Zhu Chenyu, Huang Tingting, Fu Jiaqi, Li Min, Tan Luyi, Zhang Xinyu, Cheng Wenli, Lai Caiyun, Wang Zhangying, Zhang Wenji, Zhang Wenjuan
Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou, Guangdong, China.
Key Laboratory of Crop Genetic Improvement of Guangdong Province, Crops Research Institute, Guangdong Academy of Agricultural Sciences, Guangzhou, Guangdong, China.
mSystems. 2025 Jul 22;10(7):e0164724. doi: 10.1128/msystems.01647-24. Epub 2025 Jun 16.
UNLABELLED: Hydrogen peroxide (HO) is a typical representative substance of environmental oxidative stress. Exogenous substances can alter epigenetic modifications from the DNA to the RNA level through oxidative stress. We investigated methylation profiles of whole RNA m6A and DNA 5mC in the epitranscriptome and epigenome of human lung embryonic fibroblasts in replicative senescence and HO-induced premature senescence. By RNA-seq, the expression of most RNA m6A and DNA 5mC regulators was reduced in both replicative and premature senescence respectively, whereas the expression of most senescence-associated secretory phenotypes, such as SASP, was increased in premature senescence. MeRIP-seq revealed that RNA m6A methylation sites were relatively conserved in replicative and premature senescence, but that premature senescence had higher levels of m6A methylation than replicative senescence. MeDIP-seq results showed that 5mC methylation was higher in replicative senescence than in premature senescence, and the methylation peak with the largest difference appeared on chromosome 19. DO enrichment analysis indicated that RNA m6A methylation played a key role in malignant tumor regulation in replicative senescence, whereas DNA 5mC promoted malignant tumor in premature senescence. Next, to explore the interaction of RNA m6A and DNA 5mC in the senescent state, we screened common hub genes for replicative and premature senescence. Four m6A-modified target genes, namely, , , , and , were all closely associated with mitosis and cell cycle regulation. In addition, we also screened 5mC target genes including , and . IMPORTANCE: RNA-seq showed that most of the m6A and 5mC regulators and the majority of SASP expression were downregulated. The m6A motif was conserved in replicative and premature senescence, and its methylation was higher in replicative senescence. The most differentially 5mC methylation peak was located on chromosome 19, and its methylation was higher in premature senescence. Gene regulation by m6A in replicative senescence and 5mC in premature senescence was enriched in malignant tumors.
未标记：过氧化氢（HO）是环境氧化应激的典型代表物质。外源性物质可通过氧化应激改变从DNA到RNA水平的表观遗传修饰。我们研究了人类肺胚胎成纤维细胞在复制性衰老和HO诱导的早衰过程中，全RNA m6A和DNA 5mC在表观转录组和表观基因组中的甲基化谱。通过RNA测序，大多数RNA m6A和DNA 5mC调节因子的表达在复制性衰老和早衰中分别降低，而大多数衰老相关分泌表型（如SASP）的表达在早衰中增加。MeRIP-seq显示，RNA m6A甲基化位点在复制性衰老和早衰中相对保守，但早衰中的m6A甲基化水平高于复制性衰老。MeDIP-seq结果表明，5mC甲基化在复制性衰老中高于早衰，差异最大的甲基化峰出现在19号染色体上。DO富集分析表明，RNA m6A甲基化在复制性衰老中的恶性肿瘤调控中起关键作用，而DNA 5mC在早衰中促进恶性肿瘤。接下来，为了探索RNA m6A和DNA 5mC在衰老状态下的相互作用，我们筛选了复制性衰老和早衰的共同枢纽基因。四个m6A修饰的靶基因，即 、 、 和 ，均与有丝分裂和细胞周期调控密切相关。此外，我们还筛选了包括 、 和 在内的5mC靶基因。 重要性：RNA测序表明，大多数m6A和5mC调节因子以及大多数SASP表达均下调。m6A基序在复制性衰老和早衰中保守，其甲基化在复制性衰老中更高。差异最大的5mC甲基化峰位于19号染色体上，其甲基化在早衰中更高。复制性衰老中m6A和早衰中5mC的基因调控在恶性肿瘤中富集。
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