Transcriptome of iPSC-derived neuronal cells reveals a module of co-expressed genes consistently associated with autism spectrum disorder

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Griesi-Oliveira, K. ^{[1, 2]} ; Fogo, M. S. ^{[1, 2]} ; Pinto, B. G. G. ^[2] ; Alves, A. Y. ^[2] ; Suzuki, A. M. ^[1] ; Morales, A. G. ^[1] ; Ezquina, S. ^[1] ; Sosa, O. J. ^[3] ; Sutton, G. J. ^[4] ; Sunaga-Franze, D. Y. ^[5] ; Bueno, A. P. ^[2] ; Seabra, G. ^[6] ; Sardinha, L. ^[2] ; Costa, S. S. ^[1] ; Rosenberg, C. ^[1] ; Zachi, E. C. ^[7] ; Sertie, A. L. ^[2] ; Martins-de-Souza, D. ^{[6, 8, 9]} ; Reis, E. M. ^[10] ; Voineagu, I. ^[4] ; Passos-Bueno, M. R. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Biociencias, Dept Genet & Biol Evolut, Sao Paulo - Brazil

^[2] Hosp Israelita Albert Einstein, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Programa Interunidades Posgrad Bioinformat, Sao Paulo - Brazil

^[4] Univ New South Wales, Sch Biotechnol & Biomol Sci, Sydney, NSW - Australia

^[5] Helmholtz Assoc, Max Delbruck Ctr Mol Med, Berlin - Germany

^[6] Univ Campinas UNICAMP, Inst Biol, Dept Biochem & Tissue Biol, Lab Neuroprote, Sao Paulo - Brazil

^[7] Univ Sao Paulo, Inst Psicol, Dept Psicol Expt, Nucleo Neurociencias & Comportamento, Sao Paulo - Brazil

^[8] Conselho Nacl Desenvolvimento Cient & Tecnol CNPq, Inst Nacl Biomarcadores Neuropsiquiatria INBION, Sao Paulo - Brazil

^[9] Univ Estadual Campinas, Expt Med Res Cluster EMC, Campinas - Brazil

^[10] Univ Sao Paulo, Inst Quim, Dept Bioquim, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: MOLECULAR PSYCHIATRY; v. 26, n. 5, p. 1589-1605, MAY 2021.
• Citações Web of Science: 14

Resumo

Evaluation of expression profile in autism spectrum disorder (ASD) patients is an important approach to understand possible similar functional consequences that may underlie disease pathophysiology regardless of its genetic heterogeneity. Induced pluripotent stem cell (iPSC)-derived neuronal models have been useful to explore this question, but larger cohorts and different ASD endophenotypes still need to be investigated. Moreover, whether changes seen in this in vitro model reflect previous findings in ASD postmortem brains and how consistent they are across the studies remain underexplored questions. We examined the transcriptome of iPSC-derived neuronal cells from a normocephalic ASD cohort composed mostly of high-functioning individuals and from non-ASD individuals. ASD patients presented expression dysregulation of a module of co-expressed genes involved in protein synthesis in neuronal progenitor cells (NPC), and a module of genes related to synapse/neurotransmission and a module related to translation in neurons. Proteomic analysis in NPC revealed potential molecular links between the modules dysregulated in NPC and in neurons. Remarkably, the comparison of our results to a series of transcriptome studies revealed that the module related to synapse has been consistently found as upregulated in iPSC-derived neurons-which has an expression profile more closely related to fetal brain-while downregulated in postmortem brain tissue, indicating a reliable association of this network to the disease and suggesting that its dysregulation might occur in different directions across development in ASD individuals. Therefore, the expression pattern of this network might be used as biomarker for ASD and should be experimentally explored as a therapeutic target. (AU)

• Processo FAPESP: 13/08028-1 - CEGH-CEL - Centro de Estudos do Genoma Humano e de Células-Tronco
• Beneficiário: Mayana Zatz
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 16/50324-5 - Gene expression analysis on in vitro neuronal models and post-mortem brain tissues to understand Autism Spectrum Disorder
• Beneficiário: Andréa Laurato Sertié
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 14/10068-4 - EMU concedido no processo 13/08711-3: espectrômetro de massas Waters SYNAPT G2-Si HDMs + nanoACQUITY UPLC
• Beneficiário: Daniel Martins-de-Souza
• Modalidade de apoio: Auxílio à Pesquisa - Programa Equipamentos Multiusuários