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      TET2 and TET3 regulate GlcNAcylation and H3K4 methylation through OGT and SET1/COMPASS

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          Abstract

          TET proteins convert 5-methylcytosine to 5-hydroxymethylcytosine, an emerging dynamic epigenetic state of DNA that can influence transcription. Evidence has linked TET1 function to epigenetic repression complexes, yet mechanistic information, especially for the TET2 and TET3 proteins, remains limited. Here, we show a direct interaction of TET2 and TET3 with O-GlcNAc transferase (OGT). OGT does not appear to influence hmC activity, rather TET2 and TET3 promote OGT activity. TET2/3–OGT co-localize on chromatin at active promoters enriched for H3K4me3 and reduction of either TET2/3 or OGT activity results in a direct decrease in H3K4me3 and concomitant decreased transcription. Further, we show that Host Cell Factor 1 (HCF1), a component of the H3K4 methyltransferase SET1/COMPASS complex, is a specific GlcNAcylation target of TET2/3–OGT, and modification of HCF1 is important for the integrity of SET1/COMPASS. Additionally, we find both TET proteins and OGT activity promote binding of the SET1/COMPASS H3K4 methyltransferase, SETD1A, to chromatin. Finally, studies in Tet2 knockout mouse bone marrow tissue extend and support the data as decreases are observed of global GlcNAcylation and also of H3K4me3, notably at several key regulators of haematopoiesis. Together, our results unveil a step-wise model, involving TET–OGT interactions, promotion of GlcNAcylation, and influence on H3K4me3 via SET1/COMPASS, highlighting a novel means by which TETs may induce transcriptional activation.

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          Most cited references11

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          Molecular signals of epigenetic states.

          Epigenetic signals are responsible for the establishment, maintenance, and reversal of metastable transcriptional states that are fundamental for the cell's ability to "remember" past events, such as changes in the external environment or developmental cues. Complex epigenetic states are orchestrated by several converging and reinforcing signals, including transcription factors, noncoding RNAs, DNA methylation, and histone modifications. Although all of these pathways modulate transcription from chromatin in vivo, the mechanisms by which epigenetic information is transmitted through cell division remain unclear. Because epigenetic states are metastable and change in response to the appropriate signals, a deeper understanding of their molecular framework will allow us to tackle the dysregulation of epigenetics in disease.
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            Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells.

            5-hydroxymethylcytosine (5hmC) is a modified base present at low levels in diverse cell types in mammals. 5hmC is generated by the TET family of Fe(II) and 2-oxoglutarate-dependent enzymes through oxidation of 5-methylcytosine (5mC). 5hmC and TET proteins have been implicated in stem cell biology and cancer, but information on the genome-wide distribution of 5hmC is limited. Here we describe two novel and specific approaches to profile the genomic localization of 5hmC. The first approach, termed GLIB (glucosylation, periodate oxidation, biotinylation) uses a combination of enzymatic and chemical steps to isolate DNA fragments containing as few as a single 5hmC. The second approach involves conversion of 5hmC to cytosine 5-methylenesulphonate (CMS) by treatment of genomic DNA with sodium bisulphite, followed by immunoprecipitation of CMS-containing DNA with a specific antiserum to CMS. High-throughput sequencing of 5hmC-containing DNA from mouse embryonic stem (ES) cells showed strong enrichment within exons and near transcriptional start sites. 5hmC was especially enriched at the start sites of genes whose promoters bear dual histone 3 lysine 27 trimethylation (H3K27me3) and histone 3 lysine 4 trimethylation (H3K4me3) marks. Our results indicate that 5hmC has a probable role in transcriptional regulation, and suggest a model in which 5hmC contributes to the 'poised' chromatin signature found at developmentally-regulated genes in ES cells.
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              The language of histone crosstalk.

              It has been suggested that a specific pattern of histone posttranslational modifications and their crosstalk may constitute a code that determines transcriptional outcomes. However, recent studies indicate that histone modifications have context-dependent effects, making their interplay more like a language within the chromatin signaling pathway than a code. Copyright 2010 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                EMBO J
                EMBO J
                The EMBO Journal
                Nature Publishing Group
                0261-4189
                1460-2075
                06 March 2013
                25 January 2013
                25 January 2013
                : 32
                : 5
                : 645-655
                Affiliations
                [1 ]Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles , Brussels, Belgium
                [2 ]Promega Corporation , Madison, WI, USA
                [3 ]Department of Haematology, Cambridge Institute for Medical Research , Cambridge, UK
                [4 ]Department of Pathology, Gurdon Institute, University of Cambridge , Cambridge, UK
                [5 ]Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center , New York, USA
                [6 ]INSERM UMR 985, Institut Gustave Roussy, Université Paris XI , Villejuif, France
                [7 ]INSERM UMR 1009, Institut Gustave Roussy, Université Paris XI , Villejuif, France
                Author notes
                [a ]Promega Corporation , 2800 Woods Hollow Road, Madison, WI 53703, USA. Tel.:+1 608 274 4330; Fax:+1 608 277 2601; E-mail: danette.daniels@ 123456promega.com
                [b ]Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles , 808 Route de Lennik, Brussels 1070, Belgium. Tel.:+32 2 555 62 45; Fax:+32 2 555 62 57; E-mail: ffuks@ 123456ulb.ac.be
                [*]

                These authors contributed equally to this work

                Article
                emboj2012357
                10.1038/emboj.2012.357
                3590984
                23353889
                35614b85-f915-4fcc-a9f5-2ddfab2000f0
                Copyright © 2013, European Molecular Biology Organization

                This article is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Licence.

                History
                : 05 December 2012
                : 21 December 2012
                Categories
                Article

                Molecular biology
                chromatin,epigenetics,tet proteins
                Molecular biology
                chromatin, epigenetics, tet proteins

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