The ability of cells to adopt new fates—termed ‘plasticity’—is at the heart of the most powerful applications of stem cell-based regenerative medicine including induced human pluripotent and embryonic stem cells (IPSCs; ESCs). However, surprisingly the mechanisms regulating plasticity are mostly unknown. Our goal is to produce transformative knowledge about plasticity to bridge this important gap. The assumption in the field is that transcription factors such as Oct4 are the key plasticity regulators. We challenge that dogma with our hypothesis that plasticity is regulated by an exciting new mechanism involving histone proteins that control gene function. We hypothesize more specifically that a very unusual type of histone called H3.3 controls plasticity. H3.3 is the only histone in its family that exhibits flexibility in terms of how it binds to and regulates DNA function such as gene expression. We predict that the unique flexibility of H3.3 is integral to cellular plasticity. Using innovative tools including powerful mouse and human iPSCs and ESCs that lack H3.3, we will determine the role of H3.3 in plasticity. The proposed studies will catalyze cutting-edge new technological advances that will have great clinical significance for the stem cell and regenerative medicine fields. This work also has important implications for childhood brain tumors, where H3.3 is mutated. Overall, in these ways the potential for rapid transformative impact from this research is exceptional.
Statement of Benefit to California:
The proposed research will greatly benefit the State of California in a number of ways. The studies will be transformative for stem cell research leading to new medical therapies based on stem cells and regenerative medicine that will aid the people of California. The research also directly bears on cancer and knowledge gained may provide a foundation for new cancer therapies that benefit the State. New technologies may also be developed based on the data produced by the proposed work enabling economic development and increased employment in the State.