MRC London Institute of Medical Sciences (LMS), London, UK.
Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK.
Nature. 2021 Dec;600(7890):737-742. doi: 10.1038/s41586-021-04208-5. Epub 2021 Dec 8.
Stability of the epigenetic landscape underpins maintenance of the cell-type-specific transcriptional profile. As one of the main repressive epigenetic systems, DNA methylation has been shown to be important for long-term gene silencing; its loss leads to ectopic and aberrant transcription in differentiated cells and cancer. The developing mouse germ line endures global changes in DNA methylation in the absence of widespread transcriptional activation. Here, using an ultra-low-input native chromatin immunoprecipitation approach, we show that following DNA demethylation the gonadal primordial germ cells undergo remodelling of repressive histone modifications, resulting in a sex-specific signature in mice. We further demonstrate that Polycomb has a central role in transcriptional control in the newly hypomethylated germline genome as the genetic loss of Ezh2 leads to aberrant transcriptional activation, retrotransposon derepression and dramatic loss of developing female germ cells. This sex-specific effect of Ezh2 deletion is explained by the distinct landscape of repressive modifications observed in male and female germ cells. Overall, our study provides insight into the dynamic interplay between repressive chromatin modifications in the context of a developmental reprogramming system.
表观遗传景观的稳定性是维持细胞类型特异性转录特征的基础。作为主要的抑制性表观遗传系统之一，DNA 甲基化对于长期的基因沉默很重要；其缺失会导致分化细胞和癌症中的异位和异常转录。在没有广泛转录激活的情况下，发育中的小鼠生殖系经历 DNA 甲基化的全局变化。在这里，我们使用超低输入的天然染色质免疫沉淀方法，表明在 DNA 去甲基化后，性腺原始生殖细胞经历了抑制性组蛋白修饰的重塑，导致在小鼠中产生了性别特异性的特征。我们进一步证明，多梳蛋白在新的低甲基化生殖系基因组的转录控制中起着核心作用，因为 Ezh2 的遗传缺失导致异常的转录激活、逆转录转座子去抑制和发育中雌性生殖细胞的大量丢失。Ezh2 缺失的这种性别特异性效应可以通过在雄性和雌性生殖细胞中观察到的不同的抑制性修饰景观来解释。总的来说，我们的研究提供了在发育重编程系统背景下抑制性染色质修饰之间动态相互作用的深入了解。
