Department of Stem Cell and Regenerative Biology, Harvard University, Massachusetts, United States.
Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany.
Elife. 2018 Nov 23;7:e40757. doi: 10.7554/eLife.40757.
DNA methylation plays an essential role in mammalian genomes and expression of the responsible enzymes is tightly controlled. Deregulation of the de novo DNA methyltransferase DNMT3B is frequently observed across cancer types, yet little is known about its ectopic genomic targets. Here, we used an inducible transgenic mouse model to delineate rules for abnormal DNMT3B targeting, as well as the constraints of its activity across different cell types. Our results explain the preferential susceptibility of certain CpG islands to aberrant methylation and point to transcriptional state and the associated chromatin landscape as the strongest predictors. Although DNA methylation and H3K27me3 are usually non-overlapping at CpG islands, H3K27me3 can transiently co-occur with DNMT3B-induced DNA methylation. Our genome-wide data combined with ultra-deep locus-specific bisulfite sequencing suggest a distributive activity of ectopically expressed Dnmt3b that leads to discordant CpG island hypermethylation and provides new insights for interpreting the cancer methylome.
DNA 甲基化在哺乳动物基因组中起着至关重要的作用，负责的酶的表达受到严格控制。在癌症类型中，从头甲基转移酶 DNMT3B 的失调经常被观察到，但对其异位基因组靶标知之甚少。在这里，我们使用可诱导的转基因小鼠模型来描绘异常 DNMT3B 靶向的规则，以及其在不同细胞类型中的活性限制。我们的结果解释了某些 CpG 岛易受异常甲基化的原因，并指出转录状态和相关染色质景观是最强的预测因子。尽管 DNA 甲基化和 H3K27me3 通常在 CpG 岛上不重叠，但 H3K27me3 可以与 DNMT3B 诱导的 DNA 甲基化瞬时共存。我们的全基因组数据结合超深度局部亚硫酸氢盐测序表明，异位表达的 Dnmt3b 具有分布式活性，导致 CpG 岛过度甲基化不一致，并为解释癌症甲基组提供了新的见解。
