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<p>Innate lymphoid cells (ILCs) are rare tissue-resident lymphocytes that functionally mirror cells of CD4<sup>+</sup> T helper lineage but lack antigen receptors. Type 3 ILCs (ILC3s) are enriched at barrier sites, regulating inflammation and promoting tissue integrity. Here we profile the promoter-anchored chromosomal contacts of primary human ILC3s using low-input, high-resolution targeted chromosome conformation capture and compare them with those in CD4<sup>+</sup> T cells. We use these data to link Crohn’s disease genome-wide association study variants with target genes, implicating both known and unanticipated candidates, including <i>CLN3</i>, a causal gene for Batten disease. We show that <i>Cln3</i> overexpression in a mouse ILC3-like cell line alters stimulation-induced transcriptional programs and cytokine secretion. Extending our approach to five additional immune genome-wide association study traits reveals enrichment for regulators of ILC3 activation. Our work develops methods, maps long-range gene regulation in ILC3s, and prioritizes immune disease risk genes with roles in this clinically relevant immune cell type.</p>

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High-resolution promoter interaction analysis implicates genes involved in activation of type 3 innate lymphoid cells in immune disease risk

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年8月4日

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  • Valeriya Malysheva,
  • Helen Ray-Jones,
  • Nora Lakes,
  • Rachel A. Brown,
  • Tareian A. Cazares,
  • Owen Clay,
  • David E. Ohayon,
  • Pavel Artemov,
  • Joseph A. Wayman,
  • Zi F. Yang,
  • Monica Della Rosa,
  • Carmen Petitjean,
  • Clarissa Booth,
  • Joseph I. J. Ellaway,
  • Jenna R. Barnes,
  • Andrew W. Dangel,
  • Ankita Saini,
  • William R. Orchard,
  • Xiaoting Chen,
  • Sreeja Parameswaran,
  • Frances Burden,
  • Mattia Frontini,
  • Takashi Nagano,
  • Peter Fraser,
  • Stefan Schoenfelder,
  • Matthew T. Weirauch,
  • Leah C. Kottyan,
  • David F. Smith,
  • Nick Powell,
  • Jill M. Weimer,
  • Eugene M. Oltz,
  • Chris Wallace,
  • Emily R. Miraldi,
  • Stephen N. Waggoner,
  • Mikhail Spivakov

摘要

Innate lymphoid cells (ILCs) are rare tissue-resident lymphocytes that functionally mirror cells of CD4+ T helper lineage but lack antigen receptors. Type 3 ILCs (ILC3s) are enriched at barrier sites, regulating inflammation and promoting tissue integrity. Here we profile the promoter-anchored chromosomal contacts of primary human ILC3s using low-input, high-resolution targeted chromosome conformation capture and compare them with those in CD4+ T cells. We use these data to link Crohn’s disease genome-wide association study variants with target genes, implicating both known and unanticipated candidates, including CLN3, a causal gene for Batten disease. We show that Cln3 overexpression in a mouse ILC3-like cell line alters stimulation-induced transcriptional programs and cytokine secretion. Extending our approach to five additional immune genome-wide association study traits reveals enrichment for regulators of ILC3 activation. Our work develops methods, maps long-range gene regulation in ILC3s, and prioritizes immune disease risk genes with roles in this clinically relevant immune cell type.