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

Item Type:Article
Title:Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation
Creators Name:Baubec, T. and Colombo, D.F. and Wirbelauer, C. and Schmidt, J. and Burger, L. and Krebs, A.R. and Akalin, A. and Schübeler, D.
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.
Keywords:Cell Line, Chromatin, CpG Islands, DNA (Cytosine-5-)-Methyltransferase, DNA Methylation, Embryonic Stem Cells, Genetic Enhancer Elements, Genetic Epigenesis, Genetic Promoter Regions, Genetic Transcription, Genome, Genomics, Histone-Lysine N-Methyltransferase, Histones, Lysine, Protein Binding, Protein Transport, Tertiary Protein Structure, Animals, Mice
Source:Nature
ISSN:0028-0836
Publisher:Nature Publishing Group (U.K.)
Volume:520
Number:7546
Page Range:243-247
Date:9 April 2015
Official Publication:https://doi.org/10.1038/nature14176
PubMed:View item in PubMed

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