X Chromosome Reactivation Initiates in Nascent Primordial Germ Cells in Mice

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Abstract
During primordial germ cell (PGC) development, epigenetic reprogramming events represented by X chromosome reactivation and erasure of genomic imprinting are known to occur. Although precise timing is not given, X reactivation is thought to take place over a short period of time just before initiation of meiosis. Here, we show that the cessation of Xist expression commences in nascent PGCs, and re-expression of some X-linked genes begins in newly formed PGCs. The X reactivation process was not complete in E14.5 PGCs, indicating that X reactivation in developing PGCs occurs over a prolonged period. These results set the reactivation timing much earlier than previously thought and suggest that X reactivation may involve slow passive steps. X chromosome inactivation is a mechanism to compensate gene dosage difference between XY males and XX females in mammals. During early embryogenesis, one of two X chromosomes in every female cell is inactivated, and the inactive X chromosome is stably inherited through cell divisions of somatic cells. Although precise timing is not given, the inactive X chromosome is known to be reactivated during germ cell development. It is generally believed that the dynamics of X chromosome activity is tightly correlated with major genomic reprogramming events occurring during mammalian development. Therefore, elucidation of the X reactivation kinetics is important for understanding the mechanism of X chromosome inactivation/reactivation processes and the epigenetic reprogramming processes as well. Here we investigated when X reactivation is initiated during development of female mouse germ cells. Contrary to the previous suggestions, X reactivation already begins in nascent primordial germ cells in female mice and proceeds gradually requiring a prolonged period. The activity status of the X chromosomes of germ cells appears to vary from cell-to-cell and from gene-to-gene during the reactivation processes. These results indicate that the X reactivation coincides with the formation of germ cells and suggest that this involves slow passive steps.