Role of cytidine deaminases in epigenetic reprogramming and demethylation of DNA

Genetic information is passed from generation to generation and is the material upon which natural selection acts. On top of this genetic information the genome also contains epigenetic information in the form of chemical and other modifications to DNA, which are associated with gene expression and genome function. Epigenetic mechanisms of gene regulation are of key importance in development, stem cell biology and regenerative medicine, and cancer. During certain periods of early development of an embryo, epigenetic modifications including DNA methylation are reprogrammed on a genome wide level. This may be important in order to establish totipotency (the ability to give rise to an entire organism) of the embryonic genome. The mechanisms of the removal of DNA methylation from the genome are unknown in mammals. This student project investigates a class of candidate enzymes in the mouse which have been shown to be able to chemically alter methylated cytosines. There are four of these candidate genes in the mouse genome, for three of which we have knockout mutations (to create 'inactive' genes). A fourth knockout is being constructed, and knockouts will then be examined for altered DNA methylation and development. If methylated cytosines are chemically altered, the DNA needs to be repaired following this event. The project also investigates the DNA repair pathways which would be responsible.