title: Transcriptional activation of REST by Sp1 in Huntington's disease models.
abstract: In Huntington's disease (HD), mutant huntingtin (mHtt) disrupts the normal transcriptional program of disease neurons by altering the function of several gene expression regulators such as Sp1. REST (Repressor Element-1 Silencing Transcription Factor), a key regulator of neuronal differentiation, is also aberrantly activated in HD by a mechanism that remains unclear. Here, we show that the level of REST mRNA is increased in HD mice and in NG108 cells differentiated into neuronal-like cells and expressing a toxic mHtt fragment. Using luciferase reporter gene assay, we delimited the REST promoter regions essential for mHtt-mediated REST upregulation and found that they contain Sp factor binding sites. We provide evidence that Sp1 and Sp3 bind REST promoter and interplay to fine-tune REST transcription. In undifferentiated NG108 cells, Sp1 and Sp3 have antagonistic effect, Sp1 acting as an activator and Sp3 as a repressor. Upon neuronal differentiation, we show that the amount and ratio of Sp1/Sp3 proteins decline, as does REST expression, and that the transcriptional role of Sp3 shifts toward a weak activator. Therefore, our results provide new molecular information to the transcriptional regulation of REST during neuronal differentiation. Importantly, specific knockdown of Sp1 abolishes REST upregulation in NG108 neuronal-like cells expressing mHtt. Our data together with earlier reports suggest that mHtt triggers a pathogenic cascade involving Sp1 activation, which leads to REST upregulation and repression of neuronal genes.
authors.affiliation: Institute of Genetics and Molecular and Cellular Biology (IGBMC), U964/Centre National de Recherche Scientifique (CNRS) UMR 1704/Université de Strasbourg, Illkirch, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Ravache
authors.forename: Chantal
authors.initials: C
authors.lastname: Weber
authors.forename: Karine
authors.initials: K
authors.lastname: Mérienne
authors.forename: Yvon
authors.initials: Y
authors.lastname: Trottier
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D051381:Rats; D012097:Repressor Proteins / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D015533:Transcriptional Activation; D000099229:RE1-Silencing Transcription Factor
chemical_list: D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D016329:Sp1 Transcription Factor; D000099229:RE1-Silencing Transcription Factor; C499524:Htt protein, rat; C493231:Slc6a4 protein, mouse