Staying true to yourself: mechanisms of DNA methylation maintenance in mammals - PubMed (original) (raw)

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Staying true to yourself: mechanisms of DNA methylation maintenance in mammals

Nataliya Petryk et al. Nucleic Acids Res. 2021.

Abstract

DNA methylation is essential to development and cellular physiology in mammals. Faulty DNA methylation is frequently observed in human diseases like cancer and neurological disorders. Molecularly, this epigenetic mark is linked to other chromatin modifications and it regulates key genomic processes, including transcription and splicing. Each round of DNA replication generates two hemi-methylated copies of the genome. These must be converted back to symmetrically methylated DNA before the next S-phase, or the mark will fade away; therefore the maintenance of DNA methylation is essential. Mechanistically, the maintenance of this epigenetic modification takes place during and after DNA replication, and occurs within the very dynamic context of chromatin re-assembly. Here, we review recent discoveries and unresolved questions regarding the mechanisms, dynamics and fidelity of DNA methylation maintenance in mammals. We also discuss how it could be regulated in normal development and misregulated in disease.

© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.

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Figures

Figure 1.

Figure 1.

The landscape and machinery of chromatin replication. (A) Replication timing along a segment of mammalian chromosome. Horizontal axis: genomic distance along the segment. Vertical axis: time at which the region is replicated during S-phase. The functionally different elements of the genome are replicated at distinct times, for instance enhancers replicate early and heterochromatin replicates late. We also indicate the typical CpG-richness of these elements (triangle at the right), and whether these CpGs are mostly unmethylated (in blue) or methylated (in red). (B) DNA methylation maintenance in the context of DNA replication and chromatin assembly. This scheme is simplified and only presents the actors mentioned in the text. Parental DNA strands are in grey, leading DNA strand in magenta, lagging DNA strand in blue. CpG dinucleotides are represented by lollipops, which are filled in white when unmethylated, and in red when methylated. The nucleosomes are shown as balls, with ‘old’ H3–H4 in orange, and new H3–H4 in white. Some of the old H3 contain H3K9me3 modifications (red flags), whereas the newly synthesized H3 do not. The DNA replication machinery generates hemimethylated CpGs.

Figure 2.

Figure 2.

DNMT1 and UHRF1, key actors of DNA methylation maintenance. (A) Domain architecture and interactors of DNMT1 (top) and UHRF1 (bottom). Bidirectional black arrows indicate interactions. Green arrows show enzymatic modification. Lilac arrows denote inhibitory interactions. (B) Several pathways have been shown to permit DNMT1 recruitment. Additional pathways may remain to be discovered. It is not yet clear which modes of recruitment predominate in different situations.

Figure 3.

Figure 3.

Different kinetic phases of DNA methylation maintenance. The kinetics of DNA methylation maintenance combine a replication-coupled component, operating within minutes of DNA replication (left-hand panel), and a post-replication component, operating over hours (right-hand panel). The actors identified to take part in each phase are indicated at the bottom. Full red lollipops indicate the methylated 5mC and empty lollipops indicate the unmethylated (unrestored) 5mC.

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