Cited by 705Epigenetics and DNA MethylationGenomics and Chromatin DynamicsGenetic Syndromes and Imprinting

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Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation

Baubec, Tuncay, Colombo, Daniele F., Wirbelauer, Christiane, Schmidt, Juliane, Burger, Lukas, Krebs, Arnaud R., Akalin, Altuna, Schübeler, Dirk·2015·Nature

DOI 10.1038/nature14176

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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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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
ORCID: Baubec, Tuncay
Colombo, Daniele F.
Burger, Lukas
Krebs, Arnaud R.
Akalin, Altuna
Schübeler, Dirk
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2015-01-21
Volume: 520
Issue: 7546
Pages: 243-247
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature14176
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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Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation

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