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Genomic targets and selective inhibition of DNA methyltransferase isoforms

Sae-Lee, Chanachai, Barrow, Timothy, Colicino, Elena, Choi, Si Ho, Rabanal-Ruiz, Yoana, Green, Daniel, Korolchuk, Viktor I, Mathers, John C and Byun, Hyang-Min (2022) Genomic targets and selective inhibition of DNA methyltransferase isoforms. Clinical Epigenetics, 14. p. 103. ISSN 1868-7083

Item Type: Article


Background: DNA methylation in the human genome is established and maintained by DNA methyltransferases (DNMTs). DNMT isoforms show differential expression by cell lineage and during development, but much remains to be elucidated about their shared and unique genomic targets.

Results: We examined changes in the epigenome following overexpression of 13 DNMT isoforms in HEK293T cells. We observed increased methylation (Δβ > 0.2) at 43,405 CpG sites, with expression of DNMT3A2, DNMTΔ3B4 and DNMTΔ3B2 associated with the greatest impact. De novo methylation occurred primarily within open sea regions and at loci with intermediate methylation levels (β: 0.2-0.6). 53% of differentially methylated loci showed specificity towards a single DNMT subfamily, primarily DNMTΔ3B and DNMT3A and 39% towards a single isoform. These loci were significantly enriched for pathways related to neuronal development (DNMTΔ3B4), calcium homeostasis (DNMTΔ3B3) and ion transport (DNMT3L). Repetitive elements did not display differential sensitivity to overexpressed DNMTs, but hypermethylation of Alu elements was associated with their evolutionary age following overexpression of DNMT3A2, DNMT3B1, DNMT3B2 and DNMT3L. Differential methylation (Δβ > 0.1) was observed at 121 of the 353 loci associated with the Horvath 'epigenetic clock' model of ageing, with 51 showing isoform specificity, and was associated with reduction of epigenetic age by 5-15 years following overexpression of seven isoforms. Finally, we demonstrate the potential for dietary constituents to modify epigenetic marks through isoform-specific inhibition of methylation activity.

Conclusions: Our results provide insight into regions of the genome methylated uniquely by specific DNMT isoforms and demonstrate the potential for dietary intervention to modify the epigenome.

Clin Epigenetics - DNMT specificity.pdf
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Depositing User: Timothy Barrow


Item ID: 15078
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ISSN: 1868-7083
Official URL: https://clinicalepigeneticsjournal.biomedcentral.c...

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ORCID for Timothy Barrow: ORCID iD

Catalogue record

Date Deposited: 31 Aug 2022 16:28
Last Modified: 31 Aug 2022 16:30


Author: Timothy Barrow ORCID iD
Author: Chanachai Sae-Lee
Author: Elena Colicino
Author: Si Ho Choi
Author: Yoana Rabanal-Ruiz
Author: Daniel Green
Author: Viktor I Korolchuk
Author: John C Mathers
Author: Hyang-Min Byun

University Divisions

Faculty of Health Sciences and Wellbeing > School of Nursing and Health Sciences


Sciences > Biomedical Sciences
Sciences > Health Sciences

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