Wednesday, September 30, 2009
04:30 PM in REC 315
Professor R. W. Doerge
Department of Statistics and Department of Agronomy, Purdue University

Statistics, Epigenomics, and Cancer

Abstract

Epigenomics is the study of heritable changes in genome function that occur in the absence of changes to the DNA sequence itself, and is considered by many to be the second-code of instruction that affects gene activity. Although, this change in behavior of DNA is heritable, it is not well understood by the scientific and medical communities. To date it has been well established that some genes have methyl (chemical) groups attached to their DNA complex, while others do not. A change in methylation status may modify the behavior of a gene, and as a result it may modify the proteins that a gene is responsible for producing. These methylation changes have been linked to known cancer events.

Initially, we studied epigenomic changes in the model plant organism Arabidopsis1 using DNA microarray technology. Proof of concept for this approach was established analytically using statistical methods based on linear models that tested hypotheses of both methylation changes and histone modification changes between two Arabidopsis mutants known to be different in their heterochromatic structure. Although there are similarities (e.g., array, dye, treatment effects) in the statistical models that are used to test differential (gene) expression changes, testing for epigenomic modifications is quite different, and is a good example of when testing the incorrect hypothesis will lead to the wrong conclusion.

Based on the promising results from our studies in plants, we have also investigated epigenomic changes in humans2, as related to cancer. Using a unique microarray platform for cytosine methylation profiling, the DNA methylation landscape of the human genome was monitored at numerous sites across the human genome. Specific targets displayed cell line and tumor specific differential methylation when compared with normal brain samples, suggesting they may have utility as biomarkers. Both novel and well established statistical analyses have enabled epigenomic investigations by identifying loci associated with carcinogenesis.

References:

  1. Z. Lippman, A.-V. Gendrel, M. Black, M. Vaughn, N. Dedhia, W.R. McCombie, K. Lavine, V. Mittal, B. May, K. Kasschau, J.C. Carrington, R.W. Doerge, V. Colot, and R. Martienssen. 2004. Transposable elements mediate heterochromatin and epigenetic control. Nature. 430:471-476.
  2. J. M. Ordway, J.A. Bedell, R.W. Citek, A. Nunberg, A. Garrido, R. Kendall, J.R. Stevens, D. Cao, R.W. Doerge, Y. Korshunova, H. Holemon, J. D. McPherson, N. Lakey, J. Leon, R.A. Martienssen and J.A. Jeddeloh. 2006. Comprehensive DNA methylation profiling in a human cancer genome identifies novel epigenetic targets. Carcinogenesis. 27(12):2409-2423.