A British team of researchers recently decided to take closer look at the role of DNA methylation in conserved consensus motifs. Dr. Roger Foo from the Department of Medicine, University of Cambridge was nice enough to share a bit about their approach that recently published in BMC Genomics (Sept 2010) last week.
Transcription factors recognise specific DNA sequence motifs as their cognate binding sites genome-wide. Conserved consensus motifs, each of which are on average 14 bases in length, are not usually located near protein-coding genes. Therefore it is intriguing whether all of these conserved DNA motifs are involved in transcription factor binding and how binding at these sites may be regulated.
Our team looked at conserved consensus motifs present across the human genome and discovered that the large majority of these are not biological/empirical transcription factor binding sites (TFBS) because they have not been detected by chromatin immunoprecipitation and high-throughput sequencing (ChIP-seq). For some time now, this has been suspected because conversely, empirical TFBS often do not bear the expected consensus motif for the specific TF.
Since DNA methylation may regulate gene expression by modulating the interaction between DNA and proteins or protein complexes, our team hypothesised that DNA methylation at conserved consensus motifs prevents promiscuous or disorderly transcription factor binding.
Using genome-wide methylation maps of the human heart and sperm, we found that:
- All conserved consensus motifs have an aggregate profile of hyper-methylation
- In contrast, empirical TFBS with conserved consensus motifs have a profile of hypo-methylation
- 40% of the empirical TFBS with conserved consensus motifs locate to CpG islands
- Only 7% of all conserved consensus motifs are in CpG islands
Also, a minority subset of TFs whose profiles are either hypo-methylated or neutral at their respective conserved consensus motifs suggesting that these TF may be responsible for establishing or maintaining an un-methylated DNA state, or whose binding is not regulated by DNA methylation.
This work supports the hypothesis that at least for a subset of transcription factors, empirical binding to conserved consensus motifs genome-wide may be controlled by DNA methylation. Big thanks to Dr. Foo and the rest of his team for their contribution to the field and EpiGenie. Check out the binding details at: BMC Genomics , Sept 2010.