A time-resolved multi-omics atlas of transcriptional regulation in response to high-altitude hypoxia across whole-body tissues

Ze Yan, Ji Yang, Wen-Tian Wei, Ming-Liang Zhou, Dong-Xin Mo, Xing Wan, Rui Ma, Mei-Ming Wu, Jia-Hui Huang, Ya-Jing Liu, Feng-Hua Lv and Meng-Hua Li ()
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Ze Yan: China Agricultural University
Ji Yang: China Agricultural University
Wen-Tian Wei: China Agricultural University
Ming-Liang Zhou: Sichuan Academy of Grassland Science
Dong-Xin Mo: China Agricultural University
Xing Wan: China Agricultural University
Rui Ma: China Agricultural University
Mei-Ming Wu: China Agricultural University
Jia-Hui Huang: China Agricultural University
Ya-Jing Liu: China Agricultural University
Feng-Hua Lv: China Agricultural University
Meng-Hua Li: China Agricultural University

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: Abstract High-altitude hypoxia acclimatization requires whole-body physiological regulation in highland immigrants, but the underlying genetic mechanism has not been clarified. Here we use sheep as an animal model for low-to-high altitude translocation. We generate multi-omics data including whole-genome sequences, time-resolved bulk RNA-Seq, ATAC-Seq and single-cell RNA-Seq from multiple tissues as well as phenotypic data from 20 bio-indicators. We characterize transcriptional changes of all genes in each tissue, and examine multi-tissue temporal dynamics and transcriptional interactions among genes. Particularly, we identify critical functional genes regulating the short response to hypoxia in each tissue (e.g., PARG in the cerebellum and HMOX1 in the colon). We further identify TAD-constrained cis-regulatory elements, which suppress the transcriptional activity of most genes under hypoxia. Phenotypic and transcriptional evidence indicate that antenatal hypoxia could improve hypoxia tolerance in offspring. Furthermore, we provide time-series expression data of candidate genes associated with human mountain sickness (e.g., BMPR2) and high-altitude adaptation (e.g., HIF1A). Our study provides valuable resources and insights for future hypoxia-related studies in mammals.

Date: 2024
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DOI: 10.1038/s41467-024-48261-w

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