بررسی و مطالعه دی‌ان‌ای متیلاسیون در حیوانات

ABSTRACT Studies of DNA methylation in animals

The predominant methylated sequence in all animals is the self-complementary dinucleotide CpG. In vertebrates, most CpGs in the genome are methylated at the 5 position on the cytosine ring. Several biological consequences of this postsynthetic modification are known. Best understood is the methylation-associated mutagenesis that has caused the under-representation of CpG in the genome and is responsible for over one third of the point mutations that give rise to human genetic diseases (Bird, 1980; Jones et al., 1992). It is difficult to see this as a selected advantage of DNA méthylation. More likely it is an unavoidable price to be paid for some other benefit of methyl-CpG. Strikingly, the invertebrates (which account for well over 95% of animal species) may not pay this price, as few, if any of their genes are methylated (see below). The need for DNA méthylation during normal mammalian development has been shown by disruption of the gene for cytosine methyltransferase (MTase) in mice (Li et al., 1992).

Mutant embryos have greatly reduced levels of DNA méthylation, and die in mid-gestation. In seeking an explanation for this embryonic lethal phenotype, it is tempting to focus on the well-known effects of méthylation on transcription. DNA méthylation has long been correlated with transcriptional repression. That it causes repression has been shown by introduction of artificially methylated constructs into cells (Vardimin et al., 1982; Stein et al., 1982), and by the use of drugs that inhibit the MTase (Jones and Taylor, 1980). A reasonable hypothesis is that embryos lacking the MTase die because the methylation-mediated repression mechanism fails.