Publications
bioRxiv : the preprint server for biologyOct 2024 DOI:
10.1101/2024.10.07.617092

Linking candidate causal autoimmune variants to T cell networks using genetic and epigenetic screens in primary human T cells

Ho, Ching-Huang; Dippel, Maxwell A; McQuade, Meghan S; Mishra, Arpit; Pribitzer, Stephan; Nguyen, LeAnn P; Hardy, Samantha; Chandok, Harshpreet; Chardon, Florence; McDiarmid, Troy A; DeBerg, Hannah A; Buckner, Jane H; Shendure, Jay; de Boer, Carl G; Guo, Michael H; Tewhey, Ryan; Ray, John P
Product Used
Variant Libraries
Abstract
Genetic variants associated with autoimmune diseases are highly enriched within putative cis -regulatory regions of CD4 + T cells, suggesting that they alter disease risk via changes in gene regulation. However, very few genetic variants have been shown to affect T cell gene expression or function. We tested >18,000 autoimmune disease-associated variants for allele-specific expression using massively parallel reporter assays in primary human CD4 + T cells. The 545 expression-modulating variants (emVars) identified greatly enrich for likely causal variants. We provide evidence that many emVars are mediated by common upstream regulatory conduits, and that putative target genes of primary T cell emVars 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 novel target genes that regulate T cell proliferation, providing plausible mechanisms by which these variants alter autoimmune disease risk.
Product Used
Variant Libraries

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