The BAF chromatin remodeling complex in experience-induced neuronal gene transcription and synapse maturation; implications for autism spectrum disorders

PROJECT SUMMARY Neurodevelopmental disorders (NDDs), especially autism spectrum disorders (ASD), are alarmingly prevalent among our children. Recent genome-wide studies suggest a strong correlation between ASD and loss-of-function mutations in genes encoding subunits of a particular chromatin remodeling complex, called the Brahma Associated Factor (BAF; alias, mSWI/SNF). However, despite such strong correlation, the precise role(s) of the neuronal BAF (nBAF) complex in brain development-related gene transcription remains largely unclear. In response to the NIH funding opportunity titled, ‘Cellular and Molecular Biology of Complex Brain Disorders’ (PAR-24-025), this project is designed to elucidate neurodevelopmental functions of SMARCC2 (fundamental biology), a high confidence ASD candidate gene product of the BAF complex. In working with SMARCC2, our project will organically extend to other subunits of the BAF complex, many of which are also implicated in NDDs. SMARCC2 and several other members of the BAF complex feature unstructured Intrinsically Disordered Regions (IDR), which will be the focus of this study. Our central hypothesis is: ‘In maturing neurons, the nBAF complex drives RNA Pol2 productive elongation (molecular role), and thereby synapse maturation (cellular role) via IDR-mediated multivalent interactions’. This hypothesis will be tested via two specific aims: 1) determine if nBAF and its core subunit SMARCC2 mediates RNA Pol2 elongation via IDR-dependent multivalent interactions and liquid-liquid phase separation (LLPS), and 2) determine if the nBAF complex, via transcription of synapse-related genes, regulates synapse maturation. We will use pharmacological nBAF complex inhibitors and degraders, RNAi of key BAF subunits, and genetically encoded expression of mutated BAF subunits to perform studies both in vitro and in vivo. Taken together, this study will generate valuable insights into nBAF complex functions and epigenetic mechanisms driving normal and altered ASD-related neurodevelopment, which will fill in the knowledge gap between BAF mutations and their outcomes, such as ASD. Our findings will also have broader implications in other fields, such as cancer, where BAF subunit mutations are quite common.