Dissecting and Targeting Polycomb Dysregulation in Cancer

Cancer is a disease of cells that are defined by the abnormal ability to continue replicating. This characteristic immortality is conferred by maintaining a young, or progenitor-like state. We are gaining increasing appreciation that many cancers acquire these features through reorganization of the patterns by which their genome is packaged and structured, termed the epigenome. The epigenome provides information for cells to assume and preserve their identity, through a code of chemical modifications made to histone proteins that package DNA. A single chemical modification, termed H3K27me3, is central to specifying cell fates. Cancer cells recurrently display altered patterns of H3K27me3 throughout the epigenome. Furthermore, specific groups of cancers can be effectively treated in patients through administering drugs that diminish H3K27me3. We aim to systemically chart the ways that cancers reorganize H3K27me3, and precisely identify the causal role of these changes play to drive cancer growth. A newly developed technology allows us to target and remove specific genes within individual cells in a population, then study the consequences to their epigenome. We accomplish this by measuring H3K27me3 in each cell and delineating the genes that cause altered levels of the modification when lost. A second approach allows us to localize a designed tool to a specific region of a cancer cell's genome sequence and remove H3K27me3. By studying the consequence of this change to the cancer cell's growth, we can causally define the basis of why cancers require H3K27me3. This unbiased approach can systematically screen tens of thousands of potential factors that cancers may depend upon, providing an exhaustive picture of the pathways that could be targeted by drugs to treat cancers. Knowledge gleaned from this work further aims to help identify groups of cancer patients that will benefit from strategies targeting the epigenome.