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Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation
Abstract
DNA methylation is an epigenetic modification associated with transcriptional repression of promoters and is essential for mammalian development. Establishment of DNA methylation is mediated by the de novo DNA methyltransferases DNMT3A and DNMT3B, whereas DNMT1 ensures maintenance of methylation through replication. Absence of these enzymes is lethal, and somatic mutations in these genes have been associated with several human diseases. How genomic DNA methylation patterns are regulated remains poorly understood, as the mechanisms that guide recruitment and activity of DNMTs in vivo are largely unknown. To gain insights into this matter we determined genomic binding and site-specific activity of the mammalian de novo DNA methyltransferases DNMT3A and DNMT3B. We show that both enzymes localize to methylated, CpG-dense regions in mouse stem cells, yet are excluded from active promoters and enhancers. By specifically measuring sites of de novo methylation, we observe that enzymatic activity reflects binding. De novo methylation increases with CpG density, yet is excluded from nucleosomes. Notably, we observed selective binding of DNMT3B to the bodies of transcribed genes, which leads to their preferential methylation. This targeting to transcribed sequences requires SETD2-mediated methylation of lysine 36 on histone H3 and a functional PWWP domain of DNMT3B. Together these findings reveal how sequence and chromatin cues guide de novo methyltransferase activity to ensure methylome integrity.
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In the citing paper
“As DNMT3B regulates intragenic DNA methylation levels54, high levels of DNA methylation levels are consistent with high levels of DNMT3B binding on intragenic CGIs”
From Alternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes (2023) · cites this paper as [54]
In the citing paper
“Studies with mESC and a heterologous yeast system found that the establishment of intragenic 5mC is a controlled process carried out by de novo DNA methyltransferase DNMT3B and co-transcriptionally regulated histone modification H3K36me (32, 33).”
From Dynamic DNA methylation: In the right place at the right time (2018) · cites this paper as [32]
In the citing paper
“The interaction between DNMT3B and H3K36me leads to greater levels of intragenic 5mC for active genes in mESC (32).”
From Dynamic DNA methylation: In the right place at the right time (2018) · cites this paper as [32]
In the citing paper
“Functional analyses of 5mC have traditionally relied on pharmacological or genetic perturbations that affect 5mC levels genome-wide (30, 32).”
From Dynamic DNA methylation: In the right place at the right time (2018) · cites this paper as [32]
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Metadata
- Authors
- Baubec, T., Colombo, D. F., Wirbelauer, C., Schmidt, J., Burger, L., Krebs, A. R., Akalin, A., & Schübeler, D.
- Affiliations
- Friedrich Miescher Institute (CH)
- University of Basel (CH)
- Corresponding author
- Baubec, Tuncay
- Schübeler, Dirk
- Venue
- Nature
- Published
- 2015-01-21
- Volume
- 520
- Issue
- 7546
- Pages
- 243-247
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2092116145
- Cited by
- 705
- References
- 51
- Citations by year
- 2026: 48 · 2025: 43 · 2024: 48 · 2023: 60 · 2022: 69 · 2021: 53 · 2020: 70 · 2019: 70 · 2018: 66 · 2017: 75 · 2016: 59 · 2015: 42
- FWCI
- 34.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Keywords
- DNMT3A, DNMT3B, de novo methylation, gene body methylation, PWWP domain, H3K36me3, SETD2, histone H3 lysine 36 methylation, mouse embryonic stem cells, chromatin targeting, transcriptional repression, epigenetic regulation
- MeSH terms
- DNA Methyltransferase 3A, DNA Methyltransferase 3B, Animals, Cell Line, Chromatin, DNA (Cytosine-5-)-Methyltransferases, Enhancer Elements, Genetic, Histones, Lysine, Promoter Regions, Genetic, Protein Binding, Histone-Lysine N-Methyltransferase, Transcription, Genetic, Genome, Protein Structure, Tertiary, CpG Islands, DNA Methylation, Protein Transport, Genomics, Epigenesis, Genetic, Mice, Embryonic Stem Cells
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