Genetic studies in mice and humans have established an essential role for the Pax2 gene in the development of epithelial structures, including the kidneys, ureters, female uterus, and male ejaculatory ducts. Furthermore, the Pax2 protein is overexpresed in a variety of disease states, inluuding renal cell carcinoma, polycystic kidney disease, Wilms'tumor, and prostate carcinoma. Pax proteins bind DNA and are thought to specify cell fate or cell lineages such that specific structures develop in response to inductive cues and positional information. Pax2 is essential for mediating the inductive signals that generate the renal epithelia. Such inductive signals can phosphorylate the Pax2 protein and promote transcriptional activation of Pax2 response elements. In the kidney, Pax2 is likely to regulate hundreds of loci that respond to inductive signaling and as such sits near the top of a genetic network that specifies the nephrons, collecting ducts, and ureters. Previous work and new preliminary data from the PI's lab demonstrate that Pax2 interacts with cellular complexes to modify chromatin by histone methylation. These changes in histone methylation are inherited epigenetic marks that can alter chromatin structure and provide intrinsic cellular memory such that the fate of progenitor cells becomes fixed. Our working hypothesis is that Pax2 can confer an active chromatin state to renal epithelial specific genes while also conferring an inactive chromatin state to non-renal genes. These activities depend on the phosphorylated state of Pax2 and the interacting partners available. To address this hypothesis, we propose to systematically identify target genes for Pax2 and address the local changes in chromatin structure in response to external signaling cues known to regulate renal development and regeneration. Experimental strategies will utilize both cell based and genetic systems to determine Pax2 binding along the genome in vivo. These data will be correlated to changes in expression of candidate target genes. The biochemical changes occuring at Pax2 regulated sites, in a Pax2 dependent manner, will be examined using chromatin immunoprecipitation techniques to map modifications of histones. Thus, we will determine how Pax2 alters chromatin at the biochemical level, which genes are affected, and how this complex genetic network ultimately works to specify normal renal epithelial cells.
The development of the mammalian urogenital system requires precise genetic networks to activate or repress specific genes, both spatially and temporally, so that growth, differentiation, and patterning are achieved in highly reproducible manner. Any perturbations of such networks can result in congenital defects, such as hypoplastic and cystic kidneys, hydronephrosis, ureteral obstructions, embryonal carcinomas, and lower urinary tract malformations. Furthermore, the genetic networks that control development are also important in regeneration and cancer. Thus, understanding the genetic and biochemical mechanisms that underlie urogenital development is essential not only for a basic science perspective but also for framing the context of regenerative medicine, for developing novel biological therapies, and for designing targeted anticancer drugs.
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