Transcriptomic and Epigenomic Reponses During Human Adaptation to High‐Altitude Hypoxia

Abstract

Little is known about early genomic responses in human adaptation to high‐altitude hypoxia. At 5260 m (PB=406 Torr) we studied transcriptomic and epigenomic responses of 21 young, healthy men and women during 16 days, and again on return after 7 days in normoxia. Physiological responses showed marked improvement in performance at day 16 compared to day 1, with better SaO2%, submaximal work capacity and cognitive function, and complete protection from altitude illness. Most of these improvements were maintained after 7 days in normoxia. Accompanying these changes, 6350 genes were differentially expressed (DE, q<=0.01) from sea level (SL) on day 7/16, with 3557 (48%/52% up/down) only on day 7 (early), 1418 at both day 7 & 16 (40%/60% up/down), and on day 16 (late) 1375 (44%/56% up/down). Differential methylation (DM, q<0.01) was also observed genome‐wide, and followed a similar time pattern. The DE and DM genes include many known hypoxia‐responsive genes (HIF1α, HIF2α, VEGF, HMOX, etc.). Surprisingly, 1608 genes were DM from SL to day 16, and maintained their DM status after 7 days in normoxia, making these genes prime candidates for control of the onset and retention of physiological adjustments to hypoxia. These data provide a unique resource for future exploration of the molecular and cellular mechanisms controlling human adaptation to hypoxia. Funding for AltitudeOmics was provided, in part, by US DoD W81XWH‐11‐2‐0040 (RCR).