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  • 1
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    Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1 (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-04-18
    Description: 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715015/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715015/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tahiliani, Mamta -- Koh, Kian Peng -- Shen, Yinghua -- Pastor, William A -- Bandukwala, Hozefa -- Brudno, Yevgeny -- Agarwal, Suneet -- Iyer, Lakshminarayan M -- Liu, David R -- Aravind, L -- Rao, Anjana -- AI44432/AI/NIAID NIH HHS/ -- K08 HL089150/HL/NHLBI NIH HHS/ -- R01 GM065865/GM/NIGMS NIH HHS/ -- R01 GM065865-05A1/GM/NIGMS NIH HHS/ -- R01GM065865/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2009 May 15;324(5929):930-5. doi: 10.1126/science.1170116. Epub 2009 Apr 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Harvard Medical School and Immune Disease Institute, 200 Longwood Avenue, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19372391" target="_blank"〉PubMed〈/a〉
    Keywords: 5-Methylcytosine/*metabolism ; Amino Acid Sequence ; Animals ; Cell Line ; Cytosine/*analogs & derivatives/analysis/metabolism ; DNA/chemistry/*metabolism ; DNA Methylation ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Dinucleoside Phosphates/metabolism ; Embryonic Stem Cells/chemistry/metabolism ; Humans ; Hydroxylation ; Mass Spectrometry ; Mice ; Molecular Sequence Data ; Proto-Oncogene Proteins/chemistry/genetics/*metabolism ; RNA Interference ; Sequence Alignment ; Transfection
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 2
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    Modulation of TET2 expression and 5-methylcytosine oxidation by the CXXC domain protein IDAX (2013)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2013-04-09
    Description: TET (ten-eleven-translocation) proteins are Fe(ii)- and alpha-ketoglutarate-dependent dioxygenases that modify the methylation status of DNA by successively oxidizing 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxycytosine, potential intermediates in the active erasure of DNA-methylation marks. Here we show that IDAX (also known as CXXC4), a reported inhibitor of Wnt signalling that has been implicated in malignant renal cell carcinoma and colonic villous adenoma, regulates TET2 protein expression. IDAX was originally encoded within an ancestral TET2 gene that underwent a chromosomal gene inversion during evolution, thus separating the TET2 CXXC domain from the catalytic domain. The IDAX CXXC domain binds DNA sequences containing unmethylated CpG dinucleotides, localizes to promoters and CpG islands in genomic DNA and interacts directly with the catalytic domain of TET2. Unexpectedly, IDAX expression results in caspase activation and TET2 protein downregulation, in a manner that depends on DNA binding through the IDAX CXXC domain, suggesting that IDAX recruits TET2 to DNA before degradation. IDAX depletion prevents TET2 downregulation in differentiating mouse embryonic stem cells, and short hairpin RNA against IDAX increases TET2 protein expression in the human monocytic cell line U937. Notably, we find that the expression and activity of TET3 is also regulated through its CXXC domain. Taken together, these results establish the separate and linked CXXC domains of TET2 and TET3, respectively, as previously unknown regulators of caspase activation and TET enzymatic activity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3643997/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3643997/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ko, Myunggon -- An, Jungeun -- Bandukwala, Hozefa S -- Chavez, Lukas -- Aijo, Tarmo -- Pastor, William A -- Segal, Matthew F -- Li, Huiming -- Koh, Kian Peng -- Lahdesmaki, Harri -- Hogan, Patrick G -- Aravind, L -- Rao, Anjana -- CA151535/CA/NCI NIH HHS/ -- R01 AI040127/AI/NIAID NIH HHS/ -- R01 AI044432/AI/NIAID NIH HHS/ -- R01 AI40127/AI/NIAID NIH HHS/ -- R01 CA151535/CA/NCI NIH HHS/ -- R01 HD065812/HD/NICHD NIH HHS/ -- England -- Nature. 2013 May 2;497(7447):122-6. doi: 10.1038/nature12052. Epub 2013 Apr 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Signaling and Gene Expression, La Jolla Institute for Allergy & Immunology, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23563267" target="_blank"〉PubMed〈/a〉
    Keywords: 5-Methylcytosine/*metabolism ; Animals ; Base Sequence ; Caspases/metabolism ; Catalytic Domain ; CpG Islands/genetics ; DNA Methylation/genetics ; DNA-Binding Proteins/biosynthesis/*chemistry/deficiency/genetics/*metabolism ; Dioxygenases/chemistry/genetics/metabolism ; Down-Regulation ; Embryonic Stem Cells/metabolism ; Enzyme Activation ; HEK293 Cells ; Humans ; Mice ; Oxidation-Reduction ; Promoter Regions, Genetic/genetics ; Protein Interaction Domains and Motifs ; Protein Structure, Tertiary ; Proto-Oncogene Proteins/biosynthesis/chemistry/genetics/*metabolism ; Transcription Factors/*chemistry/deficiency/genetics/*metabolism ; U937 Cells
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2 (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-11-09
    Description: TET2 is a close relative of TET1, an enzyme that converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA. The gene encoding TET2 resides at chromosome 4q24, in a region showing recurrent microdeletions and copy-neutral loss of heterozygosity (CN-LOH) in patients with diverse myeloid malignancies. Somatic TET2 mutations are frequently observed in myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap syndromes including chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemias (AML) and secondary AML (sAML). We show here that TET2 mutations associated with myeloid malignancies compromise catalytic activity. Bone marrow samples from patients with TET2 mutations displayed uniformly low levels of 5hmC in genomic DNA compared to bone marrow samples from healthy controls. Moreover, small hairpin RNA (shRNA)-mediated depletion of Tet2 in mouse haematopoietic precursors skewed their differentiation towards monocyte/macrophage lineages in culture. There was no significant difference in DNA methylation between bone marrow samples from patients with high 5hmC versus healthy controls, but samples from patients with low 5hmC showed hypomethylation relative to controls at the majority of differentially methylated CpG sites. Our results demonstrate that Tet2 is important for normal myelopoiesis, and suggest that disruption of TET2 enzymatic activity favours myeloid tumorigenesis. Measurement of 5hmC levels in myeloid malignancies may prove valuable as a diagnostic and prognostic tool, to tailor therapies and assess responses to anticancer drugs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3003755/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3003755/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ko, Myunggon -- Huang, Yun -- Jankowska, Anna M -- Pape, Utz J -- Tahiliani, Mamta -- Bandukwala, Hozefa S -- An, Jungeun -- Lamperti, Edward D -- Koh, Kian Peng -- Ganetzky, Rebecca -- Liu, X Shirley -- Aravind, L -- Agarwal, Suneet -- Maciejewski, Jaroslaw P -- Rao, Anjana -- 1 UL1 RR 025758-02/RR/NCRR NIH HHS/ -- K08 HL089150/HL/NHLBI NIH HHS/ -- K24 HL077522/HL/NHLBI NIH HHS/ -- R01 AI044432/AI/NIAID NIH HHS/ -- R01 AI044432-12/AI/NIAID NIH HHS/ -- R01 AI044432-13/AI/NIAID NIH HHS/ -- R01 AI44432/AI/NIAID NIH HHS/ -- R01 HD065812/HD/NICHD NIH HHS/ -- R01 HG4069/HG/NHGRI NIH HHS/ -- R01 HL098522/HL/NHLBI NIH HHS/ -- R37 CA042471/CA/NCI NIH HHS/ -- R37 CA042471-20/CA/NCI NIH HHS/ -- R37 CA042471-21/CA/NCI NIH HHS/ -- RC1 DA028422/DA/NIDA NIH HHS/ -- RC1 DA028422-01/DA/NIDA NIH HHS/ -- RC1 DA028422-02/DA/NIDA NIH HHS/ -- UL1 RR025758/RR/NCRR NIH HHS/ -- England -- Nature. 2010 Dec 9;468(7325):839-43. doi: 10.1038/nature09586.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Harvard Medical School, Immune Disease Institute and Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21057493" target="_blank"〉PubMed〈/a〉
    Keywords: 5-Methylcytosine/*metabolism ; Animals ; Biocatalysis ; Cell Differentiation ; Cell Line ; CpG Islands/genetics ; DNA Methylation ; DNA, Neoplasm/chemistry/metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Humans ; *Hydroxylation ; Leukemia, Myeloid, Acute/genetics/*metabolism/pathology ; Mice ; Mice, Inbred C57BL ; Mutant Proteins/genetics/*metabolism ; Mutation ; Myelodysplastic Syndromes/genetics/*metabolism/pathology ; Proto-Oncogene Proteins/genetics/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 4
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    Aptamer-guided gene targeting in yeast and human cells (2014)
    Oxford University Press
    Details
    Publication Date: 2014-04-15
    Description: Gene targeting is a genetic technique to modify an endogenous DNA sequence in its genomic location via homologous recombination (HR) and is useful both for functional analysis and gene therapy applications. HR is inefficient in most organisms and cell types, including mammalian cells, often limiting the effectiveness of gene targeting. Therefore, increasing HR efficiency remains a major challenge to DNA editing. Here, we present a new concept for gene correction based on the development of DNA aptamers capable of binding to a site-specific DNA binding protein to facilitate the exchange of homologous genetic information between a donor molecule and the desired target locus (aptamer-guided gene targeting). We selected DNA aptamers to the I-SceI endonuclease. Bifunctional oligonucleotides containing an I-SceI aptamer sequence were designed as part of a longer single-stranded DNA molecule that contained a region with homology to repair an I-SceI generated double-strand break and correct a disrupted gene. The I-SceI aptamer-containing oligonucleotides stimulated gene targeting up to 32-fold in yeast Saccharomyces cerevisiae and up to 16-fold in human cells. This work provides a novel concept and research direction to increase gene targeting efficiency and lays the groundwork for future studies using aptamers for gene targeting.
    Keywords: Recombination, Targeted inhibition of gene function
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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