Arguments are often won by whoever gets in the last word, and while CpG Islands have made the most noise in the debate over how DNA methylation controls transcription, other gene regions like exons are now chiming in too.
The classic model where methylated CpG Islands in promoters shut down transcription of a gene has recently been challenged by evidence showing that CpG shore and gene-body methylation also has something to say about gene expression. Researchers from Cornell Medical College in New York took a crack at settling the matter by checking correlations between the methylation of several gene regions (promoter, first exon, introns, internal exons, and last exons) and transcription levels of those genes.
The Cornell crew created a new method to help with the job, which they call Sequence Tag Analysis of Methylation Patterns (STAMP) that pairs MBD pulldown, and massively parallel sequencing with analysis that maps methylated fragments back to their gene elements.
The team and their tactics uncovered some surprising new insights. Here are some of the highlights:
- Exons are more heavily methylated than was previously known or expected, but first exons generally have less than those further downstream.
- Transcription start site (TSS) methylation isn’t connected with methylation of more downstreams regions, indicating that there may be multiple roles for intragenic methylation.
- Transcriptional silencing is much more tightly associated with methylation of the first exon than the promoter region upstream.
The first exon:methylation link is so strong, in fact that hypomethylation of that region seems to be a requirement even for genes with very low transcription levels, making a pretty strong statement about it’s importance.
Get all the info and decide for yourself who will have the final say on transcription at PLoS ONE, January 2011.