Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation
| Autor: | Arnaud R Krebs, Dirk Schübeler, Tuncay Baubec, Daniele F Colombo, Juliane Schmidt, Altuna Akalin, Lukas Burger, Christiane Wirbelauer |
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| Rok vydání: | 2014 |
| Předmět: |
Transcription
Genetic Biology Cell Line DNA Methyltransferase 3A Epigenesis Genetic Histones Mice Epigenetics of physical exercise Histone methylation Animals Epigenetics DNA (Cytosine-5-)-Methyltransferases Promoter Regions Genetic RNA-Directed DNA Methylation Embryonic Stem Cells Epigenomics Genetics Multidisciplinary Genome Lysine Methylation Genomics Histone-Lysine N-Methyltransferase DNA Methylation Chromatin Protein Structure Tertiary Protein Transport Enhancer Elements Genetic Histone methyltransferase embryonic structures DNA methylation CpG Islands Protein Binding |
| Zdroj: | Nature. 520(7546) |
| ISSN: | 1476-4687 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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