Trends in Genetics
Volume 28, Issue 1, January 2012, Pages 33-42
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Review
De novo DNA methylation: a germ cell perspective

https://doi.org/10.1016/j.tig.2011.09.004Get rights and content

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.

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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