Effects of forebrain ATRX deficiency in C57BL/6 male mice on offspring ATRX expression and forebrain development
LE3 .A278 2019
Bachelor of Science
Early life experience and degree of parental-infant attachment influence brain development, notably areas that support stress regulation, cognition and social behaviours. Animal models examining gestational stress suggest that sustained changes in gene expression in response to prenatal stress and/or natural variations in mother-pup interactions during the first week of postnatal life is mediated by changes in chromatin structure and DNA methylation. Although the exact mechanism is not completely understood, the chromatin remodeling factor ATRX is regulated by maternal care. ATRX is essential for brain development and plays a key role in gene expression regulation. ATRX exerts its effects by binding to heterochromatin resulting in epigenetic modifications, such DNA demethylation, responsible for downstream gene activation. ATRX is regulated and finely tuned; small changes in expression can cause synaptic deficits contributing to neurodevelopmental disorders, such as autism. Siblings of children with autism have an increased relative risk of autism themselves, suggesting a role of Atrx and environment interactions in the etiology of autism. We examined brain weight, Atrx gene expression and Atrx gene promoter methylation in brain regions relevant to autistic-like behaviours in the adult offspring of litters containing either wildtype female and male mice or wildtype female and Atrx hemizygous male mice. Our findings demonstrate a persistent effect on forebrain growth, Atrx gene expression and promoter methylation, not only in the ATRX deficient male mice, but also in their female litter mates. These results suggest that early life environment and ATRX play a role in mechanisms underlying long-term chromatin plasticity and neural growth relevant to neurodevelopmental disorders such as autism.
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