Journal Article

Chromatin accessibility landscape and regulatory network of high-altitude hypoxia adaptation

Yan, Dong-Sheng, Cui, Chaoying, Zhang, Hui, Su, Bing, Wong, Wing Hung, Feng, Zhanying, Wang, Yong, Ouzhuluobu, He, Yaoxi, Zhu, Xiang, Xin, Jingxue, Duren, Zhana, Chen, Lang, Bai, Caijuan, Luo, Xin, Zhang, Chaoyu, Yuan, Qiuyue, Qi, Xuebin

2020

Overview

High-altitude adaptation of Tibetans represents a remarkable case of natural selection during recent human evolution. Previous genome-wide scans found many non-coding variants under selection, suggesting a pressing need to understand the functional role of non-coding regulatory elements (REs). Here, we generate time courses of paired ATAC-seq and RNA-seq data on cultured HUVECs under hypoxic and normoxic conditions. We further develop a variant interpretation methodology (vPECA) to identify active selected REs (ASREs) and associated regulatory network. We discover three causal SNPs of EPAS1 , the key adaptive gene for Tibetans. These SNPs decrease the accessibility of ASREs with weakened binding strength of relevant TFs, and cooperatively down-regulate EPAS1 expression. We further construct the downstream network of EPAS1 , elucidating its roles in hypoxic response and angiogenesis. Collectively, we provide a systematic approach to interpret phenotype-associated noncoding variants in proper cell types and relevant dynamic conditions, to model their impact on gene regulation. Tibetan adaptation to the high-altitude environment represents a case of natural selection during recent human evolution. Here the authors investigated the chromatin and transcriptional landscape of umbilical endothelial cells from Tibetan and Han Chinese donors and provide genome-wide characterization of the hypoxia regulatory network associated high-altitude adaptation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38 / 38/23 / 45 / 49/91 / 631/114/2401 / 631/208/182 / 631/208/200 / 631/208/212 / 631/337/100 / Accessibility / Acclimatization - genetics / Adaptation / Altitude / Altitude Sickness - ethnology / Altitude Sickness - genetics / Altitude Sickness - metabolism / Angiogenesis / Basic Helix-Loop-Helix Transcription Factors - genetics / Cell Hypoxia - genetics / Cells, Cultured / Chromatin / Chromatin - genetics / Chromatin - metabolism / Chromatin Immunoprecipitation Sequencing / Disease Resistance - genetics / Endothelial cells / Ethnicity - genetics / Evolution / Female / Gene Expression Regulation / Gene regulation / Gene Regulatory Networks / Genomes / High altitude environments / Human Umbilical Vein Endothelial Cells / Humanities and Social Sciences / Humans / Hypoxia / Hypoxia - genetics / Hypoxia - metabolism / Models, Genetic / multidisciplinary / Natural selection / Oxygen - metabolism / Phenotypes / Polymorphism, Single Nucleotide / Pregnancy / Primary Cell Culture / Regulatory Elements, Transcriptional - genetics / Regulatory sequences / Ribonucleic acid / RNA / RNA-Seq / Science / Science (multidisciplinary) / Selection, Genetic / Single-nucleotide polymorphism / Tibet - ethnology / Transcription / Transcription Factors - metabolism / Whole Genome Sequencing