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Epigenomic analysis of primary human T cells reveals enhancers associated with TH2 memory cell differentiation and asthma susceptibility

Nature Immunology volume 15, pages 777788 (2014) | Download Citation

Abstract

A characteristic feature of asthma is the aberrant accumulation, differentiation or function of memory CD4+ T cells that produce type 2 cytokines (TH2 cells). By mapping genome-wide histone modification profiles for subsets of T cells isolated from peripheral blood of healthy and asthmatic individuals, we identified enhancers with known and potential roles in the normal differentiation of human TH1 cells and TH2 cells. We discovered disease-specific enhancers in T cells that differ between healthy and asthmatic individuals. Enhancers that gained the histone H3 Lys4 dimethyl (H3K4me2) mark during TH2 cell development showed the highest enrichment for asthma-associated single nucleotide polymorphisms (SNPs), which supported a pathogenic role for TH2 cells in asthma. In silico analysis of cell-specific enhancers revealed transcription factors, microRNAs and genes potentially linked to human TH2 cell differentiation. Our results establish the feasibility and utility of enhancer profiling in well-defined populations of specialized cell types involved in disease pathogenesis.

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Acknowledgements

We thank the staff at the Wellcome Trust Clinical Research Facility (University of Southampton) where samples were acquired from volunteers; M. North for assisting in patient recruitment, assessment and sample collection; R. Jewel and C. McGuire for providing assistance in the flow cytometry facility (University of Southampton; J. Day for assistance with high-throughput sequencing at the La Jolla Institute for Allergy and Immunology sequencing facility, and A. Moghaddas Gholami at the La Jolla Institute for Allergy and Immunology bioinformatics core for help with the SNP enrichment analysis. L.C. is funded by a Feodor Lynen Research Fellowship from the Alexander von Humboldt Foundation. This work was supported by the Dana Foundation (K.M.A.), GlaxoSmithKline National Clinician Scientist Fellowship Award and Peel Travel Fellowship Award (P.V.), R01 HL114093 (to B.P., A.R. and P.V.) and U19 AI100275 (to B.P., A.R. and P.V.).

Author information

Author notes

    • Grégory Seumois
    • , Lukas Chavez
    •  & Anna Gerasimova

    These authors contributed equally to this work.

Affiliations

  1. La Jolla Institute for Allergy & Immunology, La Jolla, California, USA.

    • Grégory Seumois
    • , Lukas Chavez
    • , Anna Gerasimova
    • , Matthias Lienhard
    • , Ashu Chawla
    • , Bjoern Peters
    • , Anjana Rao
    •  & Pandurangan Vijayanand
  2. Clinical and Experimental Sciences, Southampton National Institute for Health Research Respiratory Biomedical Research Unit, University of Southampton, Faculty of Medicine, Southampton, UK.

    • Grégory Seumois
    • , Nada Omran
    • , Lukas Kalinke
    • , Maria Vedanayagam
    • , Asha Purnima V Ganesan
    • , Ratko Djukanović
    •  & Pandurangan Vijayanand
  3. University of California San Francisco, San Francisco, California, USA.

    • Grégory Seumois
    • , K Mark Ansel
    •  & Pandurangan Vijayanand
  4. Sanford Consortium for Regenerative Medicine, La Jolla, California, USA.

    • Anjana Rao
  5. Department of Pharmacology, University of California San Diego, San Diego, California, USA.

    • Anjana Rao
  6. University of California San Diego Moores Cancer Center, San Diego, California, USA.

    • Anjana Rao

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Contributions

G.S., K.M.A., B.P., A.R. and P.V. conceived the work, designed, performed and analyzed experiments, and wrote the paper; N.O., L.K., M.V. and A.P.V.G. assisted in the performing some of the experiments under the supervision of G.S. and P.V.; R.D. provided support and direction for obtaining and processing clinical specimens; L.C. identified DERs; and A.G., M.L. and A.C. performed the bioinformatic analysis under the supervision of L.C. and B.P.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Bjoern Peters or Anjana Rao or Pandurangan Vijayanand.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–11, Supplementary Note

Excel files

  1. 1.

    Supplementary Table 1

    The detailed description of 120 ChIP-seq assays.

  2. 2.

    Supplementary Table 2

    List of differentially enriched cis-regulatory regions (DERs) for cell types comparison.

  3. 3.

    Supplementary Table 3

    Classification of the DERs into subgroups.

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    Supplementary Table 4

    List of all RefSeq promoters covered by DERs.

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    Supplementary Table 5

    Biological process-enrichment analysis.

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    Supplementary Table 6

    Genomic coordinates of enhancer DERs and linked genes.

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    Supplementary Table 7

    Biological process and pathway-enrichment analysis of target genes linked to enhancer DERs.

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    Supplementary Table 8

    Differential gene expression.

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    Supplementary Table 9

    Transcription factors motif enrichment in DERs enhancers.

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    Supplementary Table 10

    Transcription factor binding site enrichment analysis.

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    Supplementary Table 11

    GWAS SNPs enrichment analysis.

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    Supplementary Table 12

    Genomic coordinates of disease-specific enhancer DERs and linked genes.

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    Supplementary Table 13

    Transcription factor binding site enrichment analysis for disease-specific DERs.

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    Supplementary Table 14

    Biological process and pathway-enrichment analysis.

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    Supplementary Table 15

    Details of study subjects.

About this article

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DOI

https://doi.org/10.1038/ni.2937

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