Huntington’s Disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion, resulting in a mutant huntingtin protein. While it is now clear that astrocytes are affected by HD and significantly contribute to neuronal dysfunction and pathogenesis, the alterations in the transcriptional and epigenetic profiles in HD astrocytes have yet to be characterized. Here, we examine global transcription and chromatin accessibility dynamics during in vitro astrocyte differentiation in a transgenic non-human primate model of HD. We found global changes in accessibility and transcription across different stages of HD pluripotent stem cell differentiation, with distinct trends first observed in neural progenitor cells (NPCs), once cells have committed to a neural lineage. Transcription of p53 signaling and cell cycle pathway genes was highly impacted during differentiation, with depletion in HD NPCs and upregulation in HD astrocytes. E2F target genes also displayed this inverse expression pattern, and strong associations between E2F target gene expression and accessibility at nearby putative enhancers were observed. The results suggest that chromatin accessibility and transcription are altered throughout in vitro HD astrocyte differentiation and provide evidence that E2F dysregulation contributes to aberrant cell-cycle re-entry and apoptosis throughout the progression from NPCs to astrocytes.

中文翻译：

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亨廷顿病猴多能干细胞体外星形胶质细胞分化过程中的染色质可及性和转录动态。

亨廷顿病 (HD) 是一种致命的神经退行性疾病，由 CAG 重复扩增引起，导致亨廷顿蛋白突变。虽然现在已经清楚星形胶质细胞受到 HD 的影响，并且对神经元功能障碍和发病机制有显着影响，但 HD 星形胶质细胞转录和表观遗传谱的变化尚未得到表征。在这里，我们在 HD 转基因非人灵长类动物模型中检查体外星形胶质细胞分化过程中的整体转录和染色质可及性动态。我们发现 HD 多能干细胞分化不同阶段的可及性和转录发生了全局变化，一旦细胞定型为神经谱系，首先在神经祖细胞 (NPC) 中观察到明显的趋势。p53 信号传导和细胞周期通路基因的转录在分化过程中受到高度影响，HD NPC 中的缺失和 HD 星形胶质细胞中的上调。E2F 靶基因也显示出这种反向表达模式，并且观察到 E2F 靶基因表达与附近推定增强子的可及性之间存在很强的关联。结果表明，在体外 HD 星形胶质细胞分化过程中，染色质可及性和转录发生了改变，并提供了 E2F 失调导致从 NPC 到星形胶质细胞的整个过程中异常细胞周期重入和凋亡的证据。