Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Swiss Institute of Bioinformatics, Basel, Switzerland.
Nat Commun. 2020 May 29;11(1):2680. doi: 10.1038/s41467-020-16354-x.
DNA methylation is considered a stable epigenetic mark, yet methylation patterns can vary during differentiation and in diseases such as cancer. Local levels of DNA methylation result from opposing enzymatic activities, the rates of which remain largely unknown. Here we developed a theoretical and experimental framework enabling us to infer methylation and demethylation rates at 860,404 CpGs in mouse embryonic stem cells. We find that enzymatic rates can vary as much as two orders of magnitude between CpGs with identical steady-state DNA methylation. Unexpectedly, de novo and maintenance methylation activity is reduced at transcription factor binding sites, while methylation turnover is elevated in transcribed gene bodies. Furthermore, we show that TET activity contributes substantially more than passive demethylation to establishing low methylation levels at distal enhancers. Taken together, our work unveils a genome-scale map of methylation kinetics, revealing highly variable and context-specific activity for the DNA methylation machinery.
DNA 甲基化被认为是一种稳定的表观遗传标记，但在分化和癌症等疾病过程中，甲基化模式会发生变化。局部 DNA 甲基化水平源于相反的酶活性，而这些酶的活性率在很大程度上尚不清楚。在这里，我们开发了一个理论和实验框架，使我们能够推断出在小鼠胚胎干细胞中的 860,404 个 CpG 上的甲基化和去甲基化速率。我们发现，在具有相同的 DNA 甲基化稳态的 CpG 之间，酶的速率可以相差两个数量级。出乎意料的是，在转录因子结合位点处，新和成和维持甲基化活性降低，而在转录基因体中，甲基化周转率升高。此外，我们还表明，TET 活性比对非活性去甲基化对建立远端增强子的低甲基化水平贡献更大。总之，我们的工作揭示了一个全基因组范围内的甲基化动力学图谱，揭示了 DNA 甲基化机制的高度可变和特定于上下文的活性。
