title: Transcriptional regulation of the Alström syndrome gene ALMS1 by members of the RFX family and Sp1.
abstract: Mutations in the human gene ALMS1 cause Alström syndrome, a disorder characterised by neurosensory degeneration, metabolic defects and cardiomyopathy. ALMS1 encodes a centrosomal protein implicated in the assembly and maintenance of primary cilia. Expression of ALMS1 varies between tissues and recent data suggest that its transcription is modulated during adipogenesis and growth arrest. However the ALMS1 promoter has not been defined. This study focused on identifying and characterising the ALMS1 proximal promoter, initially by using 5' RACE to map transcription start sites. Luciferase reporter assay and EMSA data strongly suggest that ALMS1 transcription is regulated by the ubiquitous factor Sp1. In addition, reporter assay, EMSA, chromatin immunoprecipitation and RNA interference data indicate that ALMS1 transcription is regulated by regulatory factor X (RFX) proteins. These transcription factors are cell-type restricted in their expression profile and known to regulate genes of the ciliogenic pathway. We show binding of RFX proteins to an evolutionarily conserved X-box in the ALMS1 proximal promoter and present evidence that these proteins are responsible for ALMS1 transcription during growth arrest induced by low serum conditions. In summary, this work provides the first data on transcription factors regulating general and context-specific transcription of the disease-associated gene ALMS1.
authors.affiliation: Centre for Human Development, Stem Cells and Regeneration, Human Genetics Division, University of Southampton, UK.
authors.forename: Tracey L
authors.initials: TL
authors.lastname: Purvis
authors.forename: Tom
authors.initials: T
authors.lastname: Hearn
authors.forename: Cosma
authors.initials: C
authors.lastname: Spalluto
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Knorz
authors.forename: Karen Piper
authors.initials: KP
authors.lastname: Hanley
authors.forename: Tilman
authors.initials: T
authors.lastname: Sanchez-Elsner
authors.forename: Neil A
authors.initials: NA
authors.lastname: Hanley
authors.forename: David I
authors.initials: DI
authors.lastname: Wilson
mesh_terms: D000328:Adult; D056769:Alstrom Syndrome / Q000235:genetics*; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D002874:Chromosome Mapping; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D009154:Mutation; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics*; D034622:RNA Interference; D000071701:Regulatory Factor X Transcription Factors; D016329:Sp1 Transcription Factor / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D024363:Transcription Initiation Site; D014158:Transcription, Genetic
chemical_list: C490729:ALMS1 protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D011506:Proteins; C101059:RFX2 protein, human; D000071701:Regulatory Factor X Transcription Factors; D016329:Sp1 Transcription Factor; D014157:Transcription Factors
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