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

Abstract

SummaryGenome-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.

An ultra-low-input native ChIP-seq protocol for genome-wide profiling of rare cell populations

“…Intriguingly, while male and female E13.5 PGCs have distinct differentiation programs and transcription patterns 12,20,21 , our results indicate that their H3K27me3 distribution profiles are broadly similar ( Supplementary Fig. 6 and ref.…”

Effect of high fat diet on paternal sperm histone distribution and male offspring liver gene expression

“…16 Whether transcription activity can influence the process of H3 retention at a given gene, and whether the diet can modulate the transcription state in germ cells is not known. However, out of 75 genes developmentally activated in male gametocytes and functionally important for germ cell development, 55 we found differential H3K4me1-enrichment in HFD vs. LFD samples in the following genes: ATP dependent DNA helicase homolog (Hfm1), Left-right determination factor 2 (Lefty2), Mut S homolog 5 (Msh5), and SRY-box 2 (Sox2). We identified differential H3 retention in Foxl2, Follistatin (Fst), Gap junction protein b-3 (Gjb3) and Sidekick homolog 1 (Sdk1).…”

When is incomplete epigenetic resetting in germ cells favoured by natural selection?

“…Such effects are increasingly observed in animals and, in particular, plants (reviews in [4,5,17,19,42]), where studies of experimental lines suggest that induced patterns of DNA methylation are readily inherited [11]. Similarly, in mammals, DNA sequences can resist reprogramming [43,44], and the extent of demethylation is regulated by the methylation machinery [45,46]. Thus, although we often expect transgenerational epigenetic inheritance to be maladaptive (or fitness neutral), the extent of resetting could evolve in response to selection.…”