The Dynamics of Genome-wide DNA Methylation Reprogramming in Mouse Primordial Germ Cells

TLDR

Genome‑wide DNA methylation reprogramming occurs in mouse primordial germ cells (PGCs) and preimplantation embryos, but the precise dynamics and biological outcomes remain largely unknown. We performed whole‑genome bisulfite sequencing and RNA‑seq across key stages from E6.5 epiblast to E16.5 PGCs. We observed global passive demethylation during PGC expansion and migration, while imprints, CpG islands on the X chromosome, and germline‑specific genes remain methylated until gonadal entry; despite widespread hypomethylation, PGCs maintain a tightly regulated transcriptional program with transient pluripotency network expression, linking reprogramming to pluripotency and providing a framework for the epigenetic ground state of germline pluripotency.

Abstract

Genome-wide DNA methylation reprogramming occurs in mouse primordial germ cells (PGCs) and preimplantation embryos, but the precise dynamics and biological outcomes are largely unknown. We have carried out whole-genome bisulfite sequencing (BS-Seq) and RNA-Seq across key stages from E6.5 epiblast to E16.5 PGCs. Global loss of methylation takes place during PGC expansion and migration with evidence for passive demethylation, but sequences that carry long-term epigenetic memory (imprints, CpG islands on the X chromosome, germline-specific genes) only become demethylated upon entry of PGCs into the gonads. The transcriptional profile of PGCs is tightly controlled despite global hypomethylation, with transient expression of the pluripotency network, suggesting that reprogramming and pluripotency are inextricably linked. Our results provide a framework for the understanding of the epigenetic ground state of pluripotency in the germline.