Ryan J. Wozniak, PhD

While in the PhD program in Pharmacology and Toxicology at the University of Arizona, my research focused on trying to understand the interplay between genetic and epigenetic dysregulation in the inappropriate silencing of tumor suppressor genes in human breast cancer. Additionally, I developed a pharmacologic strategy to successfully reverse these dual silencing mechanisms and restore expression of anti-metastatic genes. I am currently at the University of Wisconsin-Madison doing post-doctoral research investigating the transcriptional regulation of GATA factors in hematopoietic stem cells. Members of the GATA transcription factor family are capable of both activating and repressing target genes, with GATA-1 and GATA-2 serving as critical regulators of blood cell development. GATA-2 is highly expressed in multipotent hematopoietic precursors and is necessary for their proliferation and survival, while GATA-1 expression is elevated as GATA-2 levels decline during hematopoiesis. GATA-1/2 levels are tightly controlled during hematopoiesis, and perturbations to their normal expression patterns or functions have been implicated in leukemias, lymphomas and myelodysplastic syndromes. Previous work by our group has defined five conserved regions that assemble GATA factor complexes over ~100 kb of the endogenous Gata2 locus, with GATA-1 and GATA-2 occupying these sites during transcriptionally repressed and active states, respectively. It is unclear, however, whether these regions function independently or collectively to control Gata2 transcription/hematopoiesis. Recent molecular studies in our lab using hematopoietic precursors indicate that individual GATA switch sites can function distinctly, suggesting that despite the common feature of binding GATA factors, these elements have important structural/functional differences. To further address this hypothesis, studies are proposed to dissect mechanisms underlying Gata2 transcriptional regulation in vivo and to identify targets of GATA-1/2 dysregulation in the development of blood cancers.
Pharmacology and Toxicology
Pharmacology and Toxicology
Toxicologist, Wisconsin Department of Health Services
Dissertation Title: 
“Mechanisms Underlying the Pharmacologic Reversal of Genetic and Epigenetic Components of Tumor Suppressor Gene Silencing in Human Breast Cancer”
1. Futscher BW, Oshiro MM, Wozniak RJ, Holtan N, Hanigan CL, Duan H, Domann FE. Role for DNA methylation in the control of cell type-specific maspin expression. Nature Genetics 31:175-179, 2002.
2. Oshiro MM, Watts GS, Wozniak RJ, Junk DJ, Munoz-Rodriguez JL, Domann FE, Futscher BW. Mutant p53 and aberrant cytosine methylation cooperate to silence gene expression. Oncogene 22(23):3624-3634, 2003.
3. Watts GS, Oshiro MM, Junk DJ, Wozniak RJ, Watterson SJ, Domann FE, Futscher BW. The acetyltransferase p300/CBP-associated factor is a p53 target gene in breast tumor cells. Neoplasia 6(3):187-94, 2004.
4. Oshiro MM, Kim CJ, Wozniak RJ, Junk DJ, Munoz-Rodriguez JL, Burr JA, Fitzgerald M, Pawar S, Cress AE, Domann FE, Futscher BW. Epigenetic silencing of DSC3 is a common event in human breast cancer. Breast Cancer Research 7(5):R669-R680, 2005.
5. Oshiro MM, Futscher BW, Lisberg A, Wozniak RJ, Klimecki WT, Domann FE, Cress AE. Epigenetic regulation of the cell type-specific gene 14-3-3_.  Neoplasia 7(9):799-808, 2005.
6.  Wozniak RJ, Klimecki WT, Lau SS, Feinstein Y, Futscher BW. 5-aza-2’-deoxycytidine-mediated reductions in G9A histone methyltransferase and histone H3 K9 di-methylation levels are linked to tumor suppressor gene reactivation. Oncogene:  in press.
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