Extensive and orderly reprogramming of genome-wide chromatin modifications associated with specification and early development of germ cells in mice.

Induction of mouse germ cells occurs from the proximal epiblast at around embryonic day (E) 7.0. These germ cells then migrate to, and enter the gonads at about E10.5 after which they undergo epigenetic reprogramming including erasure of parental imprints. However, the epigenetic properties acquired by nascent germ cells and the potential remodeling of these epigenetic marks in the subsequent migratory period have been largely unexplored. Here we have used immunohistochemistry to examine several genome-wide epigenetic modifications occurring in germ cells from their specification to their colonization of the genital ridges. We show that at around E8.0, germ cells concomitantly and significantly reduce H3-K9 dimethylation and DNA methylation, two major repressive modifications for gene expression. These events are preceded by the transient loss of all the DNA methyltransferases from their nuclei. By contrast, germ cells substantially increase the levels of H3-K27 trimethylation, another repressive modification with more plasticity, at E8.5-9.0 and maintain this state until at least E12.5. H3-K4 methylation and H3-K9 acetylation, modifications associated with transcriptionally permissive/active chromatin, are similar in germ and surrounding somatic cells but germ cells transiently increase these marks sharply upon their entry into the genital ridge. H3-K9 trimethylation, a hallmark of centromeric heterochromatin, is kept relatively constant during the periods examined. We suggest that this orderly and extensive epigenetic reprogramming in premigratory and migratory germ cells might be necessary for their reacquisition of underlying totipotency, for subsequent specific epigenetic remodeling, including the resetting of parental imprints, and for the production of gametes with an appropriate epigenotype for supporting normal development.