Statement of Benefit to California:
Year 1Human cells have a range of differentiation states from undifferentiated human embryonic stem cells to the terminally differentiated cells such as fibroblasts and other cells that make up the body. These differentiation states determine the functional identity of the cells to enable each cell to perform its function. Therefore, cellular differentiation is intimately linked to other cellular processes such as cell cycle and proliferation rate. In diseases such as cancer, cells become less differentiated while they gain increased capacity for autonomous cell cycling and proliferation. In stem cells, there is a balance between maintaining an undifferentiated state and regulated growth to prevent cancer formation but permit generation of progeny cells. Therefore it is important to understand how cellular differentiation is regulated. We hypothesized that epigenetic processes such as modifications of histone and other components of chromatin—the physiological form of the genome—can affect the cellular differentiation states by maintaining a stable gene expression pattern. We have found that this is indeed the case by examining the epigenetic patterns in a number of different cell types that span the range of differentiation states from different tissue types. We have found that a specific epigenetic pattern contributes to maintenance of chromatin in terminally differentiated cells representing different tissue types. Our data may inform in vitro reprogramming techniques such as iPS cell generation and have important implications for understanding how fully differentiated states are maintained in normal cells and reversed in cancer or other diseases.