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We reconstructed a genome\u2010scale 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\u2010target gene modules associated with age\u2010 and CAG repeat length\u2010dependent gene expression changes in\n                    <jats:italic>Htt<\/jats:italic>\n                    CAG knock\u2010in mouse striatum and replicated many of these associations in independent transcriptomic and proteomic datasets. Thirteen of 48 of these predicted TF\u2010target gene modules were also differentially expressed in striatal tissue from human disease. We experimentally validated a specific model prediction that SMAD3 regulates HD\u2010related gene expression changes using chromatin immunoprecipitation and deep sequencing (ChIP\u2010seq) of mouse striatum. We found CAG repeat length\u2010dependent changes in the genomic occupancy of SMAD3 and confirmed our model's prediction that many SMAD3 target genes are downregulated early in HD.\n                  <\/jats:p>","DOI":"10.15252\/msb.20167435","type":"journal-article","created":{"date-parts":[[2018,3,26]],"date-time":"2018-03-26T07:30:08Z","timestamp":1522049408000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["Transcriptional regulatory networks underlying gene expression changes in Huntington's disease"],"prefix":"10.1038","volume":"14","author":[{"given":"Seth A","family":"Ament","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jocelynn R","family":"Pearl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey P","family":"Cantle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert M","family":"Bragg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J","family":"Skene","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sydney R","family":"Coffey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dani E","family":"Bergey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa C","family":"Wheeler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcy E","family":"MacDonald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9157-5974","authenticated-orcid":false,"given":"Nitin S","family":"Baliga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jim","family":"Rosinski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leroy E","family":"Hood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1711-8868","authenticated-orcid":false,"given":"Jeffrey B","family":"Carroll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4157-0267","authenticated-orcid":false,"given":"Nathan D","family":"Price","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,3,26]]},"reference":[{"key":"BFMSB167435_CR1","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1038\/nbt.3587","volume":"34","author":"V Alexandrov","year":"2016","unstructured":"Alexandrov V, Brunner D, Menalled LB, Kudwa A, Watson\u2010Johnson J, Mazzella M, Russell I, Ruiz MC, Torello J, Sabath E, Sanchez A, Gomez M, Filipov I, Cox K, Kwan M, Ghavami A, Ramboz S, Lager B, Wheeler VC, Aaronson J et\u00a0al (2016) Large\u2010scale phenome analysis defines a behavioral signature for Huntington's disease genotype in mice. 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