Putative contributions of the sex chromosome proteins SOX3 and SRY to neurodevelopmental disorders

Abstract

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.

Sex differences in gene regulatory networks during mid-gestational brain development

“…Altogether, our study provides evidence that autosomal genes related to biological functions pertinent to neurodevelopment are differentially regulated between sexes. The mechanisms that are possibly responsible for these differences are the gonadal hormones, the sex chromosomes, and the sex-specific epigenetic events (McCarthy, 2016 ; Maschietto et al, 2017 ; Tahira et al, 2018 ). Our findings reinforce that CREB and MYC participate directly in the pathways that differentiate males from females during development (Auger, 2003 ), and that gene expression regulation of genes involved in metabolism, proliferation, and delamination contribute to neurodevelopmental differences between males and females.…”

“…Indeed, previous studies have described the association between males' lower adaptability to gestational stress and neuropsychological development deficits (Fink et al, 2018 ). These differences between males and females are partially attributed to differences in DNA methylation and sex chromosomes transcription factors (TFs), both being associated with the regulation of autossomal genes related to neurodevelopmental disorders (Maschietto et al, 2017 ; Tahira et al, 2018 ). In fact, TFs are mediators of cell responses to environmental stimuli and therefore are critical to proper brain development, being associated with multiple NDs including ASD (Santos-Terra et al, 2021 ).…”

Y chromosome is moving out of sex determination shadow

“…Furthermore, exclusive SRY or SOX3 target genes were found to be more associated with the late gestational and postnatal periods. Analysis of co-expressed networks of SOX3/SRY target genes provided new evidence for the regulatory role of SOX3 in both sexes while SRY exclusively contributes to ASD male predisposition [ 46 ]. Loss of chromosome Y (LOY), a mosaic aneuploidy which mainly detected in circulating white blood cells, has been considered as one of the underlying causes of aging-related diseases [ 47 , 48 ].…”

Diferenças sexuais nas redes de regulação gênica durante o período fetal do neurodesenvolvimento

“…Em relação às diferenças sexuais, existem evidências de que indivíduos do sexo feminino priorizam vias lipídicas, tanto sintetizando quanto consumindo mais lipídeos (OCKNER et al, 1979) De forma geral, este estudo fornece evidências de que genes autossômicos relacionados a funções biológicas pertinentes ao neurodesenvolvimento são diferencialmente regulados entre os sexos. Os mecanismos responsáveis por esta diferença são possivelmente os cromossomos sexuais, os hormônios esteróides sexuais e eventos epigenéticos sexo-específicos (TAHIRA et al, 2018;MCCARTHY;NUGENT, 2015;MASCHIETTO et al, 2017). Os resultados reforçam as evidências da literatura que implicam CREB e MYC diretamente nas diferenças do desenvolvimento entre homens e mulheres (AUGER, 2003), e que a regulação da expressão de genes envolvidos no metabolismo, proliferação e organização da matriz extracelular são relevantes para vias de sinalização que contribuem para as diferenças sexuais do neurodesenvolvimento.…”

“…O presente estudo propõe-se a executar estas análises e, por este motivo, é importante entender como se dão as diferenças de regulação da expressão gênica entre os sexos. contribuí para tais diferenças(TAHIRA et al, 2018). A proteína SRY, codificada no cromossomo Y, é homóloga ao SOX3(CORTEZ et al, 2014), e sua expressão no cérebro humano adulto foi demonstrada por uma série de experimentos(MAYER et al, 1998;DEWING et al, 2006;CZECH et al, 2012).…”