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, Bing Su

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number4928
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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