2Transcriptional changes occur presymptomatically and throughout Huntington's Disease (HD), 3 motivating the study of transcriptional regulatory networks (TRNs) in HD. We reconstructed a 4 genome-scale model for the target genes of 718 TFs in the mouse striatum by integrating a model 5 of the genomic binding sites with transcriptome profiling of striatal tissue from HD mouse 6 models. We identified 48 differentially expressed TF-target gene modules associated with age-7and Htt allele-dependent gene expression changes in the mouse striatum, and replicated many of 8 these associations in independent transcriptomic and proteomic datasets. Strikingly, many of 9 these predicted target genes were also differentially expressed in striatal tissue from human 10 disease. We experimentally validated a key model prediction that SMAD3 regulates HD-related 11 gene expression changes using chromatin immunoprecipitation and deep sequencing (ChIP-seq) 12 of mouse striatum. We found Htt allele-dependent changes in the genomic occupancy of 13 SMAD3 and confirmed our model's prediction that many SMAD3 target genes are down-14 regulated early in HD. Importantly, our study provides a mouse and human striatal-specific TRN 15and prioritizes a hierarchy of transcription factor drivers in HD. 16 17 peer-reviewed)
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