The authors analysed the genome-wide distribution of methylated DNA in A. thaliana and found that at least 20% of A. thaliana genes are methylated. Henikoff and his team then compared A. thaliana transcript levels with the methylation data and revealed an interesting correlation — moderately transcribed genes are most likely to be methylated, whereas genes that are expressed at either high or low levels are predominantly unmethylated. The global upregulation of gene expression in a mutant defective for a maintenance DNA methyltransferase confirmed that DNA methylation inhibits gene expression. Importantly, the analysis of a subset of methylated genes that have unmethylated promoters provided strong evidence that genic DNA methylation opposes transcript elongation in the body of the gene.
Why are transcribed genes associated with a modification that obstructs elongating RNA polymerase II (Pol II)? The authors conclude by proposing a model that reconciles this apparent paradox. The packaging of DNA in chromatin keeps most of the eukaryotic genome in a repressed state, but as Pol II traverses the gene, the nucleosome is disrupted, uncovering cryptic initiation sites and allowing aberrant transcription. In A. thaliana, these aberrant transcripts are processed into short interfering RNAs, which results in the methylation of cognate DNA and perhaps the establishment of a repressive chromatin structure. This silencing mechanism prevents further aberrant transcription from within the gene body, but at the same time reduces the efficiency of transcript elongation, probably by stalling the progression of Pol II. This model accounts for the dense methylation observed at moderately transcribed loci. By contrast, genes that are expressed at low levels experience minimal chromatin disruption, and the tightly packed elongating polymerases on highly expressed genes block access to cryptic initiation sites, accounting for the relative lack of DNA methylation at these loci.
This is a preview of subscription content, access via your institution