Cellular dynamics associated with the genome-wide epigenetic reprogramming in migrating primordial germ cells in mice

TLDR

During mouse primordial germ cell migration, genome‑wide DNA methylation and H3K9me2 are erased while H3K27me3 is gained, a process thought to reset totipotency. This study examined the cellular dynamics accompanying that epigenetic reprogramming. PGCs erase H3K9me2 and acquire H3K27me3 progressively in a cell‑by‑cell manner, with G2 arrest and transcriptional repression occurring before demethylation, independent of Nanos3, and preceded by repression of the histone methyltransferase GLP, suggesting that active enzyme repression drives successful reprogramming.

Abstract

We previously reported that primordial germ cells (PGCs) in mice erase genome-wide DNA methylation and histone H3 lysine9 dimethylation (H3K9me2),and instead acquire high levels of tri-methylation of H3K27 (H3K27me3) during their migration, a process that might be crucial for the re-establishment of potential totipotency in the germline. We here explored a cellular dynamics associated with this epigenetic reprogramming. We found that PGCs undergo erasure of H3K9me2 and upregulation of H3K27me3 in a progressive, cell-by-cell manner, presumably depending on their developmental maturation. Before or concomitant with the onset of H3K9 demethylation, PGCs entered the G2 arrest of the cell cycle, which apparently persisted until they acquired high H3K27me3 levels. Interestingly, PGCs exhibited repression of RNA polymerase II-dependent transcription, which began after the onset of H3K9me2 reduction in the G2 phase and tapered off after the acquisition of high-level H3K27me3. The epigenetic reprogramming and transcriptional quiescence were independent from the function of Nanos3. We found that before H3K9 demethylation, PGCs exclusively repress an essential histone methyltransferase, GLP, without specifically upregulating histone demethylases. We suggest the possibility that active repression of an essential enzyme and subsequent unique cellular dynamics ensures successful implementation of genome-wide epigenetic reprogramming in migrating PGCs.