Transcriptional regulatory networks underlying gene expression changes in Huntington's disease
Transcriptional regulatory networks underlying gene expression changes in Huntington's disease
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DOI：
10.15252/msb.20167435
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发表时间：
2018-03-01
影响因子：
9.9
通讯作者：
Price, Nathan D.
中科院分区：
文献类型：
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作者：
Ament, Seth A.;Pearl, Jocelynn R.;Price, Nathan D.
在亨廷顿病（HD）的症状前和整个过程中都发生转录变化，这激发了对HD中转录调控网络（TRN）的研究。我们通过整合基因组结合位点模型和HD小鼠模型纹状体组织的转录组分析，重建了小鼠纹状体中718个转录因子（TF）靶基因的基因组规模模型。我们确定了48个差异表达的TF-靶基因模块与Htt CAG敲入小鼠纹状体中年龄和CAG重复序列长度依赖性基因表达变化相关，并在独立的转录组学和蛋白质组学数据集中复制了其中许多相关性。这些预测的TF-靶基因模块中的48个中的13个也在来自人类疾病的纹状体组织中差异表达。我们实验验证了一个特定的模型预测，SMAD 3调节HD相关的基因表达变化，使用染色质免疫沉淀和深度测序（ChIP-seq）的小鼠纹状体。我们发现SMAD 3基因组占有率的CAG重复序列长度依赖性变化，并证实了我们模型的预测，即许多SMAD 3靶基因在HD早期下调。
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.