Epigenetic Mechanisms Governing Female and Male Germline Development in Mammals.

Abstract

Background: DNA methylation (DNAme) and histone posttranslational modifications (PTMs) play an integral role in the transcriptional regulation of specific sets of genes and retrotransposons. In turn, these chromatin marks are essential for cellular reprogramming, including during germline development. While DNAme is stably propagated in most somatic tissues, this epigenetic mark undergoes cycles of widespread erasure and re-establishment in the early embryo as well as in the germline.

Summary: De novo DNAme occurs at distinct developmental stages in male and female germ cells; before birth in prospermatogonia (PSG) and after birth in growing oocytes. Furthermore, while only ∼40% of the mouse genome is methylated in mature oocytes, ∼80% of the genome is methylated in mature sperm. Here, we review recent epigenome studies which reveal a complex interplay between histone PTMs and de novo DNAme in shaping the sexually dimorphic profiles of DNAme observed in mature gametes in the mouse, including in intergenic regions as well as at imprinted gametic differentially methylated regions (gDMRs). We discuss the dynamics and distribution of key histone PTMs in male and female germ cells, including H3K36me2/me3, H3K4me3, and H3K27me3, and the implications of positive and negative crosstalk between these PTMs and the DNAme machinery. Finally, we reflect on how the sex-specific epigenetic landscapes observed in the mouse germline impact transcriptional regulation in both the gametes and the early embryo.

Key messages: Investigation of the roles of chromatin modifying enzymes and the interplay between the chromatin marks that they deposit in germ cells has been facilitated by analyses of conventional or germline-specific knockout mice, combined with low-input genome-wide profiling methods that have been developed in recent years. While clearly informative, these findings generally reflect "snapshots" of chromatin states derived from analyses of cells analyzed in bulk at a specific period in development. Technological advances and novel experimental models will be required to further refine our understanding of the underlying mechanism and order of establishment of chromatin marks and the impact of sexually dimorphic epigenetic patterning on transcription and other nuclear processes in germ cells, the early embryo and beyond.