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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054740-13
Application #
8246528
Study Section
Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
Program Officer
Hoshizaki, Deborah K
Project Start
1999-01-15
Project End
2013-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
13
Fiscal Year
2012
Total Cost
$312,240
Indirect Cost
$103,969
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Dressler, Gregory R; Patel, Sanjeevkumar R (2015) Epigenetics in kidney development and renal disease. Transl Res 165:166-76
Patel, Sanjeevkumar R; Ranghini, Egon; Dressler, Gregory R (2014) Mechanisms of gene activation and repression by Pax proteins in the developing kidney. Pediatr Nephrol 29:589-95
Soofi, Abdul; Zhang, Peng; Dressler, Gregory R (2013) Kielin/chordin-like protein attenuates both acute and chronic renal injury. J Am Soc Nephrol 24:897-905
Zhang, Peng; Dressler, Gregory R (2013) The Groucho protein Grg4 suppresses Smad7 to activate BMP signaling. Biochem Biophys Res Commun 440:454-9
Schwab, Kristopher R; Smith, Gary D; Dressler, Gregory R (2013) Arrested spermatogenesis and evidence for DNA damage in PTIP mutant testes. Dev Biol 373:64-71
Patel, Sanjeevkumar R; Dressler, Gregory R (2013) The genetics and epigenetics of kidney development. Semin Nephrol 33:314-26
Soofi, Abdul; Levitan, Inna; Dressler, Gregory R (2012) Two novel EGFP insertion alleles reveal unique aspects of Pax2 function in embryonic and adult kidneys. Dev Biol 365:241-50
Li, Xiao-Yan; Zhou, Xiaoming; Rowe, R Grant et al. (2011) Snail1 controls epithelial-mesenchymal lineage commitment in focal adhesion kinase-null embryonic cells. J Cell Biol 195:729-38
Dressler, Gregory R (2011) Patterning and early cell lineage decisions in the developing kidney: the role of Pax genes. Pediatr Nephrol 26:1387-94
Lefevre, Gaelle M; Patel, Sanjeevkumar R; Kim, Doyeob et al. (2010) Altering a histone H3K4 methylation pathway in glomerular podocytes promotes a chronic disease phenotype. PLoS Genet 6:e1001142

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