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17q21 asthma-risk variants switch CTCF binding and regulate IL-2 production by T cells

Author

Listed:
  • Benjamin Joachim Schmiedel

    (La Jolla Institute for Allergy and Immunology)

  • Grégory Seumois

    (La Jolla Institute for Allergy and Immunology)

  • Daniela Samaniego-Castruita

    (La Jolla Institute for Allergy and Immunology)

  • Justin Cayford

    (La Jolla Institute for Allergy and Immunology)

  • Veronique Schulten

    (La Jolla Institute for Allergy and Immunology)

  • Lukas Chavez

    (German Cancer Research Center (DKFZ))

  • Ferhat Ay

    (La Jolla Institute for Allergy and Immunology)

  • Alessandro Sette

    (La Jolla Institute for Allergy and Immunology)

  • Bjoern Peters

    (La Jolla Institute for Allergy and Immunology)

  • Pandurangan Vijayanand

    (La Jolla Institute for Allergy and Immunology
    Clinical and Experimental Sciences, National Institute for Health Research Southampton Respiratory Biomedical Research Unit, University of Southampton, Faculty of Medicine)

Abstract

Asthma and autoimmune disease susceptibility has been strongly linked to genetic variants in the 17q21 haploblock that alter the expression of ORMDL3; however, the molecular mechanisms by which these variants perturb gene expression and the cell types in which this effect is most prominent are unclear. We found several 17q21 variants overlapped enhancers present mainly in primary immune cell types. CD4+ T cells showed the greatest increase (threefold) in ORMDL3 expression in individuals carrying the asthma-risk alleles, where ORMDL3 negatively regulated interleukin-2 production. The asthma-risk variants rs4065275 and rs12936231 switched CTCF-binding sites in the 17q21 locus, and 4C-Seq assays showed that several distal cis-regulatory elements upstream of the disrupted ZPBP2 CTCF-binding site interacted with the ORMDL3 promoter region in CD4+ T cells exclusively from subjects carrying asthma-risk alleles. Overall, our results suggested that T cells are one of the most prominent cell types affected by 17q21 variants.

Suggested Citation

  • Benjamin Joachim Schmiedel & Grégory Seumois & Daniela Samaniego-Castruita & Justin Cayford & Veronique Schulten & Lukas Chavez & Ferhat Ay & Alessandro Sette & Bjoern Peters & Pandurangan Vijayanand, 2016. "17q21 asthma-risk variants switch CTCF binding and regulate IL-2 production by T cells," Nature Communications, Nature, vol. 7(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13426
    DOI: 10.1038/ncomms13426
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    Cited by:

    1. Sourya Bhattacharyya & Ferhat Ay, 2024. "Identifying genetic variants associated with chromatin looping and genome function," Nature Communications, Nature, vol. 15(1), pages 1-22, December.

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