Epigenetic resetting in the human germline entails histone modification remodelling [ChIP-Seq]

Epigenetic resetting in the mammalian germ line entailsacute DNA demethylation, which lays the foundation for gametogenesis, totipotency,and embryonic development. We characterize the epigenome of hypomethylated human primordial germ cells (hPGCs) to reveal mechanisms preventing the widespread derepression of genesand transposable elements (TEs). Along with the loss of DNA methylation, we show that hPGCsexhibit a profound reduction of repressive histone modifications resulting in diminished heterochromatic signaturesat most genesand TEsand the acquisition of a neutral or paused epigenetic state without transcriptional activation.Efficient maintenance of a heterochromatic state is limited to a subset of genomic loci, such asevolutionarily young TEsand some developmental genes, which require H3K9me3 and H3K27me3, respectively, forefficient transcriptional repression. Accordingly, transcriptional repression in hPGCs presentsan exemplary balanced system relying on local maintenance of heterochromatic featuresand a lack of inductive cues. Overall design: Histone modifications ULI-NChIP-seq of human primordial germ cells gonadal somatic cells (two biological replicates for each cell type and sex)

哺乳动物生殖细胞系的表观重编程（Epigenetic resetting）伴随快速DNA去甲基化，该过程为配子发生、细胞全能性及胚胎发育奠定基础。本研究对低甲基化人类原始生殖细胞（hPGCs）的表观组进行表征，以揭示阻遏基因与转座因子（TEs）广泛去抑制的分子机制。研究发现，伴随DNA甲基化的丢失，人类原始生殖细胞展现出抑制性组蛋白修饰的显著降低，导致多数基因与转座因子的异染色质特征减弱，并获得一种无转录激活的中性或停滞表观遗传状态。异染色质状态的有效维持仅局限于部分基因组位点，例如进化年轻转座因子与部分发育基因，二者分别依赖组蛋白H3赖氨酸9三甲基化（H3K9me3）与组蛋白H3赖氨酸27三甲基化（H3K27me3）以实现高效转录抑制。据此，人类原始生殖细胞中的转录抑制呈现出典型的平衡调控系统，该系统依赖异染色质特征的局部维持以及诱导信号的缺失。整体实验设计：针对人类原始生殖细胞与性腺体细胞开展抑制性组蛋白修饰的超低投入核染色质免疫沉淀测序（ULI-NChIP-seq），每种细胞类型与性别的样本均设置两个生物学重复。