You are here

Nat Genet DOI:10.1038/s41588-020-0579-4

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

Publication TypeJournal Article
Year of Publication2020
AuthorsGutierrez-Arcelus, M, Baglaenko, Y, Arora, J, Hannes, S, Luo, Y, Amariuta, T, Teslovich, N, Rao, DA, Ermann, J, A Jonsson, H, Navarrete, C, Rich, SS, Taylor, KD, Rotter, JI, Gregersen, PK, Esko, T, Brenner, MB, Raychaudhuri, S
Corporate AuthorsNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
JournalNat Genet
Date Published2020 Feb 17
ISSN1546-1718
Abstract

Genetic studies have revealed that autoimmune susceptibility variants are over-represented in memory CD4 T cell regulatory elements. Understanding how genetic variation affects gene expression in different T cell physiological states is essential for deciphering genetic mechanisms of autoimmunity. Here, we characterized the dynamics of genetic regulatory effects at eight time points during memory CD4 T cell activation with high-depth RNA-seq in healthy individuals. We discovered widespread, dynamic allele-specific expression across the genome, where the balance of alleles changes over time. These genes were enriched fourfold within autoimmune loci. We found pervasive dynamic regulatory effects within six HLA genes. HLA-DQB1 alleles had one of three distinct transcriptional regulatory programs. Using CRISPR-Cas9 genomic editing we demonstrated that a promoter variant is causal for T cell-specific control of HLA-DQB1 expression. Our study shows that genetic variation in cis-regulatory elements affects gene expression in a manner dependent on lymphocyte activation status, contributing to the interindividual complexity of immune responses.

DOI10.1038/s41588-020-0579-4
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/32066938?dopt=Abstract

Alternate JournalNat. Genet.
PubMed ID32066938
Grant ListU19AI111224 / / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) /
U01GM092691 / / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) /
U01HG009379 / / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) /
HG002295 / / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) /
PUT1660 / / Ministry of Education and Research | Estonian Research Competency Council (Research Competency Council) /