A fully differentiated cell is defined by the genes it expresses and, ultimately, by its physiological functions. This normal pattern of gene expression, or transcriptome, is altered in a diseased state such that function is perturbed, growth is deregulated, and communication with other cells affected. The question is, how are these abnormal expression patterns established and maintained in the absence of genetic mutations? We propose that epigenetic modifications on the genome, and specifically histone methylation, impact gene expression changes in diseased tissues. To explore this hypothesis, we must first understand how epigenetic modifications are imprinted during development of the embryo, as cell lineages decisions are made. Previously, the PI has identified Pax2 as a critical DNA binding protein in the renal epithelial lineage. The lab then discovered PTIP as an adaptor protein that links Pax2 to a histone methylation complex to imprint positive epigenetic marks on target genes. In this application, Aim 1 will use chromatin immunoprecipitation, next generation sequencing, and specific strains of genetically altered mice to map the sites of Pax2/PTIP interactions with the genome and to correlate this with gene expression patterns. Furthermore, we have the first real evidence that altering a histone methylation pathway in a cell specific manner can lead to chronic renal disease.
In Aim 2, we will define the role of PTIP and histone methylation in renal interstitial fibrosis and correlate this with TGF-b signaling pathways that are known to mediate fibrosis. While there are many correlations of epigenetic changes in cancer and other disease states, our studies will address for the first time whether epigenetic modifications can directly initiate a disease state in the absence of other mutations or environmental insults. Our preliminary data strongly suggests that they can.

Public Health Relevance

Chronic and acute kidney disease increasingly impacts public health, yet the origin and treatment of renal diseases are not well understood. This application addresses the genetic and epigenetic basis of kidney cell physiology, how kidney cells are formed in the developing embryo, and how kidney cells maintain their normal functions in adult life. We have discovered new genes and pathways that critically impact normal development of the kidney and contribute to the initiation and progression of a variety of kidney diseases. This application will explore these pathways in depth to provide mechanistic insights for new avenues of intervention.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
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Hoshizaki, Deborah K
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Grimley, Edward; Dressler, Gregory R (2018) Are Pax proteins potential therapeutic targets in kidney disease and cancer? Kidney Int 94:259-267
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
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
Whiteman, Eileen L; Fan, Shuling; Harder, Jennifer L et al. (2014) Crumbs3 is essential for proper epithelial development and viability. Mol Cell Biol 34:43-56
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

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