Pluto Bioinformatics

GSE141877: Maternal DNMT3A-dependent de novo methylation of the zygotic paternal genome inhibits gene expression in the early embryo

Bulk RNA sequencing

De novo DNA methylation (DNAme) during mammalian spermatogenesis yields a densely methylated genome, with the exception of CpG islands (CGIs), which are hypomethylated in sperm. Following fertilization, the paternal genome undergoes widespread DNAme loss before the first S-phase. Paradoxically, recent mass spectrometry analysis revealed that a low level of de novo DNAme occurs exclusively on the zygotic paternal genome. However, the genomic loci involved and impact on genic transcription was not addressed. Here, we employ allele-specific analysis of whole-genome bisulphite sequencing (WGBS) data and show that a number of genomic loci, including several dozen CGI promoters, are de novo methylated on the paternal genome in 2-cell embryos. A subset of these promoters maintain DNAme through development to the blastocyst stage. Consistent with zygotic paternal DNAme acquisition (PDA), many of these loci are hypermethylated in androgenetic blastocysts but hypomethylated in parthenogenetic blastocysts. Strikingly, PDA is lost following maternal deletion of Dnmt3a. Furthermore, a subset of promoters showing PDA which are normally transcribed from the paternal allele in ICM cells show premature transcription at the 4C stage in maternal Dnmt3a knockout embryos. Taken together, these observations uncover an unexpected role for maternal DNMT3A activity in post-fertilization epigenetic reprogramming and transcriptional silencing of the paternal genome. SOURCE: Matthew LorinczLorincz University of British Columbia

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