PT  - JOURNAL ARTICLE
AU  - Rachel E. Gate
AU  - Christine S. Cheng
AU  - Aviva P. Aiden
AU  - Atsede Siba
AU  - Marcin Tabaka
AU  - Dmytro Lituiev
AU  - Ido Machol
AU  - M. Grace Gordon
AU  - Meena Subramaniam
AU  - Muhammad Shamim
AU  - Kendrick L. Hougen
AU  - Ivo Wortman
AU  - Su-Chen Huang
AU  - Neva C. Durand
AU  - Ting Feng
AU  - Philip L. De Jager
AU  - Howard Y. Chang
AU  - Erez Lieberman Aiden
AU  - Christophe Benoist
AU  - Michael A. Beer
AU  - Chun J. Ye
AU  - Aviv Regev
TI  - Genetic determinants of chromatin accessibility in T cell activation across humans
AID  - 10.1101/090241
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 090241
4099  - http://biorxiv.org/content/early/2018/02/07/090241.short
4100  - http://biorxiv.org/content/early/2018/02/07/090241.full
AB  - 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 sequencing (ATAC-seq) and RNA-seq profiles from activated CD4+ T cells of up to 105 healthy donors. We found that regions of accessible chromatin (ATAC-peaks) are co-accessible at kilobase and megabase resolution, in patterns consistent with the 3D organization of chromosomes measured by in situ Hi-C in T cells. 15% of genetic variants located within ATAC-peaks affected the accessibility of the corresponding peak through disrupting binding sites for transcription factors important for T cell differentiation and activation. These ATAC quantitative trait nucleotides (ATAC-QTNs) have the largest effects on co-accessible peaks, are associated with gene expression from the same aliquot of cells, are rarely affecting core binding motifs, 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.