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首页> 外文期刊>BMC Medical Genomics >Co-expression network of neural-differentiation genes shows specific pattern in schizophrenia
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Co-expression network of neural-differentiation genes shows specific pattern in schizophrenia

机译：神经分化基因的共表达网络在精神分裂症中显示特定模式

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Background Schizophrenia is a neurodevelopmental disorder with genetic and environmental factors contributing to its pathogenesis, although the mechanism is unknown due to the difficulties in accessing diseased tissue during human neurodevelopment. The aim of this study was to find neuronal differentiation genes disrupted in schizophrenia and to evaluate those genes in post-mortem brain tissues from schizophrenia cases and controls. Methods We analyzed differentially expressed genes (DEG), copy number variation (CNV) and differential methylation in human induced pluripotent stem cells (hiPSC) derived from fibroblasts from one control and one schizophrenia patient and further differentiated into neuron (NPC). Expression of the DEG were analyzed with microarrays of post-mortem brain tissue (frontal cortex) cohort of 29 schizophrenia cases and 30 controls. A Weighted Gene Co-expression Network Analysis (WGCNA) using the DEG was used to detect clusters of co-expressed genes that werenon-conserved between adult cases and controls brain samples. Results We identified methylation alterations potentially involved with neuronal differentiation in schizophrenia, which displayed an over-representation of genes related to chromatin remodeling complex (adjP?=?0.04). We found 228 DEG associated with neuronal differentiation. These genes were involved with metabolic processes, signal transduction, nervous system development, regulation of neurogenesis and neuronal differentiation. Between adult brain samples from cases and controls there were 233 DEG, with only four genes overlapping with the 228 DEG, probably because we compared single cell to tissue bulks and more importantly, the cells were at different stages of development. The comparison of the co-expressed network of the 228 genes in adult brain samples between cases and controls revealed a less conserved module enriched for genes associated with oxidative stress and negative regulation of cell differentiation. Conclusion This study supports the relevance of using cellular approaches to dissect molecular aspects of neurogenesis with impact in the schizophrenic brain. We showed that, although generated by different approaches, both sets of DEG associated to schizophrenia were involved with neocortical development. The results add to the hypothesis that critical metabolic changes may be occurring during early neurodevelopment influencing faulty development of the brain and potentially contributing to further vulnerability to the illness.
机译：背景精神分裂症是一种具有遗传和环境因素的神经发育障碍，虽然由于人类神经发育过程中难以接近患病组织，但其机制尚不清楚。这项研究的目的是发现精神分裂症中被破坏的神经元分化基因，并评估来自精神分裂症病例和对照的死后脑组织中的那些基因。方法我们分析了来自一名对照和一名精神分裂症患者的成纤维细胞的人诱导多能干细胞（hiPSC）中的差异表达基因（DEG），拷贝数变异（CNV）和差异甲基化，并进一步分化为神经元（NPC）。用死亡后脑组织（额叶皮层）队列的29名精神分裂症患者和30名对照的芯片分析DEG的表达。使用DEG的加权基因共表达网络分析（WGCNA）用于检测在成年病例和对照脑样本之间不保守的共表达基因簇。结果我们确定了精神分裂症中可能与神经元分化有关的甲基化改变，显示出与染色质重塑复合体相关的基因的过度表达（adjP？=？0.04）。我们发现228 DEG与神经元分化有关。这些基因参与代谢过程，信号转导，神经系统发育，神经发生调节和神经元分化。在病例和对照组的成人大脑样本之间有233个DEG，只有四个基因与228个DEG重叠，这可能是因为我们比较了单个细胞与组织的体积，更重要的是，这些细胞处于不同的发育阶段。病例与对照之间成人大脑样本中228个基因的共表达网络的比较显示，保守性较低的模块富含与氧化应激和细胞分化的负调控相关的基因。结论这项研究支持使用细胞方法解剖神经发生的分子方面并影响精神分裂症大脑的相关性。我们表明，尽管是通过不同的方法产生的，但与精神分裂症相关的两组DEG均与新皮层发育有关。结果增加了这样的假设，即在早期神经发育过程中可能发生关键的代谢变化，从而影响大脑的发育不良，并可能进一步加剧该病的易感性。

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