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<p>Genetic variants associated with autoimmune diseases are highly enriched within putative <i>cis</i>-regulatory regions of CD4<sup>+</sup> T cells, suggesting that they could alter disease risk through changes in gene regulation. However, very few genetic variants have been shown to affect T cell gene expression or function. Here we tested &gt;18,000 autoimmune disease-associated variants for allele-specific effects on expression using massively parallel reporter assays in primary human CD4<sup>+</sup> T cells. We find 545 variants that modulate expression in an allele-specific manner (emVars). Primary T cell emVars greatly enrich for likely causal variants, are mediated by common upstream pathways and their putative target genes are highly enriched within a lymphocyte activation network. Using bulk and single-cell CRISPR-interference screens, we confirm that emVar-containing T cell <i>cis</i>-regulatory elements modulate both known and previously unappreciated target genes that regulate T cell proliferation, providing plausible mechanisms by which these variants alter autoimmune disease risk.</p>

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Genetic and epigenetic screens in primary human T cells link candidate causal autoimmune variants to T cell networks

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月18日

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  • Ching-Huang Ho,
  • Maxwell A. Dippel,
  • Meghan S. McQuade,
  • LeAnn P. Nguyen,
  • Arpit Mishra,
  • Stephan Pribitzer,
  • Samantha Hardy,
  • Harshpreet Chandok,
  • Florence M. Chardon,
  • Troy A. McDiarmid,
  • Hannah A. DeBerg,
  • Jane H. Buckner,
  • Jay Shendure,
  • Carl G. de Boer,
  • Michael H. Guo,
  • Ryan Tewhey,
  • John P. Ray

摘要

Genetic variants associated with autoimmune diseases are highly enriched within putative cis-regulatory regions of CD4+ T cells, suggesting that they could alter disease risk through changes in gene regulation. However, very few genetic variants have been shown to affect T cell gene expression or function. Here we tested >18,000 autoimmune disease-associated variants for allele-specific effects on expression using massively parallel reporter assays in primary human CD4+ T cells. We find 545 variants that modulate expression in an allele-specific manner (emVars). Primary T cell emVars greatly enrich for likely causal variants, are mediated by common upstream pathways and their putative target genes are highly enriched within a lymphocyte activation network. Using bulk and single-cell CRISPR-interference screens, we confirm that emVar-containing T cell cis-regulatory elements modulate both known and previously unappreciated target genes that regulate T cell proliferation, providing plausible mechanisms by which these variants alter autoimmune disease risk.