Project 172185

While modern cancer radiation therapy has increased patient survival rates, the risk of secondary treatment-related complications and adverse effects is becoming a growing clinical problem. Radiation-induced tumors and other toxic radiation effects have been reported to occur to a different extent in males and females. Mechanisms of these differences remain elusive. The DNA content of each cell in a given higher organism is identical: our liver and brain cells contain the same DNA, but they are very different in their shapes and functions. This is due to the existence of different patterns in reading and translation of genes for the type of cells in question, referred to as 'gene expression'. This is the domain of the emerging science of epigenetics (literally, 'beyond genetics'). Remarkable features of epigenetic changes include simple chemical modifications of the 'C' base in DNA by attachment or removal of methyl (-CH3) groups. Highly methylated regions of DNA are turned off or silenced - a kind of cellular dimmer switch. Most amazing and contrary to popular opinion that DNA sequences determine everything, epigenetic changes can extend beyond cell division to reproduction. Although epigenetic changes are inheritable, they are reversible. A lot still has to be learned about the role of epigenetic changes in living cells and organisms and their interactions with the environment. In my laboratory, we have found that males and females respond to radiation differently due to distinct epigenetic changes in DNA methylation. These changes may lead to different levels of radiation toxicity. Currently, we would like to understand (i) which epigenetic changes occur in males and females; (ii) why epigenetic changes in males and females are different; (iii) which cellular processes they affect. We will use a set of novel state-of-the art techniques to answer these questions.