Autism spectrum disorder (ASD) is a complex brain condition with a developmental etiology rooted in corticogenesis. Human genetics studies aimed at understanding the genetic etiology of ASD implicate chromatin regulation as a nexus of convergent neuropathology. Notably, histone post-translational modifications contribute to transcriptional plasticity pivotal to differentiation and acquisition of new cellular identities. Mono-ubiquitination of histone H2A (H2AUb1) is a reversible, transcriptionally repressive histone modification.

Stephanie Bielas and colleagues identified de novo dominant truncating variants in ASXL3 as the genetic basis of Bainbridge Ropers Syndrome and syndromic ASD¹. ASXL3 is a component of the polycomb repressive deubiquitinase (PR-DUB) complex which deubiquitinates H2A. Bielas’s laboratory subsequently identified dysregulation of H2AUb1 as a key molecular pathology in primary cells derived from individuals with Bainbridge Ropers Syndrome².

Bielas and her team generated an Asxl3 null mouse to investigate Asxl3-dependent neuropathology further. In preliminary studies, funded by a previous SFARI Director Award, they observed increased levels of genome-wide H2AUb1 in the mutant mice. They also found a significant reduction in layer 5 (L5) cortical neurons, which correlated with altered timing of cortical neuron fate acquisition during corticogenesis. These findings are poignant in light of human postmortem evaluations that implicate cytoarchitectural disorganization of the cerebral cortex in ASD.

In the current project, Bielas’ team aims to extend these studies to better understand the role that Asxl3-dependent deubiquitination activity plays in specifying neural progenitor cell (NPC) transcriptional programs that instruct the neuronal diversity of the cortex. Specifically, they plan to build on the robust, highly penetrant cortical lamination defect observed in Asxl3 mutant mice to assess epigenomic changes in NPCs that accompany dysregulation of genome-wide H2AUb1 distribution and to identify molecular networks that determine L5 cortical neuronal fate.

Results from these studies are expected to identify epigenomic mechanisms that regulate cortical neuron fate restriction and novel proneural targets of ASD pathology. This will lay the foundation for future studies correlating cortical neuron and circuit abnormalities to ASD neurological and behavioral deficits.