S that happen to be down-regulated by mutant Htt at the transcriptional level, amongst other possibilities suggested by the wide selection of pathways identified as influenced by the 2aminobenzamides. On a final note, the finding of a sizable quantity of targets in the 106 probe or interacting proteins could potentially raise concern for the use of 2-aminobenzamides as human therapeutics because of possible undesirable negative effects. Similarly, the 2-aminobenzamides induce alterations in worldwide gene BNP, Human expression patterns in human lymphocytes treated ex vivo,30 once again raising concern for off-target effects. In spite of those findings, a connected 2-aminobenzamide, HDACi 109,9 has been subjected to a phase I dose-escalation clinical study in human FRDA patients, with no reported adverse effects, even on exposure to 240 mg drug/day,11 suggesting that possible offtarget effects usually are not of really serious concern.ArticleTelephone: +1-858-784-8913. Fax: +1-858-784-8965. E-mail: [email protected] Contributions#B.S. and C.X. contributed equallyNotesThe authors declare no competing economic interest.ACKNOWLEDGMENTS We wish to thank Elisabetta Soragni and Erica Campau for support with iPSC differentiation. Studies inside the Gottesfeld lab were supported by a grant in the National Institutes for Neurological Issues and Stroke (R01 NS063856). C.X. was supported by a postdoctoral fellowship from the Friedreich’s Ataxia Study Alliance (FARA). The Yates laboratory is supported by R01 MH068770, P41 GM103533, R01MH100175 and HHSN268201000035C Grants from NIH.
THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 288, NO. 29, pp. 20776 ?0784, July 19, 2013 ?2013 by The American Society for ADAM12 Protein site Biochemistry and Molecular Biology, Inc. Published in the U.S.A.Ten-Eleven Translocation 1 (Tet1) Is Regulated by O-Linked N-Acetylglucosamine Transferase (Ogt) for Target Gene Repression in Mouse Embryonic Stem CellsSReceived for publication, February eight, 2013, and in revised type, May well 29, 2013 Published, JBC Papers in Press, May possibly 31, 2013, DOI ten.1074/jbc.M113.Feng-Tao Shi1, Hyeung Kim1, Weisi Lu? Quanyuan He, Dan Liu, Margaret A. Goodell? Ma Wan2, and Zhou Songyang? From the �Key Laboratory of Gene Engineering from the Ministry of Education and State Important Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China 510275 as well as the Verna and Marrs Department of Biochemistry and Molecular Biology and tem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TexasBackground: Ogt N-acetylglucosylates proteins and plays a crucial function in mouse ES cells. Final results: The DNA demethylation enzyme Tet1 interacts with Ogt and is O-GlcNAcylated. Conclusion: Tet1 protein stability is positively regulated by O-GlcNAcylation, and its repression function on targeting genes is dependent on Ogt. Significance: Ogt-Tet1 interaction need to further our understanding of how O-GlcNAcylation is integrated into ES cell regulatory networks. As a member on the Tet (Ten-eleven translocation) family proteins which can convert 5-methylcytosine (5mC) to 5-hydroxylmethylcytosine (5hmC), Tet1 has been implicated in regulating worldwide DNA demethylation and gene expression. Tet1 is very expressed in embryonic stem (ES) cells and seems mostly to repress developmental genes for preserving pluripotency. To know how Tet1 may regulate gene expression, we carried out substantial scale immunoprecipitation followed by mass spectrometry of endogenous Tet1 in mouse ES cells. We discovered that Tet1 could.
