Co-expression network of neural-differentiation genes shows specific pattern in schizophrenia

BMC Medical Genomics

Helena Brentani²  Stevens Rehen⁷  Joana A Palha⁴  Dirce M Carraro⁶  Ana CV Krepischi⁵  Henrique Vieira¹  Paulo Belmonte-de-Abreu³  Bruna da Silveira Paulsen⁷  Daniel Mariani¹  Leandro Lima¹  Renato Puga⁸  Ana C Tahira²  Mariana Maschietto² 

[1] Post-graduation Program Institute of Mathematics and Statistics, University of Sao Paulo, São Paulo, SP, Brazil;Institute of Psychiatry-University of Sao Paulo, Medical School (FMUSP), São Paulo, SP, Brazil;Department of Psychiatry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil;Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal;Institute of Biosciences, University of São Paulo, São Paulo, SP, Brazil;International Research Center-AC Camargo Cancer Center, São Paulo, Brazil;Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil;Hospital Israelita Albert Einstein, São Paulo, Brazil

关键词: Oxidative stress;    Module analyses;    Neuronal differentiation;    Gene network;    Schizophrenia;   

Others  :  1210998
DOI  :  10.1186/s12920-015-0098-9

 received in 2014-10-23, accepted in 2015-05-05,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Maschietto et al.; licensee BioMed Central.

【 图 表 】

Figure 3.

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