New paper mapping the effect of immune SNPs in CD4+ T cells on bioRxiv
Author: Annique Claringbould
Very happy to share the last project from my postdoc with Lars Steinmetz and Judith Zaugg, out now on bioRxiv!
🧬 How do immune disease-relevant variants affect gene regulatory networks in CD4+ T cells?
We coupled two large-scale CRISPRi screens (>4M cells) to map the downstream cascades of thousands of genetic variants.
🔢 We overlapped 4,724 genetic variants across 14 immune diseases with cis-regulatory elements that were accessible in CD4+ T cells
⚡️ Perturbing these elements with TAP-seq revealed the genes they regulate. Best computational predictors? ENCODE-rE2G and eQTLs
🧪 We performed genome-wide Perturb-seq on >7500 genes; 12% modulated expression of >10 genes
Variant ➡️ CRE ➡️ gene ➡️ network: we constructed regulatory cascades from disease-associated variants by integrating both screens, which connected 85 enhancer-like elements to 56% of all genes in two steps
🎯 The results help resolve individual immune-related loci (TYK2, DEXI/CLEC16A) and combined disease-relevant biological processes
🦠 We observe shared core immune programs (response to virus, T cell activation), but also disease-specific enrichments (tight junction organisation in celiac disease)
🤝 This was a truly collaborative effort bringing together experimental and computational expertise. Many thanks to the whole team - especially my co-lead Dewi Moonen; Daniel Schraivogel and Lars Steinmetz for excellent supervision; and Andreas Gschwind, Stefan Schrod, and many others who contributed.
