Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095, USA.
Institute of Plant and Microbial Biology, Academia Sinica, Taipei 11529, Taiwan.
Dev Cell. 2022 Jun 20;57(12):1482-1495.e5. doi: 10.1016/j.devcel.2022.05.012. Epub 2022 Jun 8.
Development of primordial germ cells (PGCs) is required for reproduction. During PGC development in mammals, major epigenetic remodeling occurs, which is hypothesized to establish an epigenetic landscape for sex-specific germ cell differentiation and gametogenesis. In order to address the role of embryonic ectoderm development (EED) and histone 3 lysine 27 trimethylation (H3K27me3) in this process, we created an EED conditional knockout mouse and show that EED is essential for regulating the timing of sex-specific PGC differentiation in both ovaries and testes, as well as X chromosome dosage decompensation in testes. Integrating chromatin and whole genome bisulfite sequencing of epiblast and PGCs, we identified a poised repressive signature of H3K27me3/DNA methylation that we propose is established in the epiblast where EED and DNMT1 interact. Thus, EED joins DNMT1 in regulating the timing of sex-specific PGC differentiation during the critical window when the gonadal niche cells specialize into an ovary or testis.
原始生殖细胞 (PGC) 的发育是生殖所必需的。在哺乳动物的 PGC 发育过程中，会发生主要的表观遗传重塑，这被假设为建立性别特异性生殖细胞分化和配子发生的表观遗传景观。为了研究胚胎外胚层发育 (EED) 和组蛋白 3 赖氨酸 27 三甲基化 (H3K27me3) 在这一过程中的作用，我们创建了一个 EED 条件性敲除小鼠，并表明 EED 对于调节卵巢和睾丸中性别特异性 PGC 分化的时机以及睾丸中 X 染色体剂量补偿至关重要。整合染色质和外胚层和 PGC 的全基因组亚硫酸氢盐测序，我们确定了 H3K27me3/DNA 甲基化的一种启动抑制特征，我们提出该特征是在外胚层中建立的，其中 EED 和 DNMT1 相互作用。因此，EED 与 DNMT1 一起调节在生殖嵴细胞特化为卵巢或睾丸的关键窗口中性别特异性 PGC 分化的时机。
