Trends in Genetics
ReviewDe novo DNA methylation: a germ cell perspective
Section snippets
Remodelling of DNA methylation marks in germ cells is essential
Epigenetic marks (Glossary) are covalent modifications of the DNA (DNA methylation) or post-translational modifications of the histone proteins (histone modifications) that make up the chromatin into which our DNA is packaged. These epigenetic marks participate in the regulation of gene expression and, broadly speaking, different sets of marks are present depending on whether a gene is active or inactive. DNA methylation of promoter regions of genes, for example, is generally associated with
Erasure of epigenetic marks in primordial germ cells
Soon after the onset of gastrulation in the mouse embryo, the precursors of germ cells, or primordial germ cells (PGCs), emerge from the epiblast (embryonic day E7.25) as a founder population of <50 cells. They proliferate, migrate to and colonise the genital ridge, from which the gonads develop (E10.5-E11.5). Because PGCs originate from embryonic cells that have started to adopt a somatic fate, extensive remodelling of histone modifications and DNA methylation marks towards the requirements of
Mechanisms of DNA methylation establishment: the DNA methylation machinery
De novo DNA methylation at imprinted gDMRs, and probably at methylated CGIs in general, results in the complete methylation of the hundreds of CpGs that comprise the imprinted gDMR or CGI 13, 18. The process is therefore comprehensive, specific, and of high fidelity, and this must be considered in any model that explains DNA methylation in germ cells. Over the years several proteins involved in DNA methylation of every, or a restricted number of, imprinted gDMRs have been identified,
Mechanisms of DNA methylation establishment: the target sequence
Following the discovery of the role of DNA methylation in genomic imprinting [4] it was soon suggested that DNA sequence could be an important component in defining which CGIs become methylated in germ cells. Methylated CGIs would possess particular sequence characteristics, absent from unmethylated CGIs, allowing the specific recruitment of the DNA methylation machinery (DNMTs and other trans-factors). For example, DNMT3A and DNMT3B have been reported to have preferential and distinct target
Mechanisms of DNA methylation establishment: a link with histone modifications
DNA methylation in vivo does not occur on ‘naked’ DNA but within a chromatin environment, and biochemical studies and genetic evidence have indicated that this has a major impact on the ability of de novo DNA methylation complexes to interact with their genomic targets.
Mechanisms of DNA methylation establishment: role of transcription
Recent genome-wide analysis and other observations have raised the possibility that location of CGIs with respect to transcription units is an important factor in determining methylation in germ cells, especially in the female germline. Indeed, most imprinted gDMRs that become methylated in oocytes are located intragenically, in many cases downstream of alternative promoters specifically active in oocytes 62, 69. Interestingly, this also applies to a class of imprinted genes termed imprinted
Concluding remarks
From the foregoing discussion it is clear that multiple factors probably combine to determine DNA methylation in male and female germ cells (Figure 2). For imprinted gDMRs and other CGIs that are methylated in oocytes, DNA sequence may not be a defining characteristic. Instead, genomic targets may be specified by patterns of histone modifications, which may be determined in part by transcriptional activity, and may require the dismantling of factors bound at CGIs that otherwise provide a
Acknowledgements
We would like to thank Drs Wendy Dean and Rebecca Oakey for insightful comments and discussions, and apologise to our colleagues whose work was not cited due to space limitations. This work was supported by the Biotechnology and Biological Research Council, the Medical Research Council and the Centre for Trophoblast Research.
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