A central goal of CIRM is to develop methods for differentiating embryonic stem cells into defined tissues for regenerative medicine. This is currently an inefficient process because each cell type requires a unique differentiation regimen that its frequently inefficient. It has been difficult to identify a pathway in the cell that would have a general positive effect on all tissues. We believe we have found such a pathway that lies at the core of gene expression. We have designed a series of experiments in human and murine ES cells to test our idea. The simplicity of our idea is that it involves a protein termed HP1γ that substitutes a positively acting factor, Med26, for a negatively acting enzyme termed Cdk8. Our proposal is designed to provide a firm mechanistic understanding of this pathway and to target it using molecular methods. If successful, our work will pave the way for testing Cdk8 chemical inhibitors to promote differentiation in a wide range of systems. This is not an unrealistic goal as pharmaceutical companies are now targeting Cdk8 because it is also involved in cancer.
Statement of Benefit to California:
A major goal of CIRM is to create the framework for generating stem cell therapies that will be developed by California universities, hospitals and biotechnology companies. An understanding of how stem cells differentiate into various tissue types is essential for translating stem cell therapies into the clinic. Our research focuses on a general mechanism that we believe all stem cells use during differentiation. Our study provides both knowledge of how this mechanism influences differentiation and studies to apply it to neurons.