Recent cancer genome sequencing studies have uncovered frequent mutations in genes encoding subunits of nuclear protein complexes involved in chromatin remodeling and epigenetic regulation. We are interested in using a combination of chemical and biochemical techniques to uncover the role of chromatin structure in tumor suppression. Uncovering the mechanisms of these complexes will reveal potential therapeutic avenues for cancers that currently have few therapeutic options, such as renal clear cell carcinoma and ovarian clear cell carcinoma. Three areas of research we are currently pursuing are:
- Quantitative mass spectrometric analysis of chromatin remodeling complexes. While different subunits of the SWI/SNF chromatin remodeling complexes are mutated in approximately 20% of human malignancies, in any particular cancer the mutations are often found only in one particular subunit. Cell type specific expression of homologous subunits or interaction with cell type specific factors may explain this phenomenon. We plan to use mass spec to analyze the complex subunits and associated factors in cancer lines with and without mutations in the SWI/SNF complex.
- High throughput screening to identify inhibitors of chromatin remodelers. Aberrant function of chromatin remodelers can occur upon the deletion of a tumor-suppressive particular subunit. For example, malignant rhabdoid tumors occur when the SNF5 subunit of SWI/SNF is deleted. These tumors are dependent on the function of the remaining complex, making it a potential drug target. In addition to pursuing potential pharmaceuticals, we hope to use small molecule inhibitors of chromatin remodeling complexes to probe the mechanism and kinetics of chromatin remodeling in vivo.
- Elucidating the function and genome-wide targeting of chromatin binding domains, such as bromodomains, PHD domains and chromodomains. We wish to understand how the targeting domains found in subunits of chromatin remodeling complexes contribute to their biological function. We plan to identify histone modifications bound by these domains and to relate this information to genome wide ChIP-seq studies performed with and without deletions of these domains. Through these studies we hope to identify if the deletion of specific subunits of chromatin remodelers in cancer leads to changes in targeting across the genome and a subsequent alteration in the transcription of known oncogenes or tumor suppressors.