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

作者：Ching‐Huang Ho, Maxwell A. Dippel, Meghan S. McQuade, Arpit Mishra, Stephan Pribitzer, LeAnn P. Nguyen, 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 Ray · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2024 · DOI：10.1101/2024.10.07.617092 · 研究领域：T-cell and B-cell Immunology、Single-cell and spatial transcriptomics、Immune Cell Function and Interaction

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.