De novo dominant variants in ASXL3 are the genetic basis of ASXL3-related disorder (ARD), a developmental disorder with pronounced neurological symptoms. ASXL3 is a component of the polycomb repressive deubiquitinase (PR-DUB) complex, which removes the mono-ubiquitination of histone H2A (H2AUb1)—a conserved, traditionally repressive histone mark. While large-scale genetic studies of neurodevelopmental disorders have highlighted the importance of such epigenetic regulation, the role of ASXL3-mediated H2AUb1 in corticogenesis, and the impact of ARD variants, is unclear. As such, we aim to investigate on a genetic and molecular level how ASXL3 mediates H2AUb1 regulation and its consequences on neurodevelopment. To do so, we are using transcriptomic and epigenomic techniques to probe a cohort of CRISPR-edited and patient-derived cell lines. In both neural progenitor cells and cortical brain organoids, we see ASXL3-dependent defects in transcription and neuronal differentiation.
