Office: CGRC 258
Phone: (352) 294-8596
Education and Training
Ph.D. – Molecular Biology, Department of Molecular Biology, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovak Republic (1996)
M.Sc. – Biochemistry, Comenius University, Bratislava, Slovak Republic (1991)
Cytosine methylation is a heritable epigenetic modification affecting gene transcription and the integrity of the genome. In human malignancies, aberrant DNA methylation is the most commonly observed epimutation, often manifested by promoter hypermethylation of tumor suppressor genes and hypomethylation of intergenic non-coding regions. The DNA methyltransferases (DNMTs) DNMT1, DNMT3A, and DNMT3B are the enzymes primarily responsible for methylation of CpG dinucleotides in mammalian DNA. Mutations in the coding sequence of DNMT3A are frequently found in human hematologic malignancies indicating that decreased DNMT3A activity may promote tumorigenesis in multiple hematopoietic lineages. Using targeted inactivation of Dnmt3a in mice Opavsky lab showed that Dnmt3a plays a tumor suppressor role in prevention of chronic B-cell lymphocytic leukemia, peripheral T cell lymphoma and myeloproliferative disease. Furthermore, Dnmt3b is a tumor suppressor gene in prevention of MYC-induced T cell lymphomas. Promoter hypomethylation accompanied by increased gene expression was found to be a frequent event in both mouse and human hematologic malignancies.
Current projects in Opavsky lab focus on evaluation of functions performed by DNMTs in normal and malignant hematopoiesis utilizing mouse models, genome-wide approaches and in vivo functional studies of DNMT target genes. We are in particular interested in a role of promoter hypomethylation in cellular transformation in order to identify oncogenes for therapeutic targeting.
Hlady RA*, Novakova S*, Opavska J, Klinkebiel D, Peters SL, Bies J, Hannah J, Iqbal J, Anderson KM, Siebler HJ, Smith LM, Greiner TC, Bastola D, Joshi S, Lockridge O, Simpson MA, Felsher DW, Wagner KU, Chan WC, Christman JK, Opavsky R (2012). Loss of Dnmt3b maintenance function up-regulates the novel tumor modifier Ment and accelerates mouse lymphomagenesis. J Clin Invest. 122(1):163-177 | PubMed (* equal contribution)
Peters SL*, Hlady RA*, Opavska J, Klinkebiel D, Novakova S, Smith LM, Lewis RE, Karpf AR, Simpson MA, Wu L, Opavsky R (2013). An essential role for Dnmt1 in the prevention and maintenance of MYC-induced T-cell lymphomas. Mol Cell Biol. 33(21):4321-4333 | PubMed (* equal contribution)
Peters SL*, Hlady RA*, Opavska J, Klinkebiel D, Pirruccello SJ, Talmon GA, Sharp JG, Wu L, Jaenisch R, Simpson MA, Karpf AR, Opavsky R. (2014). Tumor suppressor functions of Dnmt3a and Dnmt3b in the prevention of malignant mouse lymphopoiesis. Leukemia 28(5):1138-1142 | PubMed (* equal contribution)
Haney SL*, Hlady RA*, Opavska J, Klinkebiel D, Pirruccello SJ, Dutta S, Datta K, Simpson MA., Wu L., Opavsky R (2015). Methylation-independent repression of Dnmt3b contributes to oncogenic activity of Dnmt3a in mouse MYC-induced T-cell lymphomagenesis. Oncogene advance online publication 2 February 2015 | PubMed (* equal contribution)
Haney SL, Upchurch GM, Opavska J, Klinkebiel D, Hlady RA, Suresh A, Pirruccello SJ, Shukla V, Lu R, Costinean S, Rizzino A, Karpf AR, Joshi S, Swanson P, Opavsky R (2016) Promoter hypomethylation and expression is conserved in mouse chronic lymphocytic leukemia induced by decreased or inactivated Dnmt3a. Cell Rep. 15; May 6, 1190–1201 | PubMed
Haney SL*, Upchurch GM*, Opavska J, Klinkebiel D, Appiah AK, Smith LM, Heavican TB, Iqbal J, Joshi S, Opavsky R (2016). Loss of Dnmt3a induces CLL and PTCL with distinct methylomes and transcriptomes in mice. Sci Rep. Sep 28;6:34222 | PubMed (* equal contribution)
Haney SL.*, Upchurch GM.*, Opavska J., Klinkebiel D., Hlady, R., Roy S., Dutta S., Datta K. Opavsky R (2016). Dnmt3a is a tumor suppressor gene in a prevention of CD8 positive T cell lymphomas. PLoS Genet., Sep 30;12(9):e1006334 | PubMed (* equal contribution)
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