Abstract
DNA methylation is dynamically remodelled during the mammalian life cycle through distinct phases of reprogramming and de novo methylation. These events enable the acquisition of cellular potential followed by the maintenance of lineage-restricted cell identity, respectively, a process that defines the life cycle through successive generations. DNA methylation contributes to the epigenetic regulation of many key developmental processes including genomic imprinting, X-inactivation, genome stability and gene regulation. Emerging sequencing technologies have led to recent insights into the dynamic distribution of DNA methylation during development and the role of this epigenetic mark within distinct genomic contexts, such as at promoters, exons or imprinted control regions. Additionally, there is a better understanding of the mechanistic basis of DNA demethylation during epigenetic reprogramming in primordial germ cells and during pre-implantation development. Here, we discuss our current understanding of the developmental roles and dynamics of this key epigenetic system.
Highlights
The mammalian life cycle is characterized by extended phases of cellular differentiation, followed by distinct periods of reprogramming in germ cells and the zygote, which resets genomic potential to restart the cycle
At two unique junctures of mammalian development—in primordial germ cells (PGCs) and pre-implantation embryos—the epigenome is comprehensively reprogrammed towards a basal state to enable relaxation of the epigenetic constraints imposed on cell potential and resetting of the life cycle [2]
It has been noted that genes involved in post-transcriptional genome-defence against transposable elements (TEs) in the germline, such as Tex19.1 [98], are preferentially regulated by promoter CpG methylation [89]. Because these genes are activated by erasure of promoter 5mC during epigenetic reprogramming in PGCs, they become expressed at precisely the time when TEs might become transcriptionally active, owing to loss of global 5mC
Summary
The mammalian life cycle is characterized by extended phases of cellular differentiation, followed by distinct periods of reprogramming in germ cells and the zygote, which resets genomic potential to restart the cycle. Multiple epigenetic systems including DNA methylation, histone modifications and small RNAs function both cooperatively and autonomously to establish the epigenome that propagates gene expression profiles through mitosis/meiosis. Disruption of these epigenetic mechanisms can lead to loss of cell identity, cellular transformation or disease, and is generally incompatible with normal development. Of particular recent interest are the mechanisms which erase and establish DNA methylation during development and the roles of these epigenetic events. Recent studies have begun to unravel many aspects of DNA methylation biology including its dynamic distribution through development, the mechanisms of demethylation, and the role of CpG methylation in regulating gene transcription in distinct genomic contexts. A deeper understanding of this key epigenetic system and the mechanisms which establish and erase it may provide opportunities to manipulate cell identity for therapeutic purposes
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