SMAD transcription factors are altered in cell models of HD and regulate HTT expression

Cell Signal. 2017 Feb;31:1-14. doi: 10.1016/j.cellsig.2016.12.005. Epub 2016 Dec 14.

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.

Keywords: EGF; Huntington's Disease; Kinase signalling; SMAD; TGF-beta; Transcription.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cluster Analysis
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Humans
  • Huntingtin Protein / genetics*
  • Huntingtin Protein / metabolism
  • Huntington Disease / metabolism*
  • Induced Pluripotent Stem Cells / metabolism
  • Mice
  • Models, Biological*
  • Molecular Sequence Annotation
  • Mutation / genetics
  • Neural Stem Cells / metabolism
  • Phosphorylation
  • Promoter Regions, Genetic / genetics
  • Signal Transduction
  • Smad Proteins / metabolism*
  • Transforming Growth Factor beta / metabolism

Substances

  • Huntingtin Protein
  • Smad Proteins
  • Transforming Growth Factor beta