A study of the entire multi-subunit BAF (mSWI/SNF) complex loss in global epigenetic regulation of cerebral cortex development

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The diversity of projection neurons in cerebral cortex is generated from pluripotent ventricular radial glial progenitors (vRGs). The chromatin and epigenetic regulation are essential for appropriate and timely gene expression in systems such as embryonic stem cells.However, such mechanism assumed to coordinate the activation or repression of gene expression programs during the acquisition of distinct neural cell fates of vRGs in cortical development, are largely unknown. In this proposal, we investigate the roles of multi-subunit chromatin remodeling BAF complexes in cortical development. At least 15 subunits assemble combinatorially to generate an extensive diversity of complexes with specialized functions in specific tissues. A loss of one BAF subunit often affects the local chromatin structure and a specific transcriptional program. Nevertheless, thus far a full understanding of BAF complexes in development is not possible due to the lack of animal mutants for the entire multi-subunit BAF complexes. Recently, we generated cortex-specific double conditional knock-out (dcKO) mice for BAF155 and BAF170 subunits. Strikingly, the loss of BAF155 and BAF170 subunits in dcKO mutants eliminates all known BAF subunits in cortical tissues and primary neurons. In addition, the loss of BAF complex resulted in a global increase in repressive marks with a concurrent overall reduction in active marks of chromatins. The generated dcKO mutants thus provide a novel powerful tool to investigate the roles of entire BAF complexes in cortical development. The main aim of this project is to examine the roles of chromatin remodeling in corticogenesis, with a focus on how chromatin regulation by BAF complex controls neural gene expression programs during cortical neurogenesis, using a combination of genetic manipulation, genomic and proteomic approaches.