Open AccessAllele-specific expression changes dynamically during T cell activation in HLA and other autoimmune loci
Author(s) -
María GutiérrezArcelus,
Yuriy Baglaenko,
Jatin Arora,
Susan Hannes,
Yang Luo,
Tiffany Amariuta,
Nikola C. Teslovich,
Deepak A. Rao,
Joerg Ermann,
Anna Helena Jonsson,
Cristivarrete,
Stephen S. Rich,
Kent D. Taylor,
Jerome I. Rotter,
Peter K. Gregersen,
Tõnu Esko,
Michael B. Brenner,
Soumya Raychaudhuri
Publication year - 2020
Publication title -
nature genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 18.861
H-Index - 573
eISSN - 1546-1718
pISSN - 1061-4036
DOI - 10.1038/s41588-020-0579-4
Subject(s) - biology , allele , genetics , gene , human leukocyte antigen , t cell , regulation of gene expression , gene expression , genetic variation , immune system , antigen
Genetic studies have revealed that autoimmune susceptibility variants are over-represented in memory CD4 + T cell regulatory elements 1-3 . Understanding how genetic variation affects gene expression in different T cell physiological states is essential for deciphering genetic mechanisms of autoimmunity 4,5 . 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.