Genetic determinants of co-accessible chromatin regions in T cell activation across humans
2017
Over 90% of genetic variants associated with complex human traits map to non-coding regions, but little is understood about how they modulate gene regulation in health and disease. In one mechanism, disease-causing variants directly affect the activity of one or more cis-regulatory elements in specific cell types leading to dysregulation of gene expression. To identify such cases, we collected Assay for Transposase-Accessible Chromatin (ATAC-seq) profiles from activated primary CD4+ T cells of 105 healthy donors and analyzed them to characterize the inter-individual variability in "ATAC-peaks" of chromatin accessibility and to identify its genetic basis. Interestingly, we found that ATAC-peaks are co-accessible across loci at kilobase and megabase scales, in patterns consistent with 3D chromosome organization as measured by in situ-Hi-C in the same cells. Genetic variants associated with ATAC-peaks (ATAC-QTLs) are widespread and those associated with correlated peaks impart the strongest genetic effects. ATAC-QTLs disrupt binding sites for transcription factors important for CD4+ T cell differentiation and activation, overlap and mediate expression QTLs from the same cells, and are enriched for autoimmune disease variants. ATAC-QTLs associated with co-accessible peaks are further enriched in the same chromatin contact domains as the associated peaks and regions of the genome annotated as super enhancers. Accessibility of regulatory elements varies in correlated manner between individuals, and is determined by genetic variation following patterns that reflects the 3D organization of the genome, and mediate genetic effects on gene expression. Our results provide insights into how genetic variants modulate cis-regulatory elements, in isolation or in concert, and influence gene expression in primary immune cells that play a key role in many human diseases.
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