Controlled X-chromosome dynamics defines meiotic potential of female mouse in vitro germ cells.

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.

The compleX balancing act of controlling X-chromosome dosage and how it impacts mammalian germline development.

In female mammals, the two X chromosomes are subject to epigenetic gene regulation in order to balance X-linked gene dosage with autosomes and in relation to males, which have one X and one Y chromosome. This is achieved by an intricate interplay of several processes; X-chromosome inactivation and reactivation elicit global epigenetic regulation of expression from one X chromosome in a stage-specific manner, whilst the process of X-chromosome upregulation responds to this by fine-tuning transcription levels of the second X. The germline is unique in its function of transmitting both the genetic and epigenetic information from one generation to the next, and remodelling of the X chromosome is one of the key steps in setting the stage for successful development. Here, we provide an overview of the complex dynamics of X-chromosome dosage control during embryonic and germ cell development, and aim to decipher its potential role for normal germline competency.