Deconvolution of transcriptional networks identifies TCF4 as a master regulator in schizophrenia
Deconvolution of transcriptional networks identifies TCF4 as a master regulator in schizophrenia
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DOI：
10.1126/sciadv.aau4139
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发表时间：
2019-09-01
期刊：
影响因子：
13.6
通讯作者：
Wang, Kai
中科院分区：
文献类型：
--
作者：
Torshizi, Abolfazl Doostparast;Armoskus, Chris;Wang, Kai
应用转录网络的组织特异性去卷积来识别神经精神疾病中的主调节因子（MR）在很大程度上尚未探索。在这里，使用两个精神分裂症（SCZ）病例对照RNA-seq数据集，一个在死后背外侧前额叶皮层（DLPFC）上，另一个在培养的嗅神经上皮上，我们对转录网络进行了去卷积，并将TCF 4确定为可能在SCZ中失调的最佳候选MR。我们通过对诱导多能干细胞（hiPSC）衍生的神经元和神经母细胞瘤细胞中TCF 4结合位点的富集分析，验证了TCF 4作为MR。我们通过敲低hiPSC衍生的神经祖细胞（NPC）和谷氨酸能神经元（Glut_Ns）中的TCF 4进一步验证了预测的TCF 4靶标。与Glut_Ns相比，NPC中受干扰的TCF 4基因网络更富含参与神经元活动的途径和SCZ相关风险基因。我们的研究结果表明，TCF 4可能作为一个MR的基因网络失调SCZ在神经发育的早期阶段。
Applying tissue-specific deconvolution of transcriptional networks to identify their master regulators (MRs) in neuropsychiatric disorders has been largely unexplored. Here, using two schizophrenia ( SCZ) case-control RNA-seq datasets, one on postmortem dorsolateral prefrontal cortex (DLPFC) and another on cultured olfactory neuroepithelium, we deconvolved the transcriptional networks and identified TCF4 as a top candidate MR that may be dysregulated in SCZ. We validated TCF4 as a MR through enrichment analysis of TCF4-binding sites in induced pluripotent stem cell (hiPSC)-derived neurons and in neuroblastoma cells. We further validated the predicted TCF4 targets by knocking down TCF4 in hiPSC-derived neural progenitor cells (NPCs) and glutamatergic neurons (Glut_Ns). The perturbed TCF4 gene network in NPCs was more enriched for pathways involved in neuronal activity and SCZ-associated risk genes, compared to Glut_Ns. Our results suggest that TCF4 may serve as a MR of a gene network dysregulated in SCZ at early stages of neurodevelopment.