Pathways of DNA Demethylation

The regulation of the genome relies on the epigenome to instruct, define and restrict the activities of growth and development. Among the cohort of epigenetic instructions, DNA methylation is perhaps the best understood. In most mammals, cycles of the addition and removal of DNA methylation constitute phases of reprogramming when the developing embryo must negotiate lineage defining and developmental commitment events. In these instances, the DNA methylation instruction is often removed, thereby allowing a change in permission for future development and a return to a more plastic and pluripotent state. Because of this, the germ line, upon demethylation, can give rise to gametes that are fully functional across generations and poised for totipotency. This return to a less differentiated state can also be achieved experimentally. The loss of DNA methylation constitutes one of the significant barriers to induced pluripotency and is a prerequisite for the generation of iPS cells. Taking fully differentiated cells, such as skin cells, and turning back the developmental clock heralded a technological breakthrough discovery in 2006 (Takahashi and Yamanaka 2006) with unprecedented promise in regenerative medicine. In this chapter, the mechanistic possibilities for DNA demethylation will be described in the context of natural and experimentally induced epigenetic reprogramming. The balance of the maintenance of this heritable mark together with its timely removal is essential for lifelong health and may be a key in our understanding of ageing.