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      DNA Methylation Targeting: The DNMT/HMT Crosstalk Challenge

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          Abstract

          Chromatin can adopt a decondensed state linked to gene transcription (euchromatin) and a condensed state linked to transcriptional repression (heterochromatin). These states are controlled by epigenetic modulators that are active on either the DNA or the histones and are tightly associated to each other. Methylation of both DNA and histones is involved in either the activation or silencing of genes and their crosstalk. Since DNA/histone methylation patterns are altered in cancers, molecules that target these modifications are interesting therapeutic tools. We present herein a vast panel of DNA methyltransferase inhibitors classified according to their mechanism, as well as selected histone methyltransferase inhibitors sharing a common mode of action.

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          Editing DNA Methylation in the Mammalian Genome.

          X. Shawn Liu, Hao Wu, Xiong Ji … (2016)
          Mammalian DNA methylation is a critical epigenetic mechanism orchestrating gene expression networks in many biological processes. However, investigation of the functions of specific methylation events remains challenging. Here, we demonstrate that fusion of Tet1 or Dnmt3a with a catalytically inactive Cas9 (dCas9) enables targeted DNA methylation editing. Targeting of the dCas9-Tet1 or -Dnmt3a fusion protein to methylated or unmethylated promoter sequences caused activation or silencing, respectively, of an endogenous reporter. Targeted demethylation of the BDNF promoter IV or the MyoD distal enhancer by dCas9-Tet1 induced BDNF expression in post-mitotic neurons or activated MyoD facilitating reprogramming of fibroblasts into myoblasts, respectively. Targeted de novo methylation of a CTCF loop anchor site by dCas9-Dnmt3a blocked CTCF binding and interfered with DNA looping, causing altered gene expression in the neighboring loop. Finally, we show that these tools can edit DNA methylation in mice, demonstrating their wide utility for functional studies of epigenetic regulation.
          Article 0 comments Cited 463 times – based on 0 reviews     Review now
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            Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation.

            Tuncay Baubec, Daniele Colombo, Christiane Wirbelauer … (2015)
            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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              Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor.

              Scott Daigle, Edward Olhava, Carly Therkelsen … (2011)
              Mislocated enzymatic activity of DOT1L has been proposed as a driver of leukemogenesis in mixed lineage leukemia (MLL). The characterization of EPZ004777, a potent, selective inhibitor of DOT1L is reported. Treatment of MLL cells with the compound selectively inhibits H3K79 methylation and blocks expression of leukemogenic genes. Exposure of leukemic cells to EPZ004777 results in selective killing of those cells bearing the MLL gene translocation, with little effect on non-MLL-translocated cells. Finally, in vivo administration of EPZ004777 leads to extension of survival in a mouse MLL xenograft model. These results provide compelling support for DOT1L inhibition as a basis for targeted therapeutics against MLL. Copyright © 2011 Elsevier Inc. All rights reserved.
              Article 0 comments Cited 299 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Gerda Egger: Role: Academic Editor
                Melanie R. Hassler: Role: Academic Editor
                Journal
                Journal ID (nlm-ta): Biomolecules
                Journal ID (iso-abbrev): Biomolecules
                Journal ID (publisher-id): biomolecules
                Title: Biomolecules
                Publisher: MDPI
                ISSN (Electronic): 2218-273X
                Publication date (Electronic): 05 January 2017
                Publication date Collection: March 2017
                Volume: 7
                Issue: 1
                Electronic Location Identifier: 3
                Affiliations
                [1 ]Univ. Lille, ICPAL, EA 7365—GRITA—Groupe de Recherche sur les formes Injectables et les Technologies Associées, 3 rue du Pr. Laguesse, F-59000 Lille, France; omar.castilloaguilera@ 123456univ-lille2.fr (O.C.-A.); patrick.depreux@ 123456univ-lille2.fr (P.D.)
                [2 ]FRE3600 Epigenetic Targeting of Cancer, CNRS, 31035 Toulouse, France; ludovic.halby@ 123456etac.cnrs.fr
                [3 ]Churchill College, Cambridge CB3 0DS, UK
                Author notes
                [* ]Correspondence: paola.arimondo@ 123456etac.cnrs.fr (P.B.A.); laurence.goossens@ 123456univ-lille2.fr (L.G.); Tel.: +33-5-61335919 (P.B.A.); +33-3-20-96-47-02 (L.G.)
                Article
                Publisher ID: biomolecules-07-00003
                DOI: 10.3390/biom7010003
                PMC ID: 5372715
                PubMed ID: 28067760
                SO-VID: c74cb0c3-7759-4191-b05b-219a77a7620c
                Copyright © © 2017 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 15 November 2016
                Date accepted : 12 December 2016
                Categories
                Subject: Review

                Keywords: dna methylation,histone methylation,dnmt/hmt crosstalk,dnmt inhibitors,hmt inhibitors
                Data availability:
                Keywords: dna methylation, histone methylation, dnmt/hmt crosstalk, dnmt inhibitors, hmt inhibitors

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