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Genetic determinants of co-accessible chromatin regions in T cell activation across humans [article]

Rachel E Gate, Christine S Cheng, Aviva P Aiden, Atsede Siba, Marcin Tabaka, Dmytro Lituiev, Ido Machol, M Gracie Gordon, Meena Subramaniam, Muhammad Shammim, Kendrick L Hougen, Ivo Wortman (+10 others)
2016 bioRxiv   pre-print

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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
more » ... f 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.
doi:10.1101/090241 fatcat:lvvq2ojg2nai7jkhp3gyrac2ui
Citation

Rachel E Gate, Christine S Cheng, Aviva P Aiden, Atsede Siba, Marcin Tabaka, Dmytro Lituiev, Ido Machol, M Gracie Gordon, Meena Subramaniam, Muhammad Shammim, Kendrick L Hougen, Ivo Wortman, Su-Chen Huang, Neva C Durand, Ting Feng, Philip L De Jager, Howard Y Chang, Erez Lieberman Aiden, Christophe Benoist, Micheal A Beer, Chun J Ye, Aviv Regev. "Genetic determinants of co-accessible chromatin regions in T cell activation across humans." bioRxiv (2016)