Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany; Centre for Rare Diseases, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany.
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany; Centre for Rare Diseases, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany.
Neuropharmacology. 2017 May 1;117:260-272. doi: 10.1016/j.neuropharm.2017.01.029. Epub 2017 Jan 30.
Huntington disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion in the gene coding for the huntingtin protein (HTT). Mutant HTT (mHTT) has been proposed to cause neuronal dysfunction and neuronal loss through multiple mechanisms. Transcriptional changes may be a core pathogenic feature of HD. Utilizing the Affymetrix platform we performed a genome-wide RNA expression analysis in two BACHD transgenic rat lines (TG5 and TG9) at 12 months of age, both of which carry full-length human mHTT but with different expression levels. By defining the threshold of significance at p < 0.01, we found 1608 genes and 871 genes differentially expressed in both TG5 and TG9 rats when compared to the wild type littermates, respectively. We only chose the highly up-/down-regulated genes for further analysis by setting an additional threshold of 1.5 fold change. Comparing gene expression profiles of human HD brains and BACHD rats revealed a high concordance in both functional and IPA (Ingenuity Pathway Analysis) canonical pathways relevant to HD. In addition, we investigated the causes leading to gene expression changes at molecular and protein levels in BACHD rats including the involvement of polyQ-containing transcription factors TATA box-binding protein (TBP), Sp1 and CBP as well as the chromatin structure. We demonstrate that the BACHD rat model recapitulates the gene expression changes of the human disease supporting its role as a preclinical research animal model. We also show for the first time that TFIID complex formation is reduced, while soluble TBP is increased in an HD model. This finding suggests that mHTT is a competitor instead of a recruiter of polyQ-containing transcription factors in the transcription process in HD.
亨廷顿病（HD）是一种常染色体显性遗传的神经退行性疾病，由编码亨廷顿蛋白（HTT）的基因中的 CAG 重复扩展引起。突变 HTT（mHTT）被认为通过多种机制导致神经元功能障碍和神经元丢失。转录变化可能是 HD 的核心致病特征。我们利用 Affymetrix 平台，在两条 BACHD 转基因大鼠（TG5 和 TG9）中进行了全基因组 RNA 表达分析，这两条大鼠均携带全长人类 mHTT，但表达水平不同。通过将显著性阈值定义为 p < 0.01，我们发现与野生型同窝仔相比，TG5 和 TG9 大鼠分别有 1608 个和 871 个基因差异表达。我们仅选择高度上调/下调的基因作为进一步分析的对象，设定了另外 1.5 倍变化的阈值。比较人类 HD 大脑和 BACHD 大鼠的基因表达谱，发现两者在与 HD 相关的功能和 IPA（Ingenuity Pathway Analysis）经典途径方面高度一致。此外，我们还研究了导致 BACHD 大鼠基因表达变化的分子和蛋白质水平的原因，包括富含 polyQ 的转录因子 TATA 盒结合蛋白（TBP）、Sp1 和 CBP 以及染色质结构的参与。我们证明 BACHD 大鼠模型再现了人类疾病的基因表达变化，支持其作为临床前研究动物模型的作用。我们还首次表明，TFIID 复合物形成减少，而可溶性 TBP 在 HD 模型中增加。这一发现表明，在 HD 转录过程中，mHTT 是 polyQ 转录因子的竞争者，而不是招募者。
