Abstract
BackgroundSchizophrenia 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.MethodsWe 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.ResultsWe 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.ConclusionThis 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-015-0098-9) contains supplementary material, which is available to authorized users.
Highlights
Schizophrenia is a neurodevelopmental disorder with genetic and environmental factors contributing to its pathogenesis, the mechanism is unknown due to the difficulties in accessing diseased tissue during human neurodevelopment
We showed that neural progenitor cells (NPCs), derived from human induced pluripotent stem cells (hiPSC) from skin fibroblasts of a schizophrenic patient had a 2-fold increase in extramitochondrial oxygen consumption compared to normal controls, and correspondingly elevated levels of reactive oxygen species (ROS), which was reduced to control levels by addition of valproic acid [24]
Characterization of molecular alterations potentially interfering with gene expression To refine the identification of genes regulated during neuronal differentiation, copy number alterations were characterized by array comparative genomic hybridization (CGH)
Summary
Schizophrenia is a neurodevelopmental disorder with genetic and environmental factors contributing to its pathogenesis, the mechanism is unknown due to the difficulties in accessing diseased tissue during human neurodevelopment. A co-expression module analysis from patients with schizophrenia (SCZP) and controls of seven studies showed that the top-modules of each study displayed a significant enrichment of neuronal markers as well as genes related to the electron transport chain and oxidative phosphorylation biological processes [15]. These alterations, through the analyses of genes and proteins, can be found in the peripheral blood suggesting that they are potential molecular markers for diagnosis or follow-up [16,17,18,19]
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