DNA methylation and polyamines in embryonic development and cancer.

Abstract

Mammalian DNA contains relatively large amounts of a modified base, 5-methyl-cytosine (m5C). Methylation of cytosine is catalyzed by DNA(cytosine-5)methyltransferase (DNA MTase). DNA methylation seems to play an important role in the regulation of gene expression during development. Thus, m5C may inhibit transcription by preventing the binding of transcription factors and/or by altering chromatin structure. The DNA methylation patterns of the male and female pronuclei are erased in the morula and early blastula, and when the blastocyst forms, most of the DNA has become demethylated. Following implantation, however, there is a surge of de novo methylation affecting the entire genome, and already by gastrulation DNA is methylated to an extent characteristic of that of the adult animal. During subsequent development, tissue-specific genes undergo programmed demethylation, which may cause their activation. Site-directed mutagenesis of the DNA MTase gene, has recently shown that DNA methylation is absolutely required for normal development of the early mouse embryo. DNA methylation and polyamine synthesis depend on a common substrate, S-adenosylmethionine (AdoMet). As a consequence, changes in cellular polyamine levels may affect the degree of DNA methylation. When the first step in the polyamine biosynthetic pathway is blocked, F9 teratocarcinoma stem cells accumulate large amounts of decarboxylated AdoMet, the aminopropyl group donor in polyamine synthesis, and go through terminal differentiation into parietal endoderm cells. The accumulation of decarboxylated AdoMet is a direct consequence of the polyamine-depleted state of the cell. Although the decarboxylated AdoMet molecule contains a methyl group, it does not act as a methyl group donor in DNA methylation. Instead it acts as a competitive inhibitor of DNA MTase. A consequence of polyamine depletion is therefore genome-wide loss of DNA methylation due to insufficient maintenance methylation during successive rounds of DNA replication. Our recent finding that prevention of the accumulation of decarboxylated AdoMet counteracts the differentiative effect lends further support to the hypothesis proposed.