ATP-Dependent Chromatin Remodeling in Human Malignancy

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Project Summary ATP-Dependent Chromatin Remodeling in Cancer Chromatin and epigenetic regulators have emerged as important contributors to human cancer. The subunits of the mSWI/SNF or BAF ATP-dependent chromatin remodeling complex are mutated in over 20% of human cancers. In addition, several other ATP-dependent remodelers make important contributions to the pathogenesis of specific cancers. These complexes often function as genetically dominant tumor suppressors, however the BAF complex also plays oncogenic roles in synovial sarcoma and squamous cell carcinoma. Despite their prevalent roles in human cancer their oncogenic mechanism(s) remain unclear and a detailed molecular understanding, necessary for therapeutic development, has been elusive. One of the most well documented roles of BAF complexes is their opposition to Polycomb Repressive Complexes (PRC) complexes. Indeed, BAF subunits were discovered in flies as suppressors of PRC1 mutations. In addition, inhibition of PRC is therapeutic in some cancers having loss of function mutations in the BAF complex. However, the mechanisms underlying the opposition between BAF chromatin remodeling complexes and Polycomb complexes is still unclear. We will obtain a detailed understanding of the physical interaction between these complexes and explore their oncogenic roles with the goal of identifying potential sites of therapeutic intervention. One possible mechanism underlying the BAF-PRC opposition is the potential of BAF complexes to exchange or evict nucleosomes modified by PRC1 and 2. Measured rates of nucleosome exchange by several techniques and by several groups show that nucleosomes exchange several times per cell cycle. This observation seems inconsistent with the widely held concept that histone and/or nucleosome modifications are the basis of epigenetic and phenotypic stability. Another way of stating this is “why do the 32 SNF2-like ATP-dependent remodelers encoded in the mammalian genome not quickly erase all histone modifications by nucleosome exchange? This conflict would be resolved if nucleosome exchange by ATP- dependent remodelers was selective to a specific remodeler and a specific nucleosomal modification. Thus, we are developing two new techniques that will fill this gap in our knowledge by measuring exchange of specifically modified nucleosomes and attributing them to specific remodelers, including their post translational or oncogenic modifications. These techniques should allow the understanding of the paradox that rates of nucleosome exchange appear to be far faster than the rate of change of histone modifications. We will use these techniques to assign changes in the epigenetic landscape to specific ATP-dependent chromatin regulators and to understand the stability of epigenetic histone modifications in normal and malignant cells. At the conclusion of our studies, we hope to have a deeper and more detailed understanding of both the normal and oncogenic mechanisms related to mutation or dysfunction of the mSWI/SNF or BAF chromatin remodeling complex.