Ho Ching-Huang, Dippel Maxwell A, McQuade Meghan S, Nguyen LeAnn P, Mishra Arpit, Pribitzer Stephan, Hardy Samantha, Chandok Harshpreet, Chardon Florence M, McDiarmid Troy A, DeBerg Hannah A, Buckner Jane H, Shendure Jay, de Boer Carl G, Guo Michael H, Tewhey Ryan, Ray John P
Benaroya Research Institute, Center for Systems Immunology, Seattle, WA, USA.
Benaroya Research Institute, Center for Translational Immunology, Seattle, WA, USA.
Nat Genet. 2025 Sep 18. doi: 10.1038/s41588-025-02301-3.
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.
与自身免疫性疾病相关的遗传变异在CD4 T细胞的假定顺式调控区域中高度富集，这表明它们可能通过基因调控的变化来改变疾病风险。然而，很少有遗传变异被证明会影响T细胞基因表达或功能。在这里，我们使用原代人CD4 T细胞中的大规模平行报告基因检测，测试了超过18000个与自身免疫性疾病相关的变异对表达的等位基因特异性影响。我们发现545个以等位基因特异性方式调节表达的变异（emVars）。原代T细胞emVars极大地富集了可能的因果变异，由常见的上游途径介导，并且它们的假定靶基因在淋巴细胞激活网络中高度富集。使用批量和单细胞CRISPR干扰筛选，我们证实含有emVar的T细胞顺式调控元件调节已知的和以前未被认识的调节T细胞增殖的靶基因，为这些变异改变自身免疫性疾病风险提供了合理的机制。
