Genome-Wide DNA Methylation Changes Associated With High-Altitude Acclimatization During an Everest Base Camp Trek

Ainash Childebayeva; Taylor Harman; Julien Weinstein; Trevor Day; Tom D Brutsaert; Abigail W Bigham

doi:10.3389/fphys.2021.660906

Genome-Wide DNA Methylation Changes Associated With High-Altitude Acclimatization During an Everest Base Camp Trek

Front Physiol. 2021 Jun 28:12:660906. doi: 10.3389/fphys.2021.660906. eCollection 2021.

Authors

Ainash Childebayeva^{1

2

3}, Taylor Harman⁴, Julien Weinstein¹, Trevor Day⁵, Tom D Brutsaert⁶, Abigail W Bigham⁷

Affiliations

¹ Department of Anthropology, University of Michigan, Ann Arbor, MI, United States.
² Department of Environmental Sciences, School of Public Health, Ann Arbor, MI, United States.
³ Department of Archaeogenetics, Max Planck Institute for the Study of Human History, Jena, Germany.
⁴ Department of Anthropology, Syracuse University, Syracuse, NY, United States.
⁵ Department of Biology, Mount Royal University, Calgary, AB, Canada.
⁶ Department of Exercise Science, Syracuse University, Syracuse, NY, United States.
⁷ Department of Anthropology, University of California, Los Angeles, Los Angeles, CA, United States.

Abstract

The individual physiological response to high-altitude hypoxia involves both genetic and non-genetic factors, including epigenetic modifications. Epigenetic changes in hypoxia factor pathway (HIF) genes are associated with high-altitude acclimatization. However, genome-wide epigenetic changes that are associated with short-term hypoxia exposure remain largely unknown. We collected a series of DNA samples from 15 participants of European ancestry trekking to Everest Base Camp to identify DNA methylation changes associated with incremental altitude ascent. We determined genome-wide DNA methylation levels using the Illumina MethylationEPIC chip comparing two altitudes: baseline 1,400 m (day 0) and elevation 4,240 m (day 7). The results of our epigenome-wide association study revealed 2,873 significant differentially methylated positions (DMPs) and 361 significant differentially methylated regions (DMRs), including significant positions and regions in hypoxia inducible factor (HIF) and the renin-angiotensin system (RAS) pathways. Our pathway enrichment analysis identified 95 significant pathways including regulation of glycolytic process (GO:0006110), regulation of hematopoietic stem cell differentiation (GO:1902036), and regulation of angiogenesis (GO:0045765). Lastly, we identified an association between the ACE gene insertion/deletion (I/D) polymorphism and oxygen saturation, as well as average ACE methylation. These findings shed light on the genes and pathways experiencing the most epigenetic change associated with short-term exposure to hypoxia.

Keywords: HIF pathway; epigenetics (DNA methylation); genome-wide DNA methylation analysis; high altitude acclimatization; hypoxia.