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Primordial germ cell DNA demethylation and development require DNA translesion synthesis

ABSTRACT: Mutations in DNA damage response (DDR) factors are associated with human infertility, which affects up to 15% of the population. It remains unclear if the role of DDR is solely in meiosis. One pathway implicated in human fertility is DNA translesion synthesis (TLS), which allows replication impediments to be bypassed. We find that TLS is essential for pre-meiotic germ cell development in the embryo. Loss of the central TLS component, REV1, significantly inhibits the induction of human PGC-like cells (hPGCLCs). This is recapitulated in mice, where deficiencies in TLS initiation (Rev1-/- or PcnaK164R/K164R) or extension (Rev7-/-) result in a >150-fold reduction in the number of primordial germ cells (PGCs) and complete sterility. In contrast, the absence of TLS does not impact the growth, function, or homeostasis of somatic tissues. Surprisingly, we find a complete failure in both DNA demethylation, a critical step in germline epigenetic reprogramming, and in activation of the germ cell transcriptional program. Our findings show that for normal fertility, DNA repair is required not only for meiotic recombination but for completion of DNA demethylation and the progression of PGC development.

ORGANISM(S): Mus musculus

PROVIDER: GSE253991 | GEO | 2024/04/15

REPOSITORIES: GEO

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Setdb1 is essential for meiotic sex chromosome inactivation in mice

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2018-11-01 | GSE107671 | GEO

HPV E6 Impairs Translesion Synthesis by Blocking POLη Induction

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2017-09-12 | GSE94136 | GEO

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2020-12-15 | PXD018217 | Pride

The NuA4 complex promotes Translesion Synthesis (TLS) - mediated DNA damage tolerance

2015-02-21 | E-GEOD-66176 | biostudies-arrayexpress

In vitro expansion of mouse primordial germ cell‐like cells recapitulates an epigenetic blank slate [ChIP-Seq]

Project description:The expansion of primordial germ cells (PGCs), the precursors for the oocytes and spermatozoa, is a key challenge in reproductive biology/medicine. Using a chemical screening exploiting PGC‐like cells (PGCLCs) induced from mouse embryonic stem cells (ESCs), we here identify key signaling pathways critical for PGCLC proliferation. We show that the combinatorial application of Forskolin and Rolipram, which stimulate cAMP signaling via different mechanisms, expands PGCLCs up to ~50‐fold in culture. The expanded PGCLCs maintain robust capacity for spermatogenesis, rescuing the fertility of infertile mice. Strikingly, during expansion, PGCLCs comprehensively erase their DNA methylome, including parental imprints, in a manner that precisely recapitulates genome‐wide DNA demethylation in gonadal germ cells, while essentially maintaining their identity as sexually uncommitted PGCs, apparently through appropriate histone modifications. By establishing a paradigm for PGCLC expansion, our system reconstitutes the epigenetic “blank slate” of the germ line, an immediate precursory state for sexually dimorphic differentiation.

2017-05-30 | GSE87645 | GEO

In vitro expansion of mouse primordial germ cell‐like cells recapitulates an epigenetic blank slate [RNA-Seq]

2017-05-30 | GSE87644 | GEO

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