@article{bdebaac7b37e438c86561de6f635a775,
title = "Chromatin accessibility landscape and regulatory network of high-altitude hypoxia adaptation",
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.",
author = "Jingxue Xin and Hui Zhang and Yaoxi He and Zhana Duren and Caijuan Bai and Lang Chen and Xin Luo and Yan, {Dong Sheng} and Chaoyu Zhang and Xiang Zhu and Qiuyue Yuan and Zhanying Feng and Chaoying Cui and Xuebin Qi and Ouzhuluobu and Wong, {Wing Hung} and Yong Wang and Bing Su",
note = "Funding Information: We would like to thank all volunteers who provide samples for this study. The authors also thank Prof. Bianbazhuoma (People{\textquoteright}s Hospital of Lhasa City) and Drs. Yi Peng, Xiaoming Zhang for providing helps during sampling, and Prof. Luonan Chen, Peng Shi, and Rui Jiang and other lab members for helpful discussions. This work was supported jointly and equally by grants from the National Natural Science Foundation of China (NSFC) (91631306 to B.S.) and the Strategic Priority Research Program of the Chinese Academy of Sciences (CAS) (XDA20040102 to X.Q.; XDB13000000 to B.S. and Y.W.). Additional resources were provided by grants from the NSFC (11871463, 61671444, and 61621003 to Y.W., 31660308 to Ou.), the Youth Innovation Promotion Association of CAS (to Y.H.), the State Key Laboratory of Genetic Resources and Evolution (GREKF18-07 to C.B.), Shanghai Municipal Science and Technology Major Project (2017SHZDZX01 to Y.W.), and the Natural Science Foundation of Yunnan Province (2019FB042 to H.Z.). W.H.W. and Z.D. were supported by NIH grants P50HG007735, R01GM109836, and R01HG010359. Publisher Copyright: {\textcopyright} 2020, The Author(s).",
year = "2020",
month = dec,
day = "1",
doi = "10.1038/s41467-020-18638-8",
language = "English (US)",
volume = "11",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}