Allele-specific Expression Changes Dynamically During T Cell Activation in HLA and Other Autoimmune Loci

Overview

Journal Nat Genet

Specialty Genetics

Date 2020 Feb 19

PMID 32066938

Citations 64

Authors

Maria Gutierrez-Arcelus

Yuriy Baglaenko

Jatin Arora

Susan Hannes

Yang Luo

Tiffany Amariuta

Nikola Teslovich

Deepak A Rao

Joerg Ermann

A Helena Jonsson

Cristina Navarrete

Stephen S Rich

Kent D Taylor

Jerome I Rotter

Peter K Gregersen

Tonu Esko

Michael B Brenner

Soumya Raychaudhuri

Affiliations

Soon will be listed here.

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.

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