BioProject

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. More...

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. One possible mechanism is that genetic variants affect the activity of one or more cis-regulatory elements leading to gene expression variation in specific cell types. To identify such cases, we analyzed Assay for Transposase-Accessible Chromatin (ATAC-seq) and RNA-seq profiles from activated primary CD4 + T cells of up to 105 healthy donors. We found that regions of chromatin accessibility (ATAC-peaks) are co-accessible at kilobase and megabase scales, in patterns consistent with the 3D organization of chromosomes measured by in situ Hi-C in T cells. Genetic variants located within ATAC-peaks often affected the accessibility of the corresponding peak and any co-accessible peaks. They also 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. Our results provide insights into how natural genetic variants modulate cis-regulatory elements, in isolation or in concert, to influence gene expression in primary immune cells that play a key role in many human diseases. Overall design: In situ HiC in activated primary CD4 + T cells NOTE: Submitter declares that the raw data will be submitted to dbGaP (https://www.ncbi.nlm.nih.gov/gap) because of patient privacy concerns. Less...