Cheng Feifei, Shen Ren-Juan, Zheng Zhili, Chen Zhen Ji, Huang Peng-Juan, Feng Zhuo-Kun, Li Xiaoman, Lin Na, Zheng Meiqin, Liang Yuanbo, Qu Jia, Lu Fan, Jin Zi-Bing, Yang Jian
School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China.
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
Cell Discov. 2025 May 6;11(1):45. doi: 10.1038/s41421-025-00795-z.
High altitude presents a challenging environment for human settlement. DNA methylation is an essential epigenetic mechanism that responds to environmental stimuli, but its roles in high-altitude short-term acclimatization (STA) and long-term adaptation (LTA) are poorly understood. Here, we conducted a methylome-wide association study involving 687 native highlanders and 299 acclimatized newcomers in the Tibetan Plateau and 462 native lowlanders to identify differentially methylated sites (DMSs) associated with STA or LTA. We identified 93 and 4070 DMSs for STA and LTA, respectively, which had no overlap, showed opposite asymmetric effect size patterns, and resided near genes enriched in distinct biological pathways/processes (e.g., cell cycle for STA and immune diseases and calcium signalling pathway for LTA). Epigenetic clock analysis revealed evidence of accelerated ageing in the acclimatized newcomers compared to the native lowlanders. Our research provides novel insights into epigenetic regulation in relation to high altitude and intervention strategies for altitude-related ageing or illnesses.
高海拔地区对人类定居构成了具有挑战性的环境。DNA甲基化是一种对环境刺激作出反应的重要表观遗传机制，但其在高海拔短期适应（STA）和长期适应（LTA）中的作用却鲜为人知。在此，我们进行了一项全基因组甲基化关联研究，涉及青藏高原的687名本地高原居民、299名适应后的新来者以及462名本地低地居民，以确定与STA或LTA相关的差异甲基化位点（DMS）。我们分别为STA和LTA鉴定出93个和4070个DMS，它们没有重叠，表现出相反的不对称效应大小模式，并且位于富集于不同生物途径/过程的基因附近（例如，STA相关的细胞周期以及LTA相关的免疫疾病和钙信号通路）。表观遗传时钟分析显示，与本地低地居民相比，适应后的新来者有加速衰老的迹象。我们的研究为与高海拔相关的表观遗传调控以及与海拔相关的衰老或疾病的干预策略提供了新的见解。
