Single-Cell Sequencing of iPSC-Dopamine Neurons Reconstructs Disease Progression and Identifies HDAC4 as a Regulator of Parkinson Cell Phenotypes
Single-Cell Sequencing of iPSC-Dopamine Neurons Reconstructs Disease Progression and Identifies HDAC4 as a Regulator of Parkinson Cell Phenotypes
复制标题
iPSC-多巴胺神经元的单细胞测序重建疾病进展，并将HDAC 4作为帕金森细胞表型的调节剂
DOI：
10.1016/j.stem.2018.10.023
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发表时间：
2019-01-03
期刊：
影响因子：
23.9
通讯作者：
Wade-Martins, Richard
中科院分区：
文献类型：
--
作者：
Lang, Charmaine;Campbell, Kieran R.;Wade-Martins, Richard
诱导多能干细胞（iPSC）衍生的多巴胺神经元提供了建模帕金森病（PD）的机会，但神经元培养物被体外疾病表型的异步和异质外观所混淆。使用高分辨率，单细胞转录组学分析iPSC衍生的多巴胺神经元携带GBA-N370 S PD风险变体，我们确定了一个渐进轴的基因表达变异导致内质网应激。对沿着该轴差异表达（DE）的基因进行伪时间分析，确定转录抑制因子组蛋白脱乙酰酶4（HDAC 4）是疾病进展的上游调节因子。HDAC 4在PD iPSC衍生的多巴胺神经元中错误定位于细胞核，并在疾病轴早期抑制基因，导致蛋白质稳态的晚期缺陷。用HDAC 4调节化合物处理iPSC衍生的多巴胺神经元上调了DE轴早期的基因，并纠正了PD相关的细胞表型。我们的研究展示了单细胞转录组学如何利用细胞异质性来揭示疾病机制并确定治疗靶点。
Induced pluripotent stem cell (iPSC)-derived dopamine neurons provide an opportunity to model Parkinson's disease (PD), but neuronal cultures are confounded by asynchronous and heterogeneous appearance of disease phenotypes in vitro. Using high-resolution, single-cell transcriptomic analyses of iPSC-derived dopamine neurons carrying the GBA-N370S PD risk variant, we identified a progressive axis of gene expression variation leading to endoplasmic reticulum stress. Pseudotime analysis of genes differentially expressed (DE) along this axis identified the transcriptional repressor histone deacetylase 4 (HDAC4) as an upstream regulator of disease progression. HDAC4 was mislocalized to the nucleus in PD iPSC-derived dopamine neurons and repressed genes early in the disease axis, leading to late deficits in protein homeostasis. Treatment of iPSC-derived dopamine neurons with HDAC4-modulating compounds upregulated genes early in the DE axis and corrected PD-related cellular phenotypes. Our study demonstrates how single-cell transcriptomics can exploit cellular heterogeneity to reveal disease mechanisms and identify therapeutic targets.