SEX-SPECIFIC REGULATION OF NEURODEVELOPMENT AND BEHAVIOR BY CHD2 IN DROSOPHILA

Abstract

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder characterized by deficits in social communication, language delays, and restricted, repetitive behaviors. The etiology of ASD is multifactorial, involving both genetic and non-genetic factors, resulting in a heterogeneous phenotype. Notably, ASD exhibits a significant sexual dimorphism, with a higher prevalence in males. Genes that act as epigenetic modulators play an important role in contributing to ASD susceptibility. Chromodomain helicase DNA binding protein (CHD2) is a crucial chromatin regulator that has been widely implicated epilepsy, however there in neurodevelopment in context of sexual dimorphism remain poorly elucidated. This study investigates the dimorphic role of CHD2 in neurodevelopment and behaviors in its Drosophila ortholog dChd2. We investigate the dimorphic roles of CHD2 ortholog (dChd2) in Drosophila neural development and behavior. Our in-silico analysis revealed that CHD2/dChd2 are differentially expressed across sexes, in human and fly brain. Multiple sleep associated CHD2 mutation has been reported that causes deleterious effect on protein structure, confirmed by our in-silico analysis. Using multiple behavioral assays, we demonstrate that dChd2 manipulation resulted in modulation of locomotion, social interaction and sleep architecture in sex-specific manner. Furthermore, our findings revealed that dChd2 manipulation has sex specific effect on synaptic and neuronal activity in the brain and NMJ. RNA seq data revealed that dChd2 manipulation resulted in dysregulated genes related to synaptic function, neurodevelopment, circadian rhythm and sleep associated abnormalities. Additionally, these genes and pathways were highly enriched in males compared to female. The sexual dimorphism in dChd2-mediated chromatin regulation offers critical insights into the epigenetic mechanisms underlying sex-specific neurodevelopment. These findings hold significant implications for comprehending the sex-biased prevalence of neurodevelopmental disorders and associated sleep disturbances in humans, potentially opening new ways for sex-specific therapeutic interventions.

Date of Award	2025
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences