Mechanism of DNA Demethylation in Vertebrates and Its Biological Significance

Abstract

The aim of this chapter is to present some general features of site-specific and genome-wide demethylation. Demethylation of DNA is part of the process responsible for the formation of specific methylation patterns. The establishment of a CpG methylation pattern during embryonic development involves at least three components: DNA methyltransferase, a demethylation system (passive or active), and sequence-specific cis-trans controlling elements located on or near the CpG methylation sites. The cis-trans controlling elements either enhance or inhibit the methylation of specific sequences. Whether a given CpG site is methylated or not depends on the mole ratio of activities of the different factors involved and of their respective affinities for a specified CpG site on the DNA. This concept of titratable factors is also valid for the cis-acting control elements. For example, the introduction of DNA-binding sites for specific proteins into the cell could possibly titrate out protein factors and engender hypermethylation of the DNA (Parker et al. 1986; Mehtali et al. 1990; Assaad et al. 1993).

The DNA-methyltransferase level could either be controlled by its synthesis at the correct time during the S phase, or it could lag behind the S phase, resulting in a lower level of DNA methylation (Adams et al. 1990). Alternatively, the level of DNA-methyltransferase activity could be regulated by small-molecular-weight peptides (E.S. Lyon et al. 1982; S.B. Lyon et al. 1987). The selective distribution of DNA methyltransferase between nuclei and the cytoplasm could favor either methylation or no methylation of DNA (Carlson et al. 1992; Leonhart...