DNA methylation shows complex correlations with gene expression, and the role of promoter hypermethylation in repressing gene transcription has been well addressed. Emerging evidence indicates that gene body methylation promotes transcription; however, the underlying mechanisms remain to be further investigated. Here, using methylated DNA immunoprecipitation sequencing (MeDIP-seq), bisulfite genomic sequencing, and immunofluorescent labeling, we show that gene body methylation is indeed positively correlated with rRNA gene (rDNA) transcription. Mechanistically, gene body methylation is largely maintained by DNA methyltransferase 1 (DNMT1), deficiency or downregulation of which during myoblast differentiation or nutrient deprivation results in decreased gene body methylation levels, leading to increased gene body occupancy of plant homeodomain (PHD) finger protein 6 (PHF6). PHF6 binds to hypomethylated rDNA gene bodies where it recruits histone methyltransferase SUV4-20H2 to establish the repressive histone modification, H4K20me3, ultimately inhibiting rDNA transcription. These findings demonstrate that DNMT1-mediated gene body methylation safeguards rDNA transcription by preventing enrichment of repressive histone modifications, suggesting that gene body methylation serves to maintain gene expression in response to developmental and/or environmental stresses.

中文翻译：

---

基因体甲基化通过阻止 PHF6 介导的抑制性组蛋白标记 H4K20me3 的富集来保护核糖体 DNA 转录。

DNA 甲基化显示出与基因表达的复杂相关性，并且启动子高甲基化在抑制基因转录中的作用已经得到很好的解决。新出现的证据表明基因体甲基化促进转录；然而，潜在的机制仍有待进一步研究。在这里，使用甲基化 DNA 免疫沉淀测序 (MeDIP-seq)、亚硫酸氢盐基因组测序和免疫荧光标记，我们表明基因体甲基化确实与 rRNA 基因 (rDNA) 转录呈正相关。从机制上讲，基因体甲基化主要由 DNA 甲基转移酶 1 (DNMT1) 维持，在成肌细胞分化或营养缺乏期间其缺乏或下调会导致基因体甲基化水平降低，导致植物同源域 (PHD) 指蛋白 6 (PHF6) 的基因体占有率增加。PHF6 与低甲基化 rDNA 基因体结合，在那里它募集组蛋白甲基转移酶 SUV4-20H2 以建立抑制性组蛋白修饰 H4K20me3，最终抑制 rDNA 转录。这些发现表明，DNMT1 介导的基因体甲基化通过阻止抑制性组蛋白修饰的富集来保护 rDNA 转录，表明基因体甲基化有助于维持基因表达以响应发育和/或环境压力。