Chromatin Accessibility Landscape and Regulatory Network of High-altitude Hypoxia Adaptation

Overview

Journal Nat Commun

Specialty Biology

Date 2020 Oct 2

PMID 33004791

Citations 39

Authors

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

Affiliations

Soon will be listed here.

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.

Citing Articles

A Novel 6-bp Repeat Unit (6-bp RU) of the 13th Intron Within the Conserved Gene in Plateau Pika Is Capable of Altering Enhancer Activity.

Tang Q, Xu Y, Song Q, Cao S, Li Y, Lan X Int J Mol Sci. 2025; 26(5).

PMID: 40076786 PMC: 11901085. DOI: 10.3390/ijms26052163.

Variations and Hematological Adaptations to High-Altitude Hypoxia in Indigenous Goats in Yunnan Province, China.

Zhu L, Tang L, Zhao Y, Li S, Gou X, Deng W Animals (Basel). 2025; 15(5).

PMID: 40075980 PMC: 11899464. DOI: 10.3390/ani15050695.

Eleutheroside B Ameliorates Cardiomyocytes Necroptosis in High-Altitude-Induced Myocardial Injury via Nrf2/HO-1 Signaling Pathway.

Duan H, Han Y, Zhang H, Zhou T, Wu C, Wang Z Antioxidants (Basel). 2025; 14(2).

PMID: 40002377 PMC: 11851825. DOI: 10.3390/antiox14020190.

Dynamic Chromatin Accessibility and Transcriptional Regulation in the Eyes of Red Tilapia (Oreochromis sp.) in Response to Wintering Stress.

Bai Y, Yang G, Liu T, Chen F, Xia J Mar Biotechnol (NY). 2025; 27(1):47.

PMID: 39937323 DOI: 10.1007/s10126-025-10424-1.

Transcriptomic analysis of iPSC-derived endothelium reveals adaptations to high altitude hypoxia in energy metabolism and inflammation.

Gray O, Witonsky D, Jousma J, Sobreira D, Van Alstyne A, Huang R PLoS Genet. 2025; 21(2):e1011570.

PMID: 39928692 PMC: 11809796. DOI: 10.1371/journal.pgen.1011570.

References

Cao H, Yu D, Yan X, Wang B, Yu Z, Song Y . Hypoxia destroys the microstructure of microtubules and causes dysfunction of endothelial cells via the PI3K/Stathmin1 pathway. Cell Biosci. 2019; 9:20. PMC: 6380067. DOI: 10.1186/s13578-019-0283-1. View

Beall C, Cavalleri G, Deng L, Elston R, Gao Y, Knight J . Natural selection on EPAS1 (HIF2alpha) associated with low hemoglobin concentration in Tibetan highlanders. Proc Natl Acad Sci U S A. 2010; 107(25):11459-64. PMC: 2895075. DOI: 10.1073/pnas.1002443107. View

Servant N, Varoquaux N, Lajoie B, Viara E, Chen C, Vert J . HiC-Pro: an optimized and flexible pipeline for Hi-C data processing. Genome Biol. 2015; 16:259. PMC: 4665391. DOI: 10.1186/s13059-015-0831-x. View

Alkorta-Aranburu G, Beall C, Witonsky D, Gebremedhin A, Pritchard J, Di Rienzo A . The genetic architecture of adaptations to high altitude in Ethiopia. PLoS Genet. 2012; 8(12):e1003110. PMC: 3516565. DOI: 10.1371/journal.pgen.1003110. View

Fishilevich S, Nudel R, Rappaport N, Hadar R, Plaschkes I, Iny Stein T . GeneHancer: genome-wide integration of enhancers and target genes in GeneCards. Database (Oxford). 2017; 2017. PMC: 5467550. DOI: 10.1093/database/bax028. View

Li H, Durbin R . Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009; 25(14):1754-60. PMC: 2705234. DOI: 10.1093/bioinformatics/btp324. View

Belaghzal H, Dekker J, Gibcus J . Hi-C 2.0: An optimized Hi-C procedure for high-resolution genome-wide mapping of chromosome conformation. Methods. 2017; 123:56-65. PMC: 5522765. DOI: 10.1016/j.ymeth.2017.04.004. View

Graham C, Fitzpatrick T, McCrae K . Hypoxia stimulates urokinase receptor expression through a heme protein-dependent pathway. Blood. 1998; 91(9):3300-7. View

Ilardo M, Moltke I, Korneliussen T, Cheng J, Stern A, Racimo F . Physiological and Genetic Adaptations to Diving in Sea Nomads. Cell. 2018; 173(3):569-580.e15. DOI: 10.1016/j.cell.2018.03.054. View

10.

Lu D, Lou H, Yuan K, Wang X, Wang Y, Zhang C . Ancestral Origins and Genetic History of Tibetan Highlanders. Am J Hum Genet. 2016; 99(3):580-594. PMC: 5011065. DOI: 10.1016/j.ajhg.2016.07.002. View

11.

Pellet-Many C, Frankel P, Jia H, Zachary I . Neuropilins: structure, function and role in disease. Biochem J. 2008; 411(2):211-26. DOI: 10.1042/BJ20071639. View

12.

Beck T, Hastings R, Gollapudi S, Free R, Brookes A . GWAS Central: a comprehensive resource for the comparison and interrogation of genome-wide association studies. Eur J Hum Genet. 2013; 22(7):949-52. PMC: 4060122. DOI: 10.1038/ejhg.2013.274. View

13.

Qi X, Cui C, Peng Y, Zhang X, Yang Z, Zhong H . Genetic evidence of paleolithic colonization and neolithic expansion of modern humans on the tibetan plateau. Mol Biol Evol. 2013; 30(8):1761-78. DOI: 10.1093/molbev/mst093. View

14.

Monteiro L, Cubillos S, Sanchez M, Acuna-Gallardo S, Venegas P, Herrera V . Reduced FOXM1 Expression Limits Trophoblast Migration and Angiogenesis and Is Associated With Preeclampsia. Reprod Sci. 2018; 26(5):580-590. DOI: 10.1177/1933719118778798. View

15.

Yoo S, Takikawa S, Geraghty P, Argmann C, Campbell J, Lin L . Integrative analysis of DNA methylation and gene expression data identifies EPAS1 as a key regulator of COPD. PLoS Genet. 2015; 11(1):e1004898. PMC: 4287352. DOI: 10.1371/journal.pgen.1004898. View

16.

Yi X, Liang Y, Huerta-Sanchez E, Jin X, Cuo Z, Pool J . Sequencing of 50 human exomes reveals adaptation to high altitude. Science. 2010; 329(5987):75-8. PMC: 3711608. DOI: 10.1126/science.1190371. View

17.

Bryois J, Garrett M, Song L, Safi A, Giusti-Rodriguez P, Johnson G . Evaluation of chromatin accessibility in prefrontal cortex of individuals with schizophrenia. Nat Commun. 2018; 9(1):3121. PMC: 6081462. DOI: 10.1038/s41467-018-05379-y. View

18.

Peng Y, Cui C, He Y, Ouzhuluobu , Zhang H, Yang D . Down-Regulation of EPAS1 Transcription and Genetic Adaptation of Tibetans to High-Altitude Hypoxia. Mol Biol Evol. 2017; 34(4):818-830. PMC: 5400376. DOI: 10.1093/molbev/msw280. View

19.

Johnson W, Li C, Rabinovic A . Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics. 2006; 8(1):118-27. DOI: 10.1093/biostatistics/kxj037. View

20.

Chen Y, Shen Y, Lin P, Tong D, Zhao Y, Allesina S . Gene regulatory network stabilized by pervasive weak repressions: microRNA functions revealed by the May-Wigner theory. Natl Sci Rev. 2021; 6(6):1176-1188. PMC: 8291590. DOI: 10.1093/nsr/nwz076. View