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

Autor: Maria Gutierrez-Arcelus, A. Helena Jonsson, Jatin Arora, Cristina Navarrete, Stephen S. Rich, Michael B. Brenner, Susan K. Hannes, Deepak A. Rao, Tõnu Esko, Jerome I. Rotter, Tiffany Amariuta, Yuriy Baglaenko, Peter K. Gregersen, Nikola Teslovich, Joerg Ermann, Soumya Raychaudhuri, Yang Luo, Kent D. Taylor
Rok vydání: 2020
Předmět:
CD4-Positive T-Lymphocytes
Genotyping Techniques
T-Lymphocytes
Autoimmunity
Lymphocyte Activation
T-Lymphocytes
Regulatory
Medical and Health Sciences
Genome
0302 clinical medicine
HLA Antigens
Gene expression
2.1 Biological and endogenous factors
HLA-DQ beta-Chains
Aetiology
Promoter Regions
Genetic
Genetics
Regulation of gene expression
Immunity
Cellular
0303 health sciences
Biological Sciences
Regulatory
medicine.anatomical_structure
Biotechnology
T cell
Human leukocyte antigen
Biology
Autoimmune Disease
Article
Cell Line
Promoter Regions
03 medical and health sciences
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Genetic
Genetic variation
medicine
Humans
Allele
Gene
Alleles
030304 developmental biology
Inflammatory and immune system
Human Genome
Immunity
Genetic Variation
Gene Expression Regulation
Genetic Loci
Cellular
CRISPR-Cas Systems
030217 neurology & neurosurgery
Developmental Biology
Zdroj: Nature genetics, vol 52, iss 3
Nature genetics
Nature Genetics
ISSN: 1546-1718
1061-4036
Popis: Genetic studies have revealed that autoimmune susceptibility variants are over-represented in memory CD4+ T cell regulatory elements1–3. Understanding how genetic variation affects gene expression in different T cell physiological states is essential for deciphering genetic mechanisms of autoimmunity4,5. 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.
Databáze: OpenAIRE
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