解放军医学院学报2025，Vol.46Issue(12)：1157-1170,14.DOI:10.12435/j.issn.2095-5227.25072203
世居平原、高原习服与世居高原三类人群DNA甲基化差异及其功能解析
DNA methylation differences and functional analysis across native lowland,acclimatized,and native highland populations
付磊 1关家伟 2宋欣雨 2徐雨竹 2何昆仑 2石金龙2
作者信息
- 1. 解放军医学院,北京 100853||解放军总医院医学创新研究部,北京 100853
- 2. 解放军总医院医学创新研究部,北京 100853
- 折叠
摘要
Abstract
Background Understanding molecular mechanisms of high-altitude adaptation is crucial for combating mountain sickness.While native highlanders exhibit distinct genetic/epigenetic traits,systematic whole-genome methylation comparisons across acclimatization stages are lacking.Objective To investigate the differences in DNA methylation among populations in plain and plateau environments and analyze their functional implications.Methods A self-established high-altitude research cohort was composed of native lowlanders(NLs),acclimatized newcomers(ANs),and native highlanders(NHs).Whole-genome bisulfite sequencing(WGBS)was used to obtain their methylation data.Differential methylated regions(DMRs)analysis and epigenome-wide association studies(EWAS)were conducted among the populations to identify differential methylation signals between the groups.GO and KEGG enrichment analyses were then performed to elucidate the biological functions of these methylation differences.Results This study included 117 NLs(all men,aged 20.15±1.43 years),162 ANs(all men,aged 22.07±2.65 years),and 124 NHs(101 men and 23 women,aged 22.10±7.34 years).After entering the plateau,the methylation levels of NLs decreased genome-wide(P＜0.01).Compared with NLs,ANs exhibited 440 DMRs and 611 differentially methylated CpGs(DMCs),driving significant changes in immune functions(such as T cell activation and NK cell cytotoxicity pathways)and energy metabolism patterns(e.g.,the LDHC gene),but also accompanied by abnormal activation of pathways related to cardiomyopathy.Compared with ANs,NHs had 1 313 DMRs and 2 022 DMCs,with differences mainly enriched in the calcium signaling pathway and gene regions such as EPAS1/EGLN1.The overall methylation level of NHs was significantly lower than that of NLs,and NHs had 247 DMRs and 688 DMCs,with differences mainly enriched in the HIF-1 pathway(q＜0.01)and the autophagy signaling pathway.Conclusion DNA methylation plays an important role in human adaptation to high-altitude environments.In comparison,NHs not only exhibit a significantly lower overall methylation level than NLs,but also display a greater number of specific differentially methylated regions,suggesting that they may achieve long-term stable adaptation to hypoxic environments and cellular homeostasis through precise regulation of the methylation status of key genes.关键词
高原适应/习服/低氧/DNA甲基化/信号通路/青年Key words
high-altitude adaptation/acclimatization/hypoxia/DNA methylation/signal transduction/young adult分类
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付磊,关家伟,宋欣雨,徐雨竹,何昆仑,石金龙..世居平原、高原习服与世居高原三类人群DNA甲基化差异及其功能解析[J].解放军医学院学报,2025,46(12):1157-1170,14.
