PGC7/Stella protects against DNA demethylation in early embryogenesis

Abstract

DNA methylation is an important means of epigenetic gene regulation and must be carefully controlled as a prerequisite for normal early embryogenesis. Although global demethylation occurs soon after fertilization, it is not evenly distributed throughout the genome. Genomic imprinting and epigenetic asymmetry between parental genomes, that is, delayed demethylation of the maternal genome after fertilization, are clear examples of the functional importance of DNA methylation. Here, we show that PGC7/Stella, a maternal factor essential for early development, protects the DNA methylation state of several imprinted loci and epigenetic asymmetry. After determining that PGC7/Stella binds to Ran binding protein 5 (RanBP5; a nuclear transport shuttle protein), mutant versions of the two proteins were used to examine exactly when and where PGC7/Stella functions within the cell. It is likely that PGC7/Stella protects the maternal genome from demethylation only after localizing to the nucleus, where it maintains the methylation of several imprinted genes. These results demonstrate that PGC7/Stella is indispensable for the maintenance of methylation involved in epigenetic reprogramming after fertilization.

Placental 5-methylcytosine and 5-hydroxymethylcytosine patterns associate with size at birth

“…30,42,43 We identified significant enrichment of 5hmC at DMR2 and, although 5hmC is also known to be present at some imprinted DMRs, including across IGF2-H19, its precise role at these loci is unclear. 30 However, studies that show that H19 remains highly enriched for 5hmC in cell culture despite the global loss of 5hmC elsewhere, 43 and that such loci are also protected from demethylation in the post-fertilization embryo, 44 suggest that 5hmC dynamics at imprinted loci may differ from those in the remainder of the genome. Additionally, since 5hmC may be an intermediate in the DNA demethylation pathway, 5hmC at DMRs could result from the conversion of 5mC during the demethylation process.…”

Genomic imprinting and its relevance to congenital disease, infertility, molar pregnancy and induced pluripotent stem cell

“…Dppa3 (also known as Pgc7 or Stella) is one protein that protects the maternal imprints from demethylation ( Figure 1). 38 It likely acts through protection against hydroxylation of 5-methylcytosine by the Tet3 protein. 39 5-hydroxymethylcytosine is not recognized by Dnmt1 and thus, without this protection, maternal imprints can be subject to replication-dependent passive demethylation.…”

Imprinted gene expression in hybrids: perturbed mechanisms and evolutionary implications

“…Concordantly, genetic mutations at ZFP57 in humans are causally involved in imprinting disorders and are linked to reduced DNA methylation at specific ICRs (Mackay et al, 2008). Other maternal factors, including DPPA3 (also called PGC7, Stella), also contribute to the methylation maintenance at ICRs in the zygote and early embryo, on both the maternally and paternally inherited copies of the genome (Nakamura et al, 2007). In interspecies hybrids, incompatibilities between maternal factors and target sequences on the paternal genome might affect genomic imprinting during the early stages of development.…”