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 |
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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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