Tang Walfred W C, Castillo-Venzor Aracely, Gruhn Wolfram H, Kobayashi Toshihiro, Penfold Christopher A, Morgan Michael D, Sun Dawei, Irie Naoko, Surani M Azim
Wellcome Trust/Cancer Research UK Gurdon Institute, Henry Wellcome Building of Cancer and Developmental Biology, Cambridge, UK.
Physiology, Development and Neuroscience Department, University of Cambridge, Cambridge, UK.
Nat Cell Biol. 2022 Apr;24(4):448-460. doi: 10.1038/s41556-022-00878-z. Epub 2022 Apr 11.
Germline-soma segregation is a fundamental event during mammalian embryonic development. Here we establish the epigenetic principles of human primordial germ cell (hPGC) development using in vivo hPGCs and stem cell models recapitulating gastrulation. We show that morphogen-induced remodelling of mesendoderm enhancers transiently confers the competence for hPGC fate, but further activation favours mesoderm and endoderm fates. Consistently, reducing the expression of the mesendodermal transcription factor OTX2 promotes the PGC fate. In hPGCs, SOX17 and TFAP2C initiate activation of enhancers to establish a core germline programme, including the transcriptional repressor PRDM1 and pluripotency factors POU5F1 and NANOG. We demonstrate that SOX17 enhancers are the critical components in the regulatory circuitry of germline competence. Furthermore, activation of upstream cis-regulatory elements by an optimized CRISPR activation system is sufficient for hPGC specification. We reveal an enhancer-linked germline transcription factor network that provides the basis for the evolutionary divergence of mammalian germlines.
生殖系与体细胞的分离是哺乳动物胚胎发育过程中的一个基本事件。在这里，我们利用体内人类原始生殖细胞（hPGC）和模拟原肠胚形成的干细胞模型，确立了人类原始生殖细胞发育的表观遗传原理。我们发现，形态发生素诱导的中内胚层增强子重塑短暂赋予了hPGC命运的能力，但进一步激活则有利于中胚层和内胚层命运。一致地，降低中内胚层转录因子OTX2的表达可促进PGC命运。在hPGC中，SOX17和TFAP2C启动增强子的激活，以建立一个核心生殖系程序，包括转录抑制因子PRDM1以及多能性因子POU5F1和NANOG。我们证明，SOX17增强子是生殖系能力调控回路中的关键组成部分。此外，通过优化的CRISPR激活系统激活上游顺式调控元件足以实现hPGC的特化。我们揭示了一个与增强子相关的生殖系转录因子网络，该网络为哺乳动物生殖系的进化分歧提供了基础。
