Umber of targets with the 106 probe or interacting mGluR7 Formulation proteins could potentially
Umber of targets in the 106 probe or interacting proteins could potentially raise concern for the use of 2-aminobenzamides as human therapeutics on account of possible undesirable side effects. Similarly, the 2-aminobenzamides induce adjustments in worldwide gene expression patterns in human lymphocytes treated ex vivo,30 once more raising concern for off-target effects. In spite of these findings, a related 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 are certainly not of serious concern.Article*Telephone: +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 monetary interest.ACKNOWLEDGMENTS We want to thank Elisabetta Soragni and Erica Campau for support with iPSC differentiation. Studies within the Gottesfeld lab had been supported by a grant from the National Institutes for Neurological Problems and Stroke (R01 NS063856). C.X. was supported by a postdoctoral fellowship from the PARP15 MedChemExpress Friedreich’s Ataxia Analysis 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 Biochemistry and Molecular Biology, Inc. Published within 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 Cells*SReceived for publication, February eight, 2013, and in revised type, May perhaps 29, 2013 Published, JBC Papers in Press, May perhaps 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 in the Ministry of Education and State Important Laboratory for Biocontrol, College of Life Sciences, Sun Yat-sen University, Guangzhou, China 510275 plus 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 role 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 should additional our understanding of how O-GlcNAcylation is integrated into ES cell regulatory networks. As a member with the Tet (Ten-eleven translocation) family proteins that may convert 5-methylcytosine (5mC) to 5-hydroxylmethylcytosine (5hmC), Tet1 has been implicated in regulating global DNA demethylation and gene expression. Tet1 is very expressed in embryonic stem (ES) cells and seems mainly to repress developmental genes for preserving pluripotency. To know how Tet1 could regulate gene expression, we conducted huge scale immunoprecipitation followed by mass spectrometry of endogenous Tet1 in mouse ES cells. We located that Tet1 could interact with a number of chromatin regulators, including Sin3A and NuRD complexes. Furthermore, we showed that Tet1 could also interact with all the O-GlcNAc transferase (Ogt) and be O-GlcNAcylated. Depletion of Ogt led to decreased Tet1.
