DNA methylation is a fundamentally important epigenetic modification of the mammalian genome that has widespread influences on gene expression. During germ-cell specification and maturation, epigenetic reprogramming occurs and the DNA methylation landscape is profoundly remodelled. Defects in this process have major consequences for embryonic development and are associated with several genetic disorders. In this review we report our current understanding of the molecular mechanisms associated with de novo DNA methylation in germ cells. We discuss recent discoveries connecting histone modifications, transcription and the DNA methylation machinery, and consider how these new findings could lead to a model for methylation establishment. Elucidating how DNA methylation marks are established in the germline has been a challenge for nearly 20 years, but represents a key step towards a full understanding of several biological processes including genomic imprinting, epigenetic reprogramming and the establishment of the pluripotent state in early embryos.
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