Shared patterns of glial transcriptional dysregulation link Huntington's disease and schizophrenia

Huntington’s disease (HD) and juvenile-onset schizophrenia (SCZ) have long been regarded as distinct disorders. However, both manifest cell-intrinsic abnormalities in glial differentiation, with resultant astrocytic dysfunction and hypomyelination. To assess whether a common mechanism might underlie the similar glial pathology of these otherwise disparate conditions, we utilized comparative correlation network approaches to analyze RNA-seq data from human glial progenitor cells (hGPCs) produced from disease-derived pluripotent stem cells. We identified gene sets preserved between HD and SCZ hGPCs yet distinct from normal controls, that included 174 highly-connected genes in the shared disease-associated network, focused on genes involved in synaptic signaling. These synaptic genes were largely suppressed in both SCZ and HD hGPCs, and gene regulatory network analysis identified a core set of upstream regulators of this network, of which OLIG2 and TCF7L2 were prominent. Among their downstream targets, ADGRL3, a modulator of glutamatergic synapses, was notably suppressed in both SCZ and HD hGPCs. ChIP-seq confirmed that OLIG2 and TCF7L2 each bound to the regulatory region of ADGRL3, whose expression was then rescued by lentiviral overexpression of these transcription factors. These data suggest that the disease-associated suppression of OLIG2 and TCF7L2-dependent transcription of glutamate signaling regulators may impair glial receptivity to neuronal glutamate. The consequent loss of activity-dependent mobilization of hGPCs may yield deficient oligodendrocyte production, and hence the hypomyelination noted in these disorders, as well as the disrupted astrocytic differentiation and attendant synaptic dysfunction associated with each. Together, these data highlight the importance of convergent glial molecular pathology in both the pathogenesis and phenotypic similarities of two otherwise unrelated disorders, HD and SCZ. RNAseq analysis of GPCs ans astrocytes derived from CTR, HD, and SCZ patients.

亨廷顿舞蹈症（Huntington’s disease, HD）与青少年起病精神分裂症（juvenile-onset schizophrenia, SCZ）长期以来被视为两类截然不同的疾病。然而二者均存在胶质细胞分化的细胞内源性异常，进而引发星形胶质细胞功能障碍与髓鞘形成不足。为探究这两种看似迥异的疾病所表现出的相似胶质病理是否共享共同的分子机制，我们采用比较相关网络分析方法，对源自疾病特异性多能干细胞的人类胶质祖细胞（human glial progenitor cells, hGPCs）的RNA测序（RNA-seq）数据开展分析。我们鉴定出HD与SCZ的hGPCs之间存在保守的基因集，且该基因集与正常对照组存在显著差异；该保守基因集在共享疾病相关网络中包含174个高连接度基因，主要富集于突触信号传导相关通路。此类突触相关基因在SCZ与HD的hGPCs中均显著下调，而基因调控网络分析进一步鉴定出该网络的核心上游调控因子，其中OLIG2与TCF7L2尤为关键。在其下游靶基因中，谷氨酸能突触调节因子ADGRL3在SCZ与HD的hGPCs中均受到显著抑制。染色质免疫沉淀测序（ChIP-seq）验证显示，OLIG2与TCF7L2均可结合ADGRL3的调控区域，且通过慢病毒过表达这两种转录因子可挽救ADGRL3的表达水平。上述数据表明，疾病相关的OLIG2与TCF7L2依赖的谷氨酸信号调控因子转录抑制，可能会削弱胶质细胞对神经元谷氨酸的反应性。由此导致的hGPCs活性依赖性动员受损，可能会造成少突胶质细胞生成不足，进而引发上述两种疾病中观察到的髓鞘形成不足，同时也会破坏星形胶质细胞分化，并伴随各自疾病中出现的突触功能障碍。综上，本研究数据揭示了HD与SCZ这两种看似无关的疾病在胶质分子病理层面的趋同性，这对于阐明二者的发病机制与表型相似性具有重要意义。本数据集包含对来自对照组（CTR）、HD及SCZ患者的胶质祖细胞与星形胶质细胞的RNA测序分析。