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Genomic Profiling of DNA Methyltransferases Reveals a Role for DNMT3B in Genic Methylation

Genomic Profiling of DNA Methyltransferases Reveals a Role for DNMT3B in Genic Methylation

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

Nature. 2015 Apr 9;520(7546):243-7.

PMID: 25607372

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42413447	DNMT3B Active from mouse			Price
IAR42416070	SETD2 active human			Price

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