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

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.

Time Domains of Hypoxia Responses and -Omics Insights

“…The authors also identified associations between DNA methylation and the altitude adaptive phenotype of fraction of exhaled nitric oxide ( Childebayeva et al, 2021a ). Surprisingly, even short-term hypoxia, such as that experienced by Europeans ascending Everest, elicited distinct epigenetic changes at key HIF loci, including EPAS1 ( Childebayeva et al, 2019a ), along with other genes in HIF and RAS pathways ( Childebayeva et al, 2021b ). These findings speak to plasticity not just in development, but potentially throughout one’s lifetime, suggesting epigenetic factors may play a role in acclimitization to high altitude.…”

Serum vascular endothelial growth factor is a potential biomarker for acute mountain sickness

“…Molecular mechanisms of HH like hypoxia-inducible factor signal cascade are well investigated (Semenza, 2006;Semenza, 2009). Hypoxia-induced inflammation can induce immune response resulting in a variety of pathologies in the context of chronic hypoxia (Walmsley et al, 2014;Krzywinska and Stockmann, Childebayeva et al, 2021). AMS and its possible deterioration including HAPE and/or HACE is mainly caused by increased capillary pressure, i.e., a non-inflammatory phenomenon (Bärtsch et al, 2003;Bärtsch et al, 2005;Bärtsch and Saltin, 2008).…”

De novo Assembly, Annotation, and Analysis of Transcriptome Data of the Ladakh Ground Skink Provide Genetic Information on High-Altitude Adaptation

“…Indeed, we identified a total of 10 out of 143 and 104 out of ~1500 key genes [ 7 , 15 ] under positive selection in the Asymblepharus transcriptome. Interestingly, several of the 10 genes ( Table 4 ) have been reported to be under positive selection or significantly enriched or differentially methylated for pathways consistent with physiological compensation for limited oxygen in high elevation dwellers, e.g., IL1RAP [ 68 ] (human), MIA3 [ 69 ] (pika), and MICU1 [ 70 ] (Ladakhi cow). Several genes we identified to be under positive selection have GO terms that suggest their involvement in, e.g., energy metabolism and DNA repair.…”