Epigenetic reprogramming enables the transition from primordial germ cell to gonocyte

Abstract

Gametes are highly specialised cells that can give rise to the next generation through their ability to generate a totipotent zygote. In mouse, germ cells are first specified in the developing embryo as primordial germ cells (PGCs) starting around embryonic day (E) 6.251 (Fig. 1a). Following subsequent migration into the developing gonad, PGCs undergo a wave of extensive epigenetic reprogramming at E10.5/E11.52–11, including genome-wide loss of 5-methylcytosine (5mC)2–5,7–11 (Fig. 1a). The underlying molecular mechanisms of this process have remained enigmatic leading to our inability to recapitulate this step of germline development in vitro12–14. Using an integrative approach, we show that this complex reprogramming process involves the coordinated interplay between promoter sequence characteristics, DNA (de)methylation, Polycomb (PRC1) complex and both DNA demethylation-dependent and -independent functions of Tet1 to enable the activation of a critical set of germline reprogramming responsive (GRR) genes involved in gamete generation and meiosis. Our results also unexpectedly reveal a role for Tet1 in safeguarding but not driving DNA demethylation in gonadal PGCs. Collectively, our work uncovers a fundamental biological role for gonadal germline reprogramming and identifies the epigenetic principles of the PGC-to-gonocyte transition that will be instructive towards recapitulating complete gametogenesis in vitro.

The contribution of active and passive mechanisms of 5mC and 5hmC removal in human T lymphocytes is differentiation‐ and activation‐dependent

“…This is also in line with recent findings showing that the activity of TET proteins is important to safeguard promoters from de novo methylation in embryonic stem cells, thereby preserving appropriate lineage‐specific transcription upon differentiation . Similarly, TET1 was shown to prevent the spreading of DNA methylation at CpG islands , and also to be required in germ cells to provide efficient protection from aberrant DNA methylation, thereby stabilizing the acquired epigenetic landscape after reprogramming events .…”

Retinoic acid signaling in regulation of meiosis during embryonic development in mice

“…PRDM14 protein has been shown to interact with the protein SUZ12, which is a component of PRC2 (polycomb repressive complex 2), and add a repressive mark in the form of H3K27me3 . This period is also characterized by epigenetic reprogramming, which includes erasure of genomic imprinting by genome-wide demethylation (Hill et al, 2018). Although signaling to induce PGC specification is active in the posterior epiblast, the anterior visceral endoderm secretes anti-BMP signaling factors that inhibit PGC induction in the anterior epiblast and thus restrict PGC induction to posterior epiblast.…”

“…By migrating and colonizing the genital ridges, PGCs actively proliferate and increase in numbers. This period is also characterized by epigenetic reprogramming, which includes erasure of genomic imprinting by genome-wide demethylation (Hill et al, 2018).…”

Two are better than one: HPoxBS - hairpin oxidative bisulfite sequencing

“…At this time point, PGCs are known to undergo a rapid replication dependent demethylation, probably supported by Tet mediated oxidation (47). We performed HPoxBS on repeat regions and indeed find indications for the presence of 5hmC in PGCs albeit at low levels.…”