Chromatin remodeling plays a critical role in regulating all processes that require access to DNA. There are four families of chromatin remodelers, defined by the ATPase subunit of the complex. Although each family is often treated as a singular entity, in reality, the composition of remodeling complexes can vary greatly based on the inclusion of different subunits. Changes to composition are found throughout development and disease, and are especially frequent in cancer. The details of how altered chromatin remodeler composition contributes to disease is complicated by the myriad combinations possible and remains poorly understood. The goal of my lab is to understand how the composition of a chromatin remodeling complex is regulated, and how altered chromatin remodeling disrupts normal chromatin state and contributes to disease. My work integrates quantitative genomics, biochemistry, and molecular biology to develop a mechanistic understanding of how changes to the composition of a chromatin remodeling complex affects its function. Currently, we are focused on defining the mechanisms that control the activity and composition of the SWI/SNF complex. Additionally, given that SWI/SNF subunits are mutated in approximately 20% of liver tumors, we are interested in understanding how disruption of this complex contributes to liver disease and liver cancer.
How is composition and assembly of the SWI/SNF complex regulated?
SWI/SNF is the chromatin remodeler that best exemplifies the idea of compositional heterogeneity. More than half of its 12-15 subunits can be filled by mutually exclusive proteins. Despite the many studies on the function of SWI/SNF, considerably fewer have focused on regulation of assembly and composition of the complex. My previous work demonstrated significant context-dependence in SWI/SNF activity, but major questions remain about how this activity is regulated. My lab has interest in using in-house generated ChIP-seq and ATAC-seq data combined with publically available genome wide data sets, such as ENCODE, to determine what different co-factors help to define the targets and function of different forms of the SWI/SNF complex. Additionally mechanisms that may control SWI/SNF composition and function such as post-translational modifications of the complex and the role of RNA in regulating SWI/SNF localization or activity are areas we have ongoing efforts.
How do mutations in SWI/SNF subunits alter chromatin and drive tumor formation?
Incidence of liver cancer is rising, and new approaches to understanding this disease are needed. Among the most commonly mutated genes in liver cancer are three of the mutually exclusive subunits of SWI/SNF (ARID1A, ARID1B, and ARID2), which are mutated in 20% of liver tumors. Liver cancer is the ultimate outcome of a progressive disease that begins with fibrosis. Currently, little is known about the chromatin changes that occur during liver disease progression, or how disruption of SWI/SNF function drives the development of liver cancer. Our lab is interested in determining how disruption of the SWI/SNF complex contribute to liver disease, whether different forms of the SWI/SNF complex give rise to tumors through distinct mechanisms, and generating novel SWI/SNF-dependent tumor models using high-throughput in vivo CRISPR editing.