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

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Maschietto, Mariana ^{[1, 2]} ; Tahira, Ana C. ^{[1, 2]} ; Puga, Renato ^[3] ; Lima, Leandro ^[4] ; Mariani, Daniel ^[4] ; Paulsen, Bruna da Silveira ^[5] ; Belmonte-de-Abreu, Paulo ^[6] ; Vieira, Henrique ^[4] ; Krepischi, Ana C. V. ^[7] ; Carraro, Dirce M. ^[8] ; Palha, Joana A. ^{[9, 10]} ; Rehen, Stevens ^{[5, 11]} ; Brentani, Helena ^{[1, 2, 12, 13]}

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^[1] Univ Sao Paulo, Med Sch USP, Med Invest Lab 23 LIM23, Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Med Sch FMUSP, Inst Psychiat, Sao Paulo, SP - Brazil

^[3] Hosp Israelita Albert Einstein, Sao Paulo - Brazil

^[4] Univ Sao Paulo, Postgrad Program, Inst Math & Stat, Sao Paulo, SP - Brazil

^[5] Univ Fed Rio de Janeiro, Inst Biomed Sci, Rio De Janeiro - Brazil

^[6] Univ Fed Rio Grande do Sul, Dept Psychiat, Porto Alegre, RS - Brazil

^[7] Univ Sao Paulo, Inst Biosci, Sao Paulo, SP - Brazil

^[8] AC Camargo Canc Ctr, Int Res Ctr, Sao Paulo - Brazil

^[9] Univ Minho, Sch Hlth Sci, Life & Hlth Sci Res Inst ICVS, Braga - Portugal

^[10] ICVS 3Bs PT Govt Associate Lab, Braga, Guimaraes - Portugal

^[11] DOr Inst Res & Educ IDOR, Rio De Janeiro - Brazil

^[12] Univ Sao Paulo, Med Sch FMUSP, Dept Psychiat, BR-05403010 Sao Paulo, SP - Brazil

^[13] CNPq, Natl Inst Dev Psychiat Children & Adolescents, Sao Paulo, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: BMC MEDICAL GENOMICS; v. 8, MAY 16 2015.
• Citações Web of Science: 21

Resumo

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. (AU)

• Processo FAPESP: 14/00041-1 - Estudo de coexpressão de genes do cromossomo Y e genes autossômicos e sua relação com o transtorno do espectro autista (TEA)
• Beneficiário: Ana Carolina Tahira
• Linha de fomento: Bolsas no Brasil - Pós-Doutorado