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

Jingxue Xin, Hui Zhang, Yaoxi He, Zhana Duren, Caijuan Bai, Lang Chen, Xin Luo, Dong-Sheng Yan, Chaoyu Zhang, Xiang Zhu, Qiuyue Yuan, Zhanying Feng, Chaoying Cui, Xuebin Qi, Ouzhuluobu, Wing Hung Wong (), Yong Wang () and Bing Su ()
Additional contact information
Jingxue Xin: Kunming Institute of Zoology, Chinese Academy of Sciences
Hui Zhang: Kunming Institute of Zoology, Chinese Academy of Sciences
Yaoxi He: Kunming Institute of Zoology, Chinese Academy of Sciences
Zhana Duren: Stanford University
Caijuan Bai: School of Medicine, Tibetan University
Lang Chen: Chinese Academy of Sciences
Xin Luo: Kunming Institute of Zoology, Chinese Academy of Sciences
Dong-Sheng Yan: School of Mathematical Science, Inner Mongolia University
Chaoyu Zhang: Chinese Academy of Sciences
Xiang Zhu: Stanford University
Qiuyue Yuan: Chinese Academy of Sciences
Zhanying Feng: Chinese Academy of Sciences
Chaoying Cui: School of Medicine, Tibetan University
Xuebin Qi: Kunming Institute of Zoology, Chinese Academy of Sciences
Ouzhuluobu: School of Medicine, Tibetan University
Wing Hung Wong: Stanford University
Yong Wang: Chinese Academy of Sciences
Bing Su: Kunming Institute of Zoology, Chinese Academy of Sciences

Nature Communications, 2020, vol. 11, issue 1, 1-20

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-18638-8

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