Epigenetic Modification of Gene Expression During Human Acclimatization to Hypobaric Hypoxia (885.4)

Epigenetic processes and hypoxia‐inducible transcription factors work in coordination to regulate transcriptional responses to hypoxia. Our aim was to determine the role of epigenetics and associated changes to gene transcription for human acclimatization to high altitude. We performed genome‐wide methylation (Infinium HumanMethylation450 BeadChip, Illumina) and expression (Affymetrix Human Gene 1.0 ST Array) studies in peripheral blood mononuclear cells obtained from 21 healthy individuals at sea level and on three occasions during acclimatization to 5260m. Acute hypoxia minimally affected DNA methylation status. After 16 days of acclimatization, we identified 183 differentially methylated sites, including several that are associated with genes known to be involved in hypoxic response (e.g., eukaryotic translation initiation factor 2C subunit 2 [EIF2C], heat shock protein [HSP] 27, DNA (cytosine‐5)‐methyltransferase 3A). Indicating the potential functional importance of these epigenetic modifications, using methQTL we found that methylation status altered the transcriptional activity of hypoxia‐related genes considered central to human acclimatization to hypoxia (e.g., HIF1AN, EIFs, HSPs). Our findings support the possibility that epigenetic modification of gene expression contributes to acclimatization to high altitude.Grant Funding Source: Supported by: W81XWH‐11‐2‐0040 (DoD), NIH‐CCTSI UL1 TR000154 (NIH‐CCTSI), & 5 K12 HD057022‐07 (NIH)