Program > Browse abstracts by speaker > Dorazehi Fereshteh

Mutations in epigenetic or chromatin regulators are a frequent cause of neurodevelopmental disorders. MORC2 is a chromatin modifying ATPase in which missense mutations lead to syndromes diagnosed as Charcot-Marie-Tooth disease and spinal muscular atrophy. At a molecular level, MORC2 is associated with human silencing hub (HUSH) complex in epigenetic silencing of transgenes and repetitive genetic elements including L1 retrotransposons and protocadherin genes. However, whether and how these functions are perturbed in MORC2 neurodevelopmental disorders is largely unknown. In this study we use a 3D organoid model to study the role of MORC2-mediated gene and transposon silencing in human brain development. CRISPR gene-editing was used in human induced pluripotent stem cells (hiPSCs) to generate clones bearing two neurodevelopmental disorder disease mutations (E27K, S87L) in the MORC2 gene. Undirected cerebral organoids were generated from each hiPSC line. To show how these mutations influence early neural development; transcriptomic, epigenomic and morphological analysis were performed at different time points of organoid culture. Interestingly, we observed distinct molecular phenotypes of repeat element deregulation in the two disease mutants, in line with previous data suggesting that loss- and gain-of-function effects may arise from different disease genotypes. Our findings provide a molecular and functional basis for understanding MORC2 neurodevelopmental disorders and represent an example of repetitive element deregulation as a potential driver of neurological disease.