated with gene expression and are enriched for autoimmune disease variants. Our results provide insights into how natural genetic variants modulate cis-regulatory elements, in isolation or in concert, to influence gene expression.

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Acknowledgements

We thank the ImmVar participants. We would like to thank J. Buenrostro for critical reading of the manuscript and advice on ATAC-seq analysis, J. Pfiffner and C. Fulco for initial experimental help with ATAC-seq, A. Schep for ATAC-seq nucleosome free caller, N. Asinovski and H.-k. Kwon for help setting up primary T cell cultures and members of the Regev and Ye laboratories for discussions. R.E.G. and C.J.Y. are supported by NIH R01-AR071522 to C.J.Y. M.A.B. and K.L.H. are supported by NIH HG007348 to M.A.B.; H.Y.C. is supported by NIH grant P50-HG007735; C.S.C. is supported by the NIH through a Ruth L. Kirschstein National Research Service Award (F32-DK096822). This work was supported by the Klarman Cell Observatory at the Broad Institute. A.R. is a Howard Hughes Medical Institute Investigator.

Author information

Author notes

  1. These authors contributed equally: Rachel E. Gate, Christine S. Cheng

Affiliations

  1. Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA

    • Rachel E. Gate
    • , Dmytro Lituiev
    • , Meena Subramaniam
    •  & Chun J. Ye
  2. Biological and Medical Informatics Graduate Program, University of California, San Francisco, San Francisco, CA, USA

    • Rachel E. Gate
    • , M. Grace Gordon
    •  & Meena Subramaniam
  3. Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    • Christine S. Cheng
    • , Atsede Siba
    • , Marcin Tabaka
    • , Ivo Wortman
    • , Philip L. De Jager
    •  & Aviv Regev
  4. Department of Biology, Boston University, Boston, MA, USA

    • Christine S. Cheng
  5. Department of Molecular and Human Genetics, the Center for Genome Architecture, Baylor College of Medicine, Houston, TX, USA

    • Aviva P. Aiden
    • , Ido Machol
    • , Muhammad Shamim
    • , Su-Chen Huang
    • , Neva C. Durand
    •  & Erez Lieberman Aiden
  6. Department of Bioengineering, Rice University, Houston, TX, USA

    • Aviva P. Aiden
  7. Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, USA

    • Muhammad Shamim
    •  & Erez Lieberman Aiden
  8. Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA

    • Kendrick L. Hougen
    •  & Michael A. Beer
  9. Division of Immunology, Department of Microbiology and Immunology, Harvard Medical School, Boston, MA, USA

    • Ting Feng
    •  & Christophe Benoist
  10. Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology and Psychiatry, Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    • Philip L. De Jager
  11. Harvard Medical School, Boston, MA, USA

    • Philip L. De Jager
  12. Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA

    • Howard Y. Chang
  13. Department of Computer Science, Rice University, Houston, TX, USA

    • Erez Lieberman Aiden
  14. Department of Computational and Applied Mathematics, Rice University, Houston, TX, USA

    • Erez Lieberman Aiden
  15. Center for Theoretical Biological Physics, Rice University, Houston, TX, USA

    • Erez Lieberman Aiden
  16. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA

    • Michael A. Beer
  17. Institute of Computational Health Sciences, University of California, San Francisco, San Francisco, CA, USA

    • Chun J. Ye
  18. Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA

    • Chun J. Ye
  19. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA

    • Chun J. Ye
  20. Howard Hughes Medical Institute, Koch Institute of Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA

    • Aviv Regev

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Contributions

A.R., C.J.Y. and C.S.C. conceived this project. C.S.C. and A.S. performed ATAC-seq and RNA-seq assays. I.W. cultured T cells and collected the fixed pellet for Hi-C assay. A.P.A., I.M., M. Shamim, S.-C.H., N.C.D. and E.L.A. performed and analyzed the Hi-C data set. R.E.G., M.T., D.L., M.G.G. and M. Subramaniam analyzed the ATAC-seq and RNA-seq data sets. K.L.H. and M.A.B. additionally analyzed the ATAC-seq data set. R.E.G. additionally analyzed the Hi-C data set. T.F., P.L.D.J. and C.B. provided the patient samples. H.Y.C. provided helpful comments and discussion. R.E.G., C.S.C., C.J.Y. and A.R. wrote the manuscript.

Competing interests

A.R. is an SAB member of ThermoFisher Scientific, Syros Pharmaceuticals and Driver group and a founder of Celsius Therapeutics.

Corresponding authors

Correspondence to Christine S. Cheng or Chun J. Ye or Aviv Regev.

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Figures 1–19

  2. Reporting Summary

  3. Supplementary Table 1

    Stimulation response

  4. Supplementary Table 2

    Hi-C

  5. Supplementary Table 3

    Covariates and mismatches

  6. Supplementary Table 4

    PC correlation to chromatin accessibility and gene expression

  7. Supplementary Table 5

    Co-accessibility

  8. Supplementary Table 6

    ATAC-QTLs

  9. Supplementary Table 7

    ATAC heritability

  10. Supplementary Table 8

    eQTLs

  11. Supplementary Table 9

    Expression heritability

  12. Supplementary Table 10

    Stimulation response

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DOI

https://doi.org/10.1038/s41588-018-0156-2