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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
Program Officer
Hoshizaki, Deborah K
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
Zip Code
Sun, Yuqing; Zhou, Bo; Mao, Fengbiao et al. (2018) HOXA9 Reprograms the Enhancer Landscape to Promote Leukemogenesis. Cancer Cell 34:643-658.e5
Ihermann-Hella, Anneliis; Hirashima, Tsuyoshi; Kupari, Jussi et al. (2018) Dynamic MAPK/ERK Activity Sustains Nephron Progenitors through Niche Regulation and Primes Precursors for Differentiation. Stem Cell Reports 11:912-928
Grimley, Edward; Dressler, Gregory R (2018) Are Pax proteins potential therapeutic targets in kidney disease and cancer? Kidney Int 94:259-267
Schaefer, Stacy A; Higashi, Atsuko Y; Loomis, Benjamin et al. (2018) From Otic Induction to Hair Cell Production: Pax2EGFP Cell Line Illuminates Key Stages of Development in Mouse Inner Ear Organoid Model. Stem Cells Dev 27:237-251
Soofi, Abdul; Wolf, Katherine I; Emont, Margo P et al. (2017) The kielin/chordin-like protein (KCP) attenuates high-fat diet-induced obesity and metabolic syndrome in mice. J Biol Chem 292:9051-9062
Grimley, Edward; Liao, Chenzhong; Ranghini, Egon J et al. (2017) Inhibition of Pax2 Transcription Activation with a Small Molecule that Targets the DNA Binding Domain. ACS Chem Biol 12:724-734
Soofi, Abdul; Wolf, Katherine I; Ranghini, Egon J et al. (2016) The kielin/chordin-like protein KCP attenuates nonalcoholic fatty liver disease in mice. Am J Physiol Gastrointest Liver Physiol 311:G587-G598
Dressler, Gregory R; Patel, Sanjeevkumar R (2015) Epigenetics in kidney development and renal disease. Transl Res 165:166-76
Abraham, Saji; Paknikar, Raghavendra; Bhumbra, Samina et al. (2015) The Groucho-associated phosphatase PPM1B displaces Pax transactivation domain interacting protein (PTIP) to switch the transcription factor Pax2 from a transcriptional activator to a repressor. J Biol Chem 290:7185-94
Ranghini, Egon J; Dressler, Gregory R (2015) Evidence for intermediate mesoderm and kidney progenitor cell specification by Pax2 and PTIP dependent mechanisms. Dev Biol 399:296-305

Showing the most recent 10 out of 39 publications