Graduate Programs in the Life Sciences

Research Focus

Project 1: Methylation of cytosines within CpG dinucleotides is critical for normal development in mammals and responds to environmental factors including nutrition. In cancer, proper regulation of DNA methylation goes awry often leading to silencing of tumor suppressors or activation of growth-stimulating genes. These events can strongly contribute to tumorigenesis. Many loci have been identified that acquire methylation or whose expression is methylation-sensitive in the normal and cancer genome, but virtually nothing is known about how methylation is regulated. Imprinted loci are useful for identifying cis-acting DNA sequences that regulate local methylation since these loci undergo predictable patterns of allele-specific methylation in normal tissue. RASGRF1 is a GTP exchange factor that activates RAS and has transforming activity. In mice, the Rasgrf1 locus is imprinted: There is paternal allele-specific methylation within a differentially methylated domain (DMD) 30 kbp 5` of the promoter and the locus is paternally-expressed. We have shown that a repeated sequence element found immediately 3` of the DMD regulates establishment and maintenance of methylation of the DMD. The DMD behaves like a methylation-sensitive enhancer-blocking element and together with the repeat sequence, represents a binary switch that regulates allele-specific expression of the locus. We have also prepared mutations at the locus which results in transfer of methylation states across homologous chromosomes. The central goal of this project is to elaborate the mechanisms by which the repeat element regulates DNA methylation. If we understand how DNA methylation is normally regulated, this may help us understand how inappropriate methylation occurs in cancer. Furthermore, these studies may identify therapeutic targets for treating diseases characterized by aberrant DNA methylation. ||Project 2: We are taking advantage of recombinant inbred (RI) lines of mice to identify genetic loci regulating whether different diets affect colon carcinogenesis. This involves feeding each RI line one of two separate diets - a control diet and one that is high in fat, low in vitamins and low in methyl donors. Mice are undergoing treatments with chemical carcinogens that induce colon cancer. By identifying RI panel members whose colon cancer phenotypes are diet sensitive, we plan to map genomic regions that are important for clinically relevant gene-nutrient interactions.||Project 3: We are collaborating with Harold Craighead in Engineering Physics to develop single molecule analysis of epigenetic states for high throughput analysis of multiple epigenetic marks.||Project 4: We are collaborating with Andy Clark in MB&G to utilize Solexa sequencing to identify new imprinted genes.

Educational Background

• Ph.D., Molecular Genetics, Princeton University, 1989 

• BA, Biochemistry, Cornell University, 1979