Characterization of the influence of covalent histone modifications on DNA methylation in mammalian cells using a novel genomic targeting system

Normally, cells in the body grow, divide, and die in an orderly manner, under the direction of their DNA, the genetic blueprint of life. However, damage to the DNA in a single cell can disrupt this regulated process, prompting the cell to begin dividing uncontrollably and becoming cancerous. A subset of cell growth regulating proteins – those encoded by the tumour suppressor genes – normally act to inhibit cell growth. In many cancer cells, these proteins are no longer produced, not because the genes that encode them have become mutated, but because they have been shut off, or “silenced”. Gene silencing frequently involves methylation, a specific chemical change in the genes’ DNA. However, the cause of methylation and its associated gene silencing cascades remain unclear. Dr. Lorincz is determining the underlying cause of DNA methylation, using a novel mouse cell model system that he has developed. The knowledge gained from this work may lead to the development of pharmaceuticals that inhibit DNA methylation and, in turn, provide new agents for the treatment of those cancers arising from aberrant methylation of tumour suppressor genes.