During development, the process of differentiation results in cells taking on the characteristics of their final forms, known as cell fate. One of the most important aspects of cell fate is the regulation of gene expression, such that the genes needed for a particular fate are turned on and other genes are turned off. Precise control of gene expression is needed to establish and maintain proper cell fate as well as to prevent dedifferentiation. Dedifferentiation happens when a cell becomes more like a stem cell and no longer only expresses genes associated with its final cell fate. Dedifferentiation occurs commonly in human cancer cells. It is especially important that genes normally expressed in germ cells (sperm and eggs) are repressed in non-germline cells, known as somatic cells. Since germ cells have special properties that allow them to continue dividing, expression of germ cell genes in somatic cells can cause somatic cells to divide in unregulated ways leading to tumors. In fact some tumors can be marked by the expression of germline genes, which is correlated with more advanced tumor stages, cells that are less differentiated, and is ultimately associated with poorer patient outcomes. While much is known about the pathways that act to repress somatic gene expression within the germline, there is an important gap in our knowledge about the pathways that act to repress germline gene expression within somatic cells. We are working with the model nematode, C. elegans, for which development is very well mapped and there exist sophisticated genetic tools to determine pathways that are important for germline gene repression in somatic cells. Our work in C. elegans has shown that synMuv B proteins are required to repress germline genes in the somatic cells. We hypothesize that repression of germline gene expression in the soma by synMuv B proteins is dependent upon specific temporal and spatial events during development. In this proposal we will investigate the role of synMuv B proteins in events that occur at specific points during development including 1) general chromatin condensation, 2) tissue specific transcription factor binding, and 3) establishment of chromatin environments, which are important in creating cell fate specific transcription programs. Understanding the role of these events in establishing germline gene repression in the soma during development will provide insight into the mechanisms that underlie dedifferentiation in cancer and provide potential targets for cancer therapies.
Tumor growth and cancer progression are the result of incorrect gene expression that changes normal cells into diseased cells. In particular, the expression in tumor cells of genes that are only normally expressed in the germline cells, sperm and oocytes, results in cancers that progress more quickly and have a poorer prognosis than other cancers that do not express these genes. This proposal will determine the steps that are important in turning germline gene expression off in healthy cells in order to uncover targets for therapies in diseased cells where germline genes are turned on.
