With genome sequence data available in massive abundance, the architecture of the mammalian genome, and the individual variation governing our traits are becoming increasingly understood. The technologies that have produced our sequence data are now being applied to characterize the structure and variation within our epigenome. Epigenetic modifications, which include DNA methylation and a variety of covalent changes to histone tails, are emerging as master regulators that control how sequence information within our genome is utilized. Proper placement and removal of epigenetic marks is essential for normal development, and misplacement of these marks are initiating events for many disease states. A host of enzymes and cofactors that place modifications in the epigenome are known, but almost nothing is known about how they select genomic locations to modify. Understanding how epigenetic states are established and maintained is of fundamental importance to human biology. My lab has identified a naturally occurring DNA sequence that has DNA methylation promoter activity: It is both necessary and sufficient to direct the placement of local DNA methylation in mice. No other naturally occurring sequence with this activity has been identified. Just as the dissection of transcriptional promoters facilitated the discovery of transcription mechanisms, the DNA methylation promoter we've discovered provides a unique opportunity for elaborating the mechanisms governing placement of this essential epigenetic mark. There are four prominent sequence features within the DNA methylation promoter hypothesized to be important for its function. The four Aims proposed here will reveal their roles in promoting DNA methylation.
