DNA methylation: a new twist in the tail

Abstract

DNA methylation is the epigenetic mark with the longest history and that we probably understand best, yet we still have no adequate account for why specific DNA sequences are selected to become methylated. Gene-specific DNA methylation is fundamental to processes such as developmental silencing of genes, classical epigenetic phenomena such as genomic imprinting, and occurs pathologically in the silencing of tumor suppressor genes in cancer. Fully understanding the mechanisms of methylation is thus of huge importance. In mammals, the acquisition of DNA methylation is determined by one of two de novo DNA methyltransferase enzymes, Dnmt3a and Dnmt3b. These activities are assisted by the related, but catalytically inactive protein Dnmt3L. Dnmt3a and Dnmt3b have similar structures, comprising a PWWP domain, PHD-like or ADD domain and a carboxy-terminal catalytic domain 1. The PWWP domains are required for binding of Dnmt3a and Dnmt3b to chromatin in vivo, and the PHD domain is thought to be dispensable for this 2. Dnmt3L, which is a truncated protein lacking the PWWP and a functional catalytic domain, forms a heterotetramer with Dnmt3a or Dnmt3b 3 and is described as stimulating the activity of its de novo partners, or guiding the recognition of DNA targets with a particular periodicity of CpG sites 3, or attenuating the inherent sequence specificities of Dnmt3a or Dnmt3b so that they methylate targets more homogenously 4.