Mechanisms of SWI/SNF complex chromatin targeting selectivity - PROJECT SUMMARY Mammalian SWI/SNF (mSWI/SNF) is a multi-subunit, ATPase-dependent chromatin remodeling complex that regulates chromatin states by altering nucleosome occupancy. Numerous studies have provided compelling evidence that the SWI/SNF complex plays pivotal roles in development. Large-scale sequencing studies have found that members of the SWI/SNF complex are frequently mutated in various human diseases. Understanding the regulation and activity of SWI/SNF has profound implications for elucidating the roles of chromatin remodelers in both development and disease. A critical knowledge gap exists regarding how SWI/SNF precisely targets, establishes, and sustains lineage-specific enhancers, as well as how it cooperates with other regulators, such as pioneer factors. This obstacle is exacerbated by the structural diversity of SWI/SNF complexes, as there are three functionally distinct major subcomplexes. The goal of this proposal is to bridge this gap by investigating the distinct functional repertoires of the major SWI/SNF subcomplexes through a model of acute protein depletion. Our central hypothesis is that the cooperativity of SWI/SNF subcomplexes enables precise mosaic regulation of discrete chromatin states. We plan to test this hypothesis through the following specific aims: deconvoluting the cooperativity and competition between SWI/SNF subcomplexes (Aim 1), elucidating the role of SWI/SNF in 3D genome architecture (Aim 2), and exploring the role of SWI/SNF in potentiating cellular dynamics (Aim 3).
