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Allele-specific expression changes dynamically during T cell activation in HLA and other autoimmune loci

By M. Gutierrez-Arcelus, Yuriy Baglaenko, Jatin Arora, Susan Hannes, Yang Luo, Tiffany Amariuta, Nikola Teslovich, Deepak A. Rao, Joerg Ermann, Helena Jonsson, Cristina Naverrete, Peter K. Gregersen, T├Ánu Esko, Michael B. Brenner, Soumya Raychaudhuri

Posted 04 Apr 2019
bioRxiv DOI: 10.1101/599449 (published DOI: 10.1038/s41588-020-0579-4)

Understanding how genetic regulatory variation affects gene expression in different T cell states is essential to deciphering autoimmunity. We conducted a high-resolution RNA-seq time course analysis of stimulated memory CD4+ T cells from 24 healthy individuals. We identified 186 genes with dynamic allele-specific expression, where the balance of alleles changes over time. These genes were four fold enriched in autoimmune loci. We found pervasive dynamic regulatory effects within six HLA genes, particularly for a major autoimmune risk gene, HLA- DQB1. Each HLA-DQB1 allele had one of three distinct transcriptional regulatory programs. Using CRISPR/Cas9 genomic editing we demonstrated that a single nucleotide variant at the promoter is causal for T cell-specific control of HLA-DQB1 expression. Our study in CD4+ T cells shows that genetic variation in cis regulatory elements may affect gene expression in a lymphocyte activation status-dependent manner contributing to the inter-individual complexity of immune responses.

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