Elucidating the Molecular Mechanisms that Establish and Maintain Global Histone Modifications
Histone modifications regulate basic processes such as transcription and are altered commonly in human disease including cancer. Studies of histone modifications have been, by and large, focused on gene-to-gene differences in their occurrences. However, when examined at the level of single nuclei (i.e., cellular or global levels), individual cells exhibit dissimilar levels of specific histone modifications, generating cellular diversity in epigenetic patterns in cell populations. Unlike gene-specific histone modifications, the biological significance of the cell-to-cell variability in histone modifications, or the underlying mechanisms, are very poorly understood. In the case of cancer, we demonstrated recently that cellular epigenetic heterogeneity is not stochastic but occurs in a stereotypical pattern that predicts clinical outcome of cancer patients, indicating for the first time that important information is embedded in cellular epigenetic diversity. We showed this initially for prostate cancer but, remarkably, the same pattern of cellular epigenetic heterogeneity also predicts outcome in cancers of lung, kidney and breast. Our findings have uncovered a specific signature of cellular epigenetic heterogeneity common to carcinomas of different tissue origins, suggesting the existence of a fundamental molecular process regulating global levels of histone modifications. This proposal aims to define the mechanisms that generate this novel cell-to-cell variability in the global levels of histone modifications. Through a genetic screen in yeast, we have identified a phosphatidylinositol 3-kinase (PI3K) as a regulator of global histone acetylation. In Aims 1 and 2, we propose to elucidate the role of PI3K signaling in maintenance of global histone acetylation and its relevance to cancer. In Aim 3, we will utilize human RNAi libraries to conduct a high-throughput screen to identify regulators of global histone modifications in cancer cell lines. Our results will determine the mechanisms that regulate histone modification levels in individual cells, and how these mechanisms might be deregulated in human cancer.
Arnold O. Beckman exemplifies the meaning of the word humanitarian. Combined with his unwavering enthusiasm for life, his keen sense of humor and his strong moral and ethical principles, he is a national icon.