DNA Methylation, H2A.Z, and the Regulation of Constitutive Expression

The most well-studied function of DNA methylation in eukaryotic cells is the transcriptional silencing of genes and trans-posons. More recent results showed that many eukaryotes methylate the bodies of genes as well and that this methylation correlates with transcriptional activity rather than repression. The purpose of gene bodymethylation remainsmysterious, but is potentially related to the histone variant H2A.Z. Studies in plants and animals have shown that the genome-wide distributions of H2A.Z and DNA methylation are strikingly anticorrelated. Furthermore, we and other investigators have shown that this relationship is likely to be the result of an ancient but unknown mechanism by which DNA methylation prevents the incorporation of H2A.Z. Recently, we discovered strong correlations between the presence of H2A.Z within gene bodies, the degree to which a gene’s expression varies across tissue types or environmental conditions, and transcriptional misregu-lation in an h2a.z mutant. We propose that one basal function of gene body methylation is the establishment of constitutive expression patterns within housekeeping genes by excluding H2A.Z from their bodies. Eukaryotic gene expression is heavily influenced by the local chromatin environment, which is defined in part by the incorporation of histone variants, posttransla-tional modification of histones, and DNA methylation in the form of 5-methylcytosine. DNAmethylation is a con