An epigenetic switch ensures transposon repression upon acute loss of DNA methylation in ES cells (WGBS). Mus musculus

DNA methylation profoundly impacts genome regulation, notably through the control of transposons. DNA methylation is extensively remodeled during two developmental periods in mammals, gametogenesis and early embryogenesis. Most of transposons families become then hypomethylated, raising the question of their regulation in absence of DNA methylation. To induce genome-wide demethylation, we relied on hypomethylation-inducing culture conditions of murine embryonic stem cells. Surprisingly, we observed two phases of transposon regulation. After a burst of derepression, which correlates with DNA methylation disappearance, both LTR and non-LTR retrotransposons were efficiently re-silenced. While histone H3 lysine 9 trimethylation (H3K9me3) remained stable, H3 lysine 27 trimethylation (H3K27me3) was reorganized upon loss of DNA methylation and contributed to transposon re-silencing. Interestingly, we observed that H3K9me3 and H3K27me3 co-occurred but in distinct regions of unmethylated transposon sequences. This unusual pattern may provide a mechanistic relay ensuring genome stability during developmental periods of programmed loss of DNA methylation. Overall design: WGBS, RNA-seq, ChIP-seq of J1 ES cell during conversion from serum to 2i+vitC medium

DNA甲基化可深刻影响基因组调控，尤其通过转座子的调控发挥核心作用。在哺乳动物中，DNA甲基化会在配子发生与早期胚胎发生这两个发育阶段被广泛重塑。此时绝大多数转座子家族会呈现低甲基化状态，这引出了关键科学问题：在DNA甲基化缺失的情况下，转座子的调控机制将如何维持？为诱导全基因组去甲基化，我们采用了小鼠胚胎干细胞的低甲基化诱导培养体系。令人意外的是，我们观察到转座子调控存在两个阶段：在与DNA甲基化消失相关的去抑制爆发之后，长末端重复序列（LTR）反转录转座子与非长末端重复序列（non-LTR）反转录转座子均被有效重新沉默。尽管组蛋白H3赖氨酸9三甲基化（H3K9me3）的水平保持稳定，但组蛋白H3赖氨酸27三甲基化（H3K27me3）会在DNA甲基化缺失时发生重排布，并参与转座子的重新沉默过程。值得注意的是，我们发现H3K9me3与H3K27me3虽共同存在于未甲基化的转座子序列中，但二者分布于不同的区域。这种特殊的表观修饰模式或许为程序性DNA甲基化缺失的发育阶段的基因组稳定性提供了一种机制性保障。总体实验设计：J1胚胎干细胞在从血清培养基转换为2i+维生素C培养基过程中的全基因组亚硫酸氢盐测序（WGBS）、RNA测序（RNA-seq）以及染色质免疫沉淀测序（ChIP-seq）