DOI:10.1038/nrm2108

In most eukaryotes, DNA cytosine methylation is found at transpo-sons and repeat sequences, where it prevents the reactivation and transposition of parasitic genomic elements. Cytosine methylation is also found at genes, but whereas methylation at promoters is known to repress transcription initiation, the biological role of methylation in the gene body remains unclear. Reporting in Nature Genetics, Steven

Henikoff and colleagues show that, in Arabidopsis thaliana, genic DNA methylation and transcription are intimately linked, and they provide a rationale for this interdependency.

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 upregula-tion 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 tran-script 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 poly-merases on highly expressed genes block access to cryptic initiation sites, accounting for the relative lack of DNA methylation at these loci.

So, at least in A. thaliana, DNA methylation and transcription are engaged in a silent pas de deux; it remains to be seen if this partnership is a feature of all eukaryotic genomes.

Shannon Amoils

ORIGINAL RESEARCH PAPER Zilberman, D. et al. Genome-wide analysis of Arabidopsis thaliana DNA methylation uncovers an interdependence between methylation and transcription. Nature Genet. 39, 61–69 (2007)

G E N E E X P R E S S I O N

A silent pas de deux

R E S E A R C H H I G H L I G H T S

NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 8 | FEBRUARY 2007

Nature Reviews Molecular Cell Biology | AOP, published online 17 January 2007; doi:10.1038/nrm2108

© 2007 Nature Publishing Group