DNA methylation in adaptation to high-altitude environments and pathogenesis of related diseases.

Abstract

High-altitude environments, characterized by hypoxia, low temperatures, and intense ultraviolet radiation, pose significant challenges to human physiology and health. DNA methylation, as a key epigenetic regulatory mechanism, plays a central role in human adaptation to high-altitude environments and in disease pathogenesis. Current research indicates that high-altitude native populations (such as Tibetans and Andeans) modulate the methylation of hypoxia-responsive genes like EPAS1 and EGLN1 to enhance oxygen transport efficiency and energy metabolism patterns, while simultaneously suppressing excessive erythropoiesis and oxidative stress damage. This epigenetic regulation not only compensates for the lag in genetic adaptation over time but also forms synergistic networks with genetic variations. For instance, the functional SNPs of the EPAS1 gene are co-localized with its differentially methylated regions, revealing a delicate balance between genetic and epigenetic interactions under environmental stress. On the other hand, aberrant methylation patterns may disrupt the homeostasis of the HIF pathway, leading to acute and chronic high-altitude illnesses. This article provides a review of the recent research progress in plateau medicine and DNA methylation (up to 2025), including human clinical studies and animal model research. This includes research on high-altitude adaptation/acclimatization, as well as studies on inadequate adaptation to high altitude in relation to acute and chronic high-altitude-related diseases, cognitive decline, and pregnancy risks. By elucidating the core mechanisms underlying the "environmen - epigenetics - phenotype" axis, this work aims to provide a theoretical foundation for precision health interventions in high-altitude regions.