TY - JOUR T1 - Genome-scale transcriptional regulatory network models for the mouse and human striatum predict roles for SMAD3 and other transcription factors in Huntington’s disease JF - bioRxiv DO - 10.1101/087114 SP - 087114 AU - Seth A. Ament AU - Jocelynn R. Pearl AU - Robert M. Bragg AU - Peter J. Skene AU - Sydney R. Coffey AU - Dani E. Bergey AU - Christopher L. Plaisier AU - Vanessa C. Wheeler AU - Marcy E. MacDonald AU - Nitin S. Baliga AU - Jim Rosinski AU - Leroy E. Hood AU - Jeffrey B. Carroll AU - Nathan D. Price Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/11/10/087114.abstract N2 - 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 TFs in the mouse striatum by integrating a model of the 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 Htt allele-dependent gene expression changes in the mouse striatum, and replicated many of these associations in independent transcriptomic and proteomic datasets. Strikingly, many of these predicted target genes were also differentially expressed in striatal tissue from human disease. We experimentally validated a key model prediction that SMAD3 regulates HD-related gene expression changes using chromatin immunoprecipitation and deep sequencing (ChIP-seq) of mouse striatum. We found Htt allele-dependent changes in the genomic occupancy of SMAD3 and confirmed our model’s prediction that many SMAD3 target genes are down-regulated early in HD. Importantly, our study provides a mouse and human striatal-specific TRN and prioritizes a hierarchy of transcription factor drivers in HD. ER -