Recent studies have shown that the transcriptional profile of a tumor cell is quite different than its normal cell counterpart. However, simply identifying the mRNA differences in normal vs. tumor cells does not provide insight into the mechanisms by which the distinct transcriptional profile of a tumor cell has been created. We believe that understanding how the tumor-specific transcriptome is generated will provide insight into the master regulators of tumorigenesis. Therefore, the focus of our proposal will be on the characterization of the mechanisms by which genes are inappropriately regulated in tumor cells. It has been hypothesized that new proliferative demands that occur as a normal cell transforms into a tumor cell require a reversion of differentiated characteristics to allow for a more stem-cell like phenotype. Accordingly, transcriptional repression of genes that contribute to a differentiated phenotype may be a requisite component of neoplastic transformation. Our recent studies have suggested that transcriptional repression complexes can be recruited to different places in the genome, depending upon the abundance of interacting site-specific transcription factors. Therefore, the focus of this current proposal will be to address the following central hypothesis: Growth-related changes in the abundance of site-specific DNA binding factors mediate tumor- specific transcriptional repression. We will focus on two different types of transcriptional repressers to test this hypothesis. First, we will investigate whether the retinoblastoma (Rb) tumor suppressor is an obligate partner with an E2F or if E2F-independent recruitment mechanisms exist. Second, we will determine if differences in the abundance of cell type-specific DNA binding factors provide for cell type-specific PRC2/3/4-mediated repression. For all of these experiments, we will perform ChlP-chip assays to identify and characterize target genes. Follow-up experiments will include both bioinformatics and mechanistic studies. The results obtained in our studies of tumor-specific repression may provide insight into how to reverse the de-differentiation process, perhaps driving tumor cells back towards their normal phenotype. Relevance: An understanding of the transcriptional mechanisms that drive tumor cells into a less differentiated phenotype may provide insight into the development of new therapeutic agents.
Showing the most recent 10 out of 15 publications
