Isoform‐specific localization of DNMT3A regulates DNA methylation fidelity at bivalent CpG islands

Abstract

DNA methylation is a prevalent epigenetic modification involved in transcriptional regulation and essential for mammalian development. While the genome‐wide distribution of this mark has been studied to great detail, the mechanisms responsible for its correct deposition, as well as the cause for its aberrant localization in cancers, have not been fully elucidated. Here, we have compared the activity of individual DNMT3A isoforms in mouse embryonic stem and neuronal progenitor cells and report that these isoforms differ in their genomic binding and DNA methylation activity at regulatory sites. We identify that the longer isoform DNMT3A1 preferentially localizes to the methylated shores of bivalent CpG island promoters in a tissue‐specific manner. The isoform‐specific targeting of DNMT3A1 coincides with elevated hydroxymethylcytosine (5‐hmC) deposition, suggesting an involvement of this isoform in mediating turnover of DNA methylation at these sites. Through genetic deletion and rescue experiments, we demonstrate that this isoform‐specific recruitment plays a role in de novo DNA methylation at CpG island shores, with potential implications on H3K27me3‐mediated regulation of developmental genes.

The contribution of active and passive mechanisms of 5mC and 5hmC removal in human T lymphocytes is differentiation‐ and activation‐dependent

“…The fact that DNA methylation has the tendency to accumulate to transcriptional inactive genes [2], and at enhancers that are not actively bound by transcription factors (a process that would be extremely deleterious for genes encoding for effector cytokines) was already proposed with the discovery that DNA-binding factors were necessary and sufficient to induce local demethylation, and that loss of transcription factor binding was conversely sufficient for DNA methylation [43,44]. This is also in line with recent findings showing that the activity of TET proteins is important to safeguard promoters from de novo methylation in embry-onic stem cells, thereby preserving appropriate lineage-specific transcription upon differentiation [45,46]. Similarly, TET1 was shown to prevent the spreading of DNA methylation at CpG islands [28], and also to be required in germ cells to provide efficient protection from aberrant DNA methylation, thereby stabilizing the acquired epigenetic landscape after reprogramming events [47].…”

Epigenetic silencing of LncRNA ANRIL enhances liver fibrosis and HSC activation through activating AMPK pathway

“…Epigenetic influences generally refer to aberrant DNA methylation and non‐coding RNA (ncRNA) modifications . With regard to the latter, de novo DNA methylation activity catalysed by DNA methyltransferase 3A (DNMT3A) is methylated by addition of transfer methyl groups to the C‐5 position in the cytosine ring . DNA methylation can establish a docking site for transcriptional repressors to permanent gene silencing .…”

Shoring up DNA methylation and H3K27me3 domain demarcation at developmental genes

“…Antagonism between DNA methylation and H3K27me3 suggests that a dynamic crosstalk between these epigenetic marks could facilitate correct gene expression programmes (Reddington et al , ). In an elegant and comprehensive study, Manzo et al examined the different roles of DNMT3 de novo methyltransferase isoforms in establishing DNA methylation patterns in an mESC model and derived neuronal cells (Manzo et al , ). Using ΩAGE sequencing data sets, they found that the short isoform DNMT3A2, lacking an N‐terminal extension, is mainly expressed during early development, whereas a longer DNMT3A1 isoform is ubiquitously expressed in the majority of samples.…”

“…CpG methylation restrains the PRC2‐catalysed H3K27me3 histone mark, as H3K27me3 and DNA methylation can exhibit mutual antagonism within CGIs of mammalian genomes. Based on Fig EV2 from Manzo et al ().…”

“… Mutual antagonism between DNA methylation and H3K27me3 histone methylation suggests a dynamic crosstalk between these epigenetic marks that could help ensure correct gene expression programmes. Work from Manzo et al () now shows that an isoform of de novo DNA methyltransferase DNMT 3A provides specificity in the system by depositing DNA methylation at adjacent “shores” of hypomethylated bivalent CpG islands (CGI) in mouse embryonic stem cells ( mESC s). DNMT 3A1‐directed methylation appears to be instructive in maintaining the H3K27me3 profile at the hypomethylated bivalent CGI promoters of developmentally important genes. …”