title: SMAD transcription factors are altered in cell models of HD and regulate HTT expression.
abstract: Transcriptional dysregulation is observable in multiple animal and cell models of Huntington's disease, as well as in human blood and post-mortem caudate. This contributes to HD pathogenesis, although the exact mechanism by which this occurs is unknown. We therefore utilised a dynamic model in order to determine the differential effect of growth factor stimulation on gene expression, to highlight potential alterations in kinase signalling pathways that may be in part responsible for the transcriptional dysregulation observed in HD, and which may reveal new therapeutic targets. We demonstrate that cells expressing mutant huntingtin have a dysregulated transcriptional response to epidermal growth factor stimulation, and identify the transforming growth factor-beta pathway as a novel signalling pathway of interest that may regulate the expression of the Huntingtin (HTT) gene itself. The dysregulation of HTT expression may contribute to the altered transcriptional phenotype observed in HD.
authors.affiliation: The MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Hadyn Ellis Building, Maindy Road, Cathays, Cardiff CF24 4HQ, UK. Electronic address: kathryn.bowles@mssm.edu.
authors.forename: K R
authors.initials: KR
authors.lastname: Bowles
authors.affiliation: The MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Hadyn Ellis Building, Maindy Road, Cathays, Cardiff CF24 4HQ, UK. Electronic address: stonetc@cardiff.ac.uk.
authors.forename: T
authors.initials: T
authors.lastname: Stone
authors.affiliation: The MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Hadyn Ellis Building, Maindy Road, Cathays, Cardiff CF24 4HQ, UK. Electronic address: holmanspa@cardiff.ac.uk.
authors.forename: P
authors.initials: P
authors.lastname: Holmans
authors.affiliation: Cardiff School of Biosciences, The Sir Martin Evans Building, Museum Avenue, Cardiff CF10 3AX, UK. Electronic address: allennd@cardiff.ac.uk.
authors.forename: N D
authors.initials: ND
authors.lastname: Allen
authors.affiliation: The Brain Repair Group, School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK. Electronic address: dunnettsb@Cardiff.ac.uk.
authors.forename: S B
authors.initials: SB
authors.lastname: Dunnett
authors.affiliation: The MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Hadyn Ellis Building, Maindy Road, Cathays, Cardiff CF24 4HQ, UK. Electronic address: jonesl1@cardiff.ac.uk.
authors.forename: L
authors.initials: L
authors.lastname: Jones
mesh_terms: D000818:Animals; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics* / Q000378:metabolism; D006816:Huntington Disease / Q000378:metabolism*; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D058977:Molecular Sequence Annotation; D009154:Mutation / Q000235:genetics; D058953:Neural Stem Cells / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000071058:Huntingtin Protein; D051785:Smad Proteins; D016212:Transforming Growth Factor beta
keywords: EGF; Huntington's Disease; Kinase signalling; SMAD; TGF-beta; Transcription