DNA methylation represents an important epigenetic regulatory mechanism for repressing gene activity which ultimately operates by affecting chromatin structure. In order to understand how this works we have developed new approaches for deciphering how methyl moieties interact with the key components of the nucleosome and other features of higher order structure.In general, methylation patterns are not inherited from the parents but rather are generated anew in each individual, and this is carried out mainly through demethylation which is directed by local cis acting sequences. Using transgenic mice it will be possible to map these elements and then isolate trans acting protein factors that may be involved in facilitating demethylation. As a result of these studies it should be possible to devise strategies for selectively altering methylation patterns in vivo and thereby control gene expression.We have devised a unique system for studying the effects of global undermethylation on the regulation of genomic repression patterns and on cellular growth properties. These studies implicate DNA methylation as a cell division counting mechanism that may mediate senescence.One of the most important roles of DNA methylation is in the control of genomic imprinting where it serves to mark the parental alleles and direct the imprinted expression pattern. We have succeeded in mapping the central control elements which regulate imprinting and can now use transgenic mice to decipher the exact cis acting sequences and trans acting factors which mediate this epigenetic mechanism at different stages of development.
