Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.
CNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
EMBO J. 2022 Jun 14;41(12):e109457. doi: 10.15252/embj.2021109457. Epub 2022 May 23.
The mammalian germline is characterized by extensive epigenetic reprogramming during its development into functional eggs and sperm. Specifically, the epigenome requires resetting before parental marks can be established and transmitted to the next generation. In the female germline, X-chromosome inactivation and reactivation are among the most prominent epigenetic reprogramming events, yet very little is known about their kinetics and biological function. Here, we investigate X-inactivation and reactivation dynamics using a tailor-made in vitro system of primordial germ cell-like cell (PGCLC) differentiation from mouse embryonic stem cells. We find that X-inactivation in PGCLCs in vitro and in germ cell-competent epiblast cells in vivo is moderate compared to somatic cells, and frequently characterized by escaping genes. X-inactivation is followed by step-wise X-reactivation, which is mostly completed during meiotic prophase I. Furthermore, we find that PGCLCs which fail to undergo X-inactivation or reactivate too rapidly display impaired meiotic potential. Thus, our data reveal fine-tuned X-chromosome remodelling as a critical feature of female germ cell development towards meiosis and oogenesis.
哺乳动物生殖细胞系在发育为有功能的卵子和精子的过程中，经历广泛的表观遗传重编程。具体来说，在建立亲代印记并将其传递给下一代之前，表观基因组需要重置。在雌性生殖细胞系中，X 染色体失活和重新激活是最显著的表观遗传重编程事件之一，但对其动力学和生物学功能知之甚少。在这里，我们使用一种从小鼠胚胎干细胞分化而来的特制的原始生殖细胞样细胞 (PGCLC) 体外分化系统来研究 X 失活和重新激活的动力学。我们发现，与体细胞相比，PGCLC 中的 X 失活和体内具有生殖细胞能力的上皮胚层细胞中的 X 失活是适度的，并且经常表现为逃避基因。X 失活后，X 会逐步重新激活，这主要发生在减数分裂前期 I 期间。此外，我们发现未能经历 X 失活或过快重新激活的 PGCLC 会显示出减数分裂能力受损。因此，我们的数据揭示了精细调控的 X 染色体重塑是雌性生殖细胞向减数分裂和卵母细胞发生发育的关键特征。
