Non-Canonical Functions of Polycomb Complexes in Health and Disease

About This Grant

Project Summary My laboratory investigates epigenetic mechanisms in health and disease. In 1R01GM141349-01A1, we proposed to investigate the mechanisms by which the E3-ligase RING1B, a core member of the Polycomb Repressive Complex 1 (PRC1), positively regulates the expression of oncogenic pathways in breast cancer. In 1R01GM146409-01, we proposed to study how the epigenome is remodeled, and genome instability is regulated, by the loss of H3K36me and Polycomb complexes (PRC1/2) in head and neck squamous cell carcinoma (HNSCC). By converting both R01s to a MIRA-R35 under the unifying umbrella of “Non-canonical functions of Polycomb complexes,” we intend to continue working on the aims we proposed in both grants and expand our research program. New research programs include to determine the role of the RING1B paralog RING1A in gene regulation in breast cancer (both in the settings of sensitive and resistance to current therapies) and the identification and characterization of the first set of non-histone substrates of RING1A and RING1B. To address these questions, we will use multiple model systems including new and established breast and HNSCC cellular models, knock-in (KI) and knock-out (KO) cell lines, patient-derived organoids (PDO), xenografts (PDX), and orthotopic xenograft models, biochemistry and mass spectrometry assays. These efforts aim to unravel novel epigenetic mechanisms deregulated in cancer to develop novel targeted therapeutic strategies, encompassing potential combinations with anti-epigenetic compounds. We also propose another original research program aiming to decode the role of novel de novo missense mutations on PRC1 genes that drive neurodevelopmental disorders. This is particularly significant because the prevalence of neurodevelopmental disabilities in children has risen sharply in recent years, while their underlying causes remain largely unknown and insufficiently studied. To address this, we generated the first set of mouse models, along with human and mouse embryonic stem cells, engineered to carry PRC1 variants newly identified by us in individuals with neurodevelopmental disorders. Our research into genetic disorders not only will provide clinical insights but also reveal fundamental mechanisms by which chromatin regulates brain development and neuronal networks underlying cognition. Overall, our program will uncover fundamental mechanisms of gene regulation that profoundly influence cell identity, differentiation, and oncogenesis, while paving the way for precision medicine and enhanced interventions for cancer and developmental disabilities.