Mechanisms of SWI/SNF complex assembly and function

Project Summary Chromatin remodeling complexes play a critical role in regulating gene expression, differentiation, and development. The SWI/SNF chromatin remodeling complex is mutated in ~25% of all human tumors. The 12-15 positions within SWI/SNF are filled from ~30 unique subunits. The combinatorial assembly of these genes can yield 1000-2000 biochemically distinct complexes . While often studied as a single complex, these biochemically distinct forms of SWI/SNF have different functions in gene regulation.Understanding the mechanisms that regulate SWI/SNF function, and that are therefore disrupted in SWI/SNF mutant tumors, is of critical importance for developing new therapies. We propose that post-translational modifications of SWI/SNF and interactions between SWI/SNF and RNA modulate function of the complex. Understanding how these mechanisms contribute to how different SWI/SNF complexes are defined is the focus of my lab. The key questions we will address in this project are 1.) Do variant SWI/SNF complexes have different functions? 2.) What regulates different activities of biochemically distinct complexes? 3.) How are changes to the composition and the targeting of complexes regulated? Our lab combines computational, molecular, and biochemical analyses to answer these questions and develop deeper insight into the mechanisms of SWI/SNF activity. Over the next five years, we will investigate mechanisms that combine to regulate the composition and function of SWI/SNF and determine how different functional outcomes are mediated by distinct SWI/SNF complexes. Given the critical role of SWI/SNF in development and disease, understanding how the complex is regulated to mediate different outcomes is critical for developing new approaches to targeting cancer and other diseases.