Statement of Benefit to California:
Year 1Regulation of Specific Chromosomal Boundary Elements by CTCF Protein Complexes in Human Embryonic Stem Cells
The genetic information contained in all human cells is arranged into distinct territories or “neighborhoods” with barriers or “fences” that protect the action in one neighborhood from spilling over into an adjacent region. In this way, one gene (A) can be working while its neighboring genes (B and C) are resting. As physiological conditions change in the body, appropriate signals are transmitted to cells that instruct genes to alter their genetic “programming” by opening or closing the fences. This allows gene A to be turned off and genes B and C to start working. Importantly, these “fences” can control large numbers of genes that regulate critical cellular processes. This proposal is designed to find the fences that border certain genes (Nanog-Stellar-GDF3) that are important to maintain stem cells in their most plastic state that is, having the ability to become any other cell type. During this funding period we have successfully identified the borders/fences of this chromosomal region in stem cells before and after their differentiation into adult cells. Our goal is now to define how the fences are open or closed. This will depend upon specific proteins that interact with the fences and serve as “latches” to keep the Nanog gene working or resting. We have identified one critical protein that interacts with the borders of the Nanog gene in both stem and differentiated cells. We are in the process of genetically removing this protein from stem cells to analyze how its loss affects Nanog gene regulation and stem cell functions. This information will contribute to the development of tools or therapies by which the Nanog gene can be selectively turned on or off. The ability to turn the Nanog gene on may facilitate stem cell self-renewal or reprogram adult somatic cells to progenitors that are more easily directed to another cell type. By contrast, the capacity to turn off the Nanog gene may be important for the treatment of stem cells that have acquired tumorigenic potential through persistent Nanog expression and inappropriate self-renewal.