The host defence function of genomic methylation patterns.

ABSTRACT

It has long been held that reversible promoter methylation allows genes to be expressed in the appropriate cell types during development. However, no endogenous gene has been proven to be regulated in this way, and it does not appear that significant numbers of promoters are methylated in non-expressing tissues. It has recently become clear that the large majority of genomic 5-methylcytosine is actually in parasitic sequence elements (transposons and endogenous retroviruses), and the primary function of DNA methylation now appears to be defence against the large burden of parasitic sequence elements, which constitute more than 35% of the human genome. Direct transcriptional repression provides short-term control, and the tendency of 5-methylcytosine to deaminate to thymidine drives irreversible inactivation. It is suggested that intragenomic parasites are recognized by virtue of their high copy number, and that the disturbances of methylation patterns commonly seen in human cancer cells activate a host of parasitic sequence elements, which destabilize the genome and tip the cell towards the transformed state.