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      Understanding the relationship between DNA methylation and histone lysine methylation

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          Abstract

          DNA methylation acts as an epigenetic modification in vertebrate DNA. Recently it has become clear that the DNA and histone lysine methylation systems are highly interrelated and rely mechanistically on each other for normal chromatin function in vivo. Here we examine some of the functional links between these systems, with a particular focus on several recent discoveries suggesting how lysine methylation may help to target DNA methylation during development, and vice versa. In addition, the emerging role of non-methylated DNA found in CpG islands in defining histone lysine methylation profiles at gene regulatory elements will be discussed in the context of gene regulation. This article is part of a Special Issue entitled: Methylation: A Multifaceted Modification — looking at transcription and beyond.

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          Highlights

          • There is an emerging realisation that DNA and histone lysine methylation in mammals are highly interrelated.

          • Targeting of DNA methylation is mechanistically linked to H3K9 methylation.

          • Uhrf1 acts as a link between H3K9 methylation and maintenance methylation during DNA replication.

          • Targeting of Dnmt3a/b is influenced by H3K4 and H3K36 methylation.

          • Non-methylated DNA at CpG islands influences histone methylation through ZF-CxxC proteins.

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          Most cited references171

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          Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1.

          DNA cytosine methylation is crucial for retrotransposon silencing and mammalian development. In a computational search for enzymes that could modify 5-methylcytosine (5mC), we identified TET proteins as mammalian homologs of the trypanosome proteins JBP1 and JBP2, which have been proposed to oxidize the 5-methyl group of thymine. We show here that TET1, a fusion partner of the MLL gene in acute myeloid leukemia, is a 2-oxoglutarate (2OG)- and Fe(II)-dependent enzyme that catalyzes conversion of 5mC to 5-hydroxymethylcytosine (hmC) in cultured cells and in vitro. hmC is present in the genome of mouse embryonic stem cells, and hmC levels decrease upon RNA interference-mediated depletion of TET1. Thus, TET proteins have potential roles in epigenetic regulation through modification of 5mC to hmC.
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            CpG islands and the regulation of transcription.

            Vertebrate CpG islands (CGIs) are short interspersed DNA sequences that deviate significantly from the average genomic pattern by being GC-rich, CpG-rich, and predominantly nonmethylated. Most, perhaps all, CGIs are sites of transcription initiation, including thousands that are remote from currently annotated promoters. Shared DNA sequence features adapt CGIs for promoter function by destabilizing nucleosomes and attracting proteins that create a transcriptionally permissive chromatin state. Silencing of CGI promoters is achieved through dense CpG methylation or polycomb recruitment, again using their distinctive DNA sequence composition. CGIs are therefore generically equipped to influence local chromatin structure and simplify regulation of gene activity.
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              Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine.

              5-methylcytosine (5mC) in DNA plays an important role in gene expression, genomic imprinting, and suppression of transposable elements. 5mC can be converted to 5-hydroxymethylcytosine (5hmC) by the Tet (ten eleven translocation) proteins. Here, we show that, in addition to 5hmC, the Tet proteins can generate 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) from 5mC in an enzymatic activity-dependent manner. Furthermore, we reveal the presence of 5fC and 5caC in genomic DNA of mouse embryonic stem cells and mouse organs. The genomic content of 5hmC, 5fC, and 5caC can be increased or reduced through overexpression or depletion of Tet proteins. Thus, we identify two previously unknown cytosine derivatives in genomic DNA as the products of Tet proteins. Our study raises the possibility that DNA demethylation may occur through Tet-catalyzed oxidation followed by decarboxylation.
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                Author and article information

                Contributors
                Journal
                Biochim Biophys Acta
                Biochim. Biophys. Acta
                Biochimica et Biophysica Acta
                Elsevier Pub. Co
                0006-3002
                1 December 2014
                December 2014
                : 1839
                : 12
                : 1362-1372
                Affiliations
                Department of Biochemistry, South Parks Road, University of Oxford, Oxford OX1 3QU, UK
                Author notes
                [* ]Corresponding author. Tel.: + 44 1865 613230. rob.klose@ 123456bioch.ox.ac.uk
                [1]

                Tel.: + 44 1865 613230.

                Article
                S1874-9399(14)00028-5
                10.1016/j.bbagrm.2014.02.007
                4316174
                24560929
                6a054dd9-39e7-412f-bfe8-fea99b9060fe
                © 2014 The Authors. Published by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

                History
                : 18 October 2013
                : 11 February 2014
                Categories
                Review

                Biochemistry
                dna methylation,histone lysine methylation,epigenetics,cpg island,embryonic development

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