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Tahira, Ana Carolina ; Barbosa, Andre Rocha ; Feltrin, Arthur Sant'Anna ; Gastaldi, Vinicius Daguano ; Calegari de Toledo, Victor Hugo ; de Carvalho Pereira, Jose Geraldo ; Garcia Lisboa, Bianca Cristina ; de Souza Reis, Viviane Neri ; Feio dos Santos, Ana Cecilia ; Maschietto, Mariana ; Brentani, Helena

• Tipo de documento: Artigo Científico
• Fonte: AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS; v. 180, n. 6, p. 25-pg., 2019-09-01.

Resumo

The male-biased prevalence of certain neurodevelopmental disorders and the sex-biased outcomes associated with stress exposure during gestation have been previously described. Here, we hypothesized that genes distinctively targeted by only one or both homologous proteins highly conserved across therian mammals, SOX3 and SRY, could induce sexual adaptive changes that result in a differential risk for neurodevelopmental disorders. ChIP-seq/chip data showed that SOX3/SRY gene targets were expressed in different brain cell types in mice. We used orthologous human genes in rodent genomes to extend the number of SOX3/SRY set (1,721). These genes were later found to be enriched in five modules of coexpressed genes during the early and mid-gestation periods (FDR < 0.05), independent of sexual hormones. Genes with differential expression (24, p < 0.0001) and methylation (40, p < 0.047) between sexes were overrepresented in this set. Exclusive SOX3 or SRY target genes were more associated with the late gestational and postnatal periods. Using autism as a model sex-biased disorder, the SOX3/SRY set was enriched in autism gene databases (FDR <= 0.05), and there were more de novo variations from the male autism spectrum disorder (ASD) samples under the SRY peaks compared to the random peaks (p < 0.024). The comparison of coexpressed networks of SOX3/SRY target genes between male autism and control samples revealed low preservation in gene modules related to stress response (99 genes) and neurogenesis (78 genes). This study provides evidence that while SOX3 is a regulatory mechanism for both sexes, the male-exclusive SRY also plays a role in gene regulation, suggesting a potential mechanism for sex bias in ASD. (AU)

• Processo FAPESP: 14/00591-1 - Estudos de redes de co-expressão gênica do córtex orbitofrontal e estriado (estudo post-mortem) de indivíduos portadores de TOC e controles
• Beneficiário: Bianca Cristina Garcia Lisboa
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 15/06281-7 - Investigação da regulação epigenética em tumores sólidos pediátricos
• Beneficiário: Mariana Camargo Maschietto
• Modalidade de apoio: Bolsas no Brasil - Jovens Pesquisadores
• 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
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 11/04956-6 - Variações no Número de Cópias no Genoma de Pacientes com Transtornos do Espectro Autista verbais e não verbais
• Beneficiário: Viviane Neri de Souza Reis
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 14/10488-3 - Comparação de métodos de priorização de genes associados a transtornos do neurodesenvolvimento
• Beneficiário: Arthur Sant'Anna Feltrin
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 11/14658-2 - Variação no número de cópias no genoma de pacientes com transtorno obsessivo compulsivo e pacientes com transtornos do espectro autista com interesses restritos e comportamentos repetitivos
• Beneficiário: Helena Paula Brentani
• Modalidade de apoio: Auxílio à Pesquisa - Regular