Shenzhen Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518124, China.
Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518124, China.
Nucleic Acids Res. 2021 Feb 22;49(3):1313-1329. doi: 10.1093/nar/gkaa1203.
DNA methylation is important for the epigenetic regulation of gene expression and plays a critical role in mammalian development. However, the dynamic regulation of genome-wide DNA methylation in skeletal muscle development remains largely unknown. Here, we generated the first single-base resolution DNA methylome and transcriptome maps of porcine skeletal muscle across 27 developmental stages. The overall methylation level decreased from the embryo to the adult, which was highly correlated with the downregulated expression of DNMT1 and an increase in partially methylated domains. Notably, we identified over 40 000 developmentally differentially methylated CpGs (dDMCs) that reconstitute the developmental trajectory of skeletal muscle and associate with muscle developmental genes and transcription factors (TFs). The dDMCs were significantly under-represented in promoter regulatory regions but strongly enriched as enhancer histone markers and in chromatin-accessible regions. Integrative analysis revealed the negative regulation of both promoter and gene body methylation in genes associated with muscle contraction and insulin signaling during skeletal muscle development. Mechanistically, DNA methylation affected the expression of muscle-related genes by modulating the accessibly of upstream myogenesis TF binding, indicating the involvement of the DNA methylation/SP1/IGF2BP3 axis in skeletal myogenesis. Our results highlight the function and regulation of dynamic DNA methylation in skeletal muscle development.
DNA 甲基化对于基因表达的表观遗传调控至关重要，在哺乳动物发育中起着关键作用。然而，骨骼肌发育中全基因组 DNA 甲基化的动态调控仍知之甚少。在这里，我们生成了猪骨骼肌在 27 个发育阶段的首个单碱基分辨率的 DNA 甲基组和转录组图谱。整体甲基化水平从胚胎期到成年期逐渐降低，这与 DNMT1 的下调表达和部分甲基化域的增加高度相关。值得注意的是，我们鉴定了超过 40000 个发育差异甲基化 CpG（dDMC），它们重新构建了骨骼肌的发育轨迹，并与骨骼肌发育基因和转录因子（TF）相关。dDMC 在启动子调控区域的代表性不足，但作为增强子组蛋白标记物和染色质可及区域强烈富集。综合分析表明，在骨骼肌发育过程中与肌肉收缩和胰岛素信号相关的基因中，启动子和基因体甲基化均受到负调控。在机制上，DNA 甲基化通过调节上游成肌细胞 TF 结合的可及性来影响肌肉相关基因的表达，表明 DNA 甲基化/SP1/IGF2BP3 轴参与了骨骼肌生成。我们的研究结果突出了动态 DNA 甲基化在骨骼肌发育中的功能和调控作用。
