title: Nurr1 represses tyrosine hydroxylase expression via SIRT1 in human neural stem cells.
abstract: Nurr1 is an orphan nuclear receptor best known for its essential role in the development and maintenance of midbrain dopaminergic (DA) neurons. During DA neurogenesis, Nurr1 directly targets human tyrosine hydroxylase (hTH). Here we investigated this targeting to identify the molecular mechanisms by which Nurr1 regulates DA neurogenesis. We previously cloned the hTH promoter and found three consensus elements for Nurr1 binding: NBRE-A, -B, and -C. In the present study, gel retardation and luciferase assays using hTH constructs showed that Nurr1 preferentially bound to NBRE-A, through which it mediated transcriptional activity. Furthermore, Nurr1 displayed dual-function transcriptional activities depending on the cell type. In DA-like SH-SY5Y cells, Nurr1 dose-dependently stimulated hTH-3174 promoter activity by 7- to 11-fold. However, in the human neural stem cell (hNSC) line HB1.F3, Nurr1 strongly repressed transcription from the same promoter. This repression was relieved by mutation of only the NBRE-A element and by nicotinamide [an inhibitor of class III histone deacetylases (HDACs), such as SIRT1], but not by trichostatin A (an inhibitor of class I and II HDACs). SIRT1 was strongly expressed in the nucleus of HB1.F3 cells, while it was localized in the cytoplasm in SH-SY5Y cells. ChIP assays of HB1.F3 cells showed that Nurr1 overexpression significantly increased the SIRT1 occupancy of the NBRE-A hTH promoter region, while low SIRT1 levels were observed in control cells. In contrast, no significant SIRT1 recruitment was observed in SH-SY5Y cells. These results indicate that differential SIRT1 localization may be involved in hTH gene regulation. Overall, our findings suggest that Nurr1 exists in dual transcriptional complexes, including co-repressor complexes that can be remodeled to become co-activators and can fine-tune hTH gene transcription during human DA neurogenesis.
authors: Brain Disease Research Center, Ajou University School of Medicine, Suwon, Korea ; Graduate School of Biomedical Sciences, Ajou University School of Medicine, Suwon, Korea.
authors: Tae Eun
authors: TE
authors: Kim
authors: Ji-Seon
authors: JS
authors: Seo
authors: Ji Sun
authors: JS
authors: Seo
authors: Jae Won
authors: JW
authors: Yang
authors: Min Woong
authors: MW
authors: Kim
authors: Rukhsana
authors: R
authors: Kausar
authors: Eunhye
authors: E
authors: Joe
authors: Bo Yeon
authors: BY
authors: Kim
authors: Myung Ae
authors: MA
authors: Lee
mesh_terms: D001483:Base Sequence; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D019070:Cell Lineage / Q000187:drug effects / Q000235:genetics; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism*; D009536:Niacinamide / Q000494:pharmacology; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000737:chemistry / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism*; D056564:Sirtuin 1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics* / Q000378:metabolism
chemical_list: D015415:Biomarkers; C539882:NR4A2 protein, human; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D012097:Repressor Proteins; D014157:Transcription Factors; D009536:Niacinamide; D014446:Tyrosine 3-Monooxygenase; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D006655:Histone Deacetylases
references: J Biol Chem. 2013 Feb 22;288(8):5506-17
references: 23283970
references: J Biol Chem. 2001 Nov 16;276(46):43277-84
references: 11553630
references: Science. 1997 Apr 11;276(5310):248-50
references: 9092472
references: Biochem Biophys Res Commun. 2003 Dec 26;312(4):1123-31
references: 14651989
references: Stem Cells. 2010 Mar 31;28(3):501-12
references: 20049900
references: Hum Mol Genet. 2005 Jul 1;14(13):1709-25
references: 15888489
references: Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):4013-8
references: 9520484
references: J Cell Physiol. 2006 Apr;207(1):49-57
references: 16252282
references: Cell Stem Cell. 2009 Dec 4;5(6):646-58
references: 19951692
references: Nucleic Acids Res. 2005 Oct 27;33(18):6024-33
references: 16254079
references: Development. 1999 Sep;126(18):4017-26
references: 10457011
references: Cell. 2006 Feb 10;124(3):615-29
references: 16469706
references: Neuropathology. 2004 Sep;24(3):159-71
references: 15484694
references: Neuroreport. 2002 Aug 7;13(11):1447-52
references: 12167771
references: Nat Rev Neurosci. 2007 Jan;8(1):21-32
references: 17180160
references: J Biol Chem. 2004 Dec 17;279(51):53338-45
references: 15456745
references: J Neurosci Res. 2003 May 1;72(3):352-62
references: 12692902
references: Mol Endocrinol. 2007 Aug;21(8):1807-21
references: 17505061
references: Nat Genet. 2003 Jan;33(1):85-9
references: 12496759
references: J Neurochem. 2005 Dec;95(5):1342-50
references: 16313515
references: Biochem Biophys Res Commun. 2003 Jun 13;305(4):1040-8
references: 12767935
references: Nat Struct Mol Biol. 2005 Apr;12(4):364-71
references: 15768032
references: Nat Rev Mol Cell Biol. 2005 Jul;6(7):542-54
references: 15957004
references: Gene. 1999 Apr 16;230(2):233-9
references: 10216262
references: J Biol Chem. 2003 Jul 18;278(29):26838-43
references: 12743114
references: Biochem Biophys Res Commun. 2006 Jul 28;346(2):426-35
references: 16764822
references: Genes Dev. 1995 Apr 1;9(7):769-82
references: 7705655
references: EMBO J. 2001 Dec 17;20(24):6969-78
references: 11742974
references: Cell. 1997 May 2;89(3):373-80
references: 9150137
references: J Biol Chem. 2003 Oct 31;278(44):43041-50
references: 12930829
references: J Biol Chem. 2007 Mar 30;282(13):9492-9504
references: 17283078
references: Stem Cells Dev. 2009 Sep;18(7):1003-12
references: 19049321
references: Mol Endocrinol. 2005 Jan;19(1):12-24
references: 15459248
references: J Biol Chem. 2004 Jan 16;279(3):2005-11
references: 14559918
references: Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2874-9
references: 16477036
references: Exp Cell Res. 2007 Apr 1;313(6):1172-80
references: 17291494
references: J Neurochem. 2003 May;85(3):622-34
references: 12694388
references: Endocrinology. 2005 Jan;146(1):237-46
references: 15486232
references: Biochem Biophys Res Commun. 2007 Jul 27;359(2):391-7
references: 17543277
references: J Cell Physiol. 2005 Aug;204(2):666-77
references: 15744773
references: J Mol Cell Cardiol. 2001 Mar;33(3):379-93
references: 11181008
references: Methods Mol Biol. 2002;198:55-65
references: 11951641
references: J Neurochem. 2003 Jun;85(6):1443-54
references: 12787064
references: Int J Cancer. 1981 Nov 15;28(5):583-9
references: 7309295
references: Stem Cells. 2008 Jun;26(6):1526-36
references: 18388307
references: J Neurochem. 2001 Mar;76(5):1565-72
references: 11238740
references: Ann Neurol. 2003 Sep;54(3):403-14
references: 12953276
references: J Biol Chem. 1999 Dec 24;274(52):37483-90
references: 10601324
references: Mol Cell Biol. 2007 Nov;27(21):7486-96
references: 17709391
references: Biochem Biophys Res Commun. 2003 Dec 26;312(4):950-7
references: 14651963
references: PLoS One. 2013;8(1):e55035
references: 23358114
references: Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15599-604
references: 18829436
references: Nucleic Acids Res. 2010 Aug;38(14):4607-19
references: 20375098
references: Development. 2009 Feb;136(4):531-40
references: 19144721