Transcriptional regulatory networks underlying gene expression changes in Huntington's disease

Mol Syst Biol. 2018 Mar 26;14(3):e7435. doi: 10.15252/msb.20167435.


Transcriptional changes occur presymptomatically and throughout Huntington's disease (HD), motivating the study of transcriptional regulatory networks (TRNs) in HD We reconstructed a genome-scale model for the target genes of 718 transcription factors (TFs) in the mouse striatum by integrating a model of genomic binding sites with transcriptome profiling of striatal tissue from HD mouse models. We identified 48 differentially expressed TF-target gene modules associated with age- and CAG repeat length-dependent gene expression changes in Htt CAG knock-in mouse striatum and replicated many of these associations in independent transcriptomic and proteomic datasets. Thirteen of 48 of these predicted TF-target gene modules were also differentially expressed in striatal tissue from human disease. We experimentally validated a specific model prediction that SMAD3 regulates HD-related gene expression changes using chromatin immunoprecipitation and deep sequencing (ChIP-seq) of mouse striatum. We found CAG repeat length-dependent changes in the genomic occupancy of SMAD3 and confirmed our model's prediction that many SMAD3 target genes are downregulated early in HD.

Keywords: Huntington's disease; SMAD3; transcription factor; transcriptional regulatory networks.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Corpus Striatum / metabolism
  • Disease Models, Animal
  • Gene Expression Profiling / methods*
  • Gene Expression Regulation
  • Gene Regulatory Networks*
  • Humans
  • Huntington Disease / genetics*
  • Huntington Disease / metabolism
  • Mice
  • Protein Interaction Maps
  • Proteomics
  • Smad3 Protein / genetics*
  • Smad3 Protein / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism


  • SMAD3 protein, human
  • Smad3 Protein
  • Transcription Factors