Research Summary
DNA methylation in mammals occurs at cytosines within the sequence CpG. Although, CpG dinucleotides are generally depleted within the human genome, they are enriched within short stretches of DNA known as CpG islands. The human genome encodes nearly 38,000 CpG islands which mostly localize to the 5’ regulatory regions of genes. While most CpG islands remain unmethylated in normal adult cells, select islands acquire aberrant methylation and an altered chromatin conformation which promote transcriptional silencing in cancer cells. Thus, along with mutations and deletions, DNA methylation serves as a mechanism for silencing and inactivating tumor suppressor genes in human cancer. However, it is not understood how CpG islands become aberrantly methylated during cancer or why specific CpG islands undergo epigenetic silencing while others remain unaffected. Utilizing a cell culture model in which overexpression of DNA methyltransferase 1 (DNMT1) evokes DNA hypermethylation, our lab has shown that only a small fraction of the genome’s CpG islands succumb to aberrant methylation despite increased de novo DNA methylation. Following global methylation analysis of 1,749 CpG islands in this model, we utilized pattern recognition and supervised machine learning techniques to develop a classifier capable of discriminating methylation-prone and methylation-resistant CpG islands based on the frequencies of seven novel sequence patterns.
Education
Ph.D., Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI, 2006.
B.S., Biology, University of Notre Dame, Notre Dame, IN, 2000.
Contact Information
E-mail: michael.mccabe@emory.edu
Phone: (404) 778-2512
Fax: (404) 778-5530
Publications
M.T. McCabe, E.K. Lee, P.M. Vertino. A Multi-Factorial Signature of DNA Sequence and Polycomb Binding Predicts Aberrant CpG Island Methylation. Cancer Research, In Press.
D.A. Frohlich, M.T. McCabe, R.S. Arnold, M.L. Day. The role of Nrf2 in increased reactive oxygen species and DNA damage in prostate tumorigenesis. Oncogene 27: 4353-4363, 2008.
C.O. Evans, C.S. Moreno, X. Zhan, M.T. McCabe, P.M. Vertino, D.M. Desiderio, N.M. Oyesiku. Molecular pathogenesis of human prolactinomas identified by gene expression profiling, RT-qPCR, and proteomic analyses. Pituitary 11(3):231-45, 2008.
C.S. Zorn, K.J. Wojno, M.T. McCabe, R. Kuefer, J.E. Gschwend, and M.L. Day. 5-aza-2’-deoxycytidine delays androgen-independent disease and improves survival in the transgenic adenocarcinoma of the mouse prostate model. Clinical Cancer Research, 13(7):2136-2143, 2007.
M.T. McCabe, J.A. Low, M.J. Imperiale, and M.L. Day. Human Polyomavirus BKV Transcriptionally Activates DNA Methyltransferase 1 Through the pRb/E2F Pathway. Oncogene, 25:2727-2735, 2006.
M.T. McCabe, J.A. Low, S. Daignault, M.J. Imperiale, K.J. Wojno, and M.L. Day. Inhibition of DNA methyltransferase activity prevents tumor progression in a mouse model of prostate cancer. Cancer Research, 66(1):385-392, 2006.
M.T. McCabe, J.N. Davis, and M.L. Day. Regulation of DNA methyltransferase 1 by the Rb/E2F pathway. Cancer Research, 65(9):3624-3632, 2005.
J.N. Davis, M.T. McCabe, S.W.
M.T. McCabe, O.A. Azih, and M.L. Day. pRb-independent growth arrest and transcriptional regulation of E2F-target genes. Neoplasia, 7(2):141-151, 2005.
K.C. Day, M.T. McCabe, X. Zhao, Y. Wang, J.N. Davis, J. Phillips, M. Von Gelden, T. Ried, M.A. Kukuruga, G.R. Cunha, S.W. Hayward, and M.L. Day.Rescue of embryonic epithelium reveals that homozygous deletion of the retinoblastoma gene confers growth factor independence and immortality, but does not influence epithelial differentiation or tissue morphogenesis. Journal of Biological Chemistry, 277(46):44475-84, 2002.
Links
American Cancer Society
Emory University
Winship Cancer Institute
Department of Radiation Oncology
Office of Post-Doctoral Education
EpiGenie - Epigenetics News