DNA Methylation: Roles in Mammalian Development

Key Points DNA methylation is essential for mammalian development and has notable roles in gene silencing, protection against spurious repetitive element activity, genomic stability during mitosis and parent-of-origin imprinting. DNA methylation functions to coordinately silence some promoter and enhancer classes that are typified by low overall CpG density. By contrast, many CpG islands, particularly those at promoters, remain generally and constitutively protected from DNA methylation through numerous opposing cis - and trans -based mechanisms. Embryonic stem cells (ESCs) remain one of the most highly studied in vitro models for dissecting epigenetic mechanisms during cellular differentiation. They are unique in their ability to retain the molecular characteristics of their cellular state in the absence of DNA methylation but cannot differentiate into embryonic lineages while simultaneously gaining extra-embryonic potential. ESCs are also unique in their heterogeneous ability to maintain repetitive element silencing through DNA methyltransferase 1 (DNMT1) maintenance activity alone and rely on the DNMT3 enzymes to re-silence these elements continuously de novo . The pre-implantation stage of development is one of the few stages at which endogeneous transposable elements are actively regulated. Promoters of germline-specific genes are coordinately repressed by DNMT3B in embryonic lineages and are reactivated during the global demethylation that accompanies primordial germ cell (PGC) specification. Haematopoiesis has served as a benchmark model for the function of DNA methylation in adult stem cells and in later lineage specification. Several notable regulatory principles for DNA methylation were originally or comprehensively described in this system, including the gating of lymphoid versus myeloid fates, the dynamics of intragenic CpG island methylation in transcript selection and demethylation as a lineage stabilizer by providing a mitotically heritable memory of transcription factor binding. DNA methylation is globally erased during specification of the germ line and during fertilization, at which point the paternal genome is specifically demethylated. These two key events have numerous related cascades of chromatin re-organization that suggest similar epigenetic mechanisms for erasure and re-establishment of global nuclear organization, although the relationship between these events remains incompletely defined. Although they have remained mysterious for more than 2 decades, the targets and mechanisms for DNA methylation erasure in the paternal genome as well as for protection of the maternal genome during fertilization are becoming clearer. For example, there are distinct temporal windows for global hydroxymethylation followed by erasure to unmodified cytosines occurring later in zygotic progression. The epigenetic determinants that retain silencing at repetitive element classes and imprints are less clear, but they are likely to be discovered as the dynamics and relationships of other epigenetic regulators are refined.