Among the mechanisms by which the regulation of gene expression is accomplished, that which controls the structure and accessibility of the DNA at the level of chromatin structure is increasingly recognized as being critically important. Particularly fascinating in this regard is the phenomenon of imprinting, whereby somatic or germ cell-derived mechanisms impose a heritable mark on particular region of DNA within chromatin through many mitoses and, in the case of parental imprinting, through meiosis as well. It seems clear that if these marks or imprints are either lost prematurely, or else imposed inappropriately, then control of the level of expression of genes can be affected adversely. Clearly if this happens to critical early growth regulatory genes, or to important cell cycle control genes, serious childhood diseases or cancerous conditions could be one result. In fact, it has been suggested that certain environmental chemicals, known to cause cancer but with no overt mutagenic properties, might create a loss of gene expression (e.g. in tumor suppressor genes) by such epigenetic means. In this proposal the goal is to test a variety of such potential environmentally dangerous chemicals contaminants for their ability to heritably alter gene expression via imposition of altered chromatin states at the genetic locus under investigation. In these experiments the genetically tractable eukaryote, Drosophila melanogaster, will serve as a highly appropriate model since there are numerous epigenetic phenomena described in this system that can be readily subjected to detailed analysis in the presence of an array of environmental agents. Moreover, the existence of a highly sophisticated set of genetic tools in this organ, including efficient transposon mobilization and controllable mutagenesis and mitotic recombination procedures, will allow a screen to be mounted that aims to identify genes that co-operate with, or mediate the interaction of, environmental agents with the chromosome substrate.
|Ortiz, Jorge G Muniz; Opoka, Robert; Kane, Daniel et al. (2009) Investigating arsenic susceptibility from a genetic perspective in Drosophila reveals a key role for glutathione synthetase. Toxicol Sci 107:416-26|