In a recent study whose original aim was to carefully characterize the intrinsic sequence preferences of the widely used footprinting enzyme DNaseI, the Bussemaker Lab uncovered a new and unexpected general mechanism by which DNA methylation can enhance binding by transcription factors (Lazarovici et al., PNAS, 2013). Specifically, it demonstrates how cytosine methylation can change the sequence preferences of DNA binding proteins by an order of magnitude. By analyzing deeply sequenced digests of purified human genomic DNA, they made two striking discoveries: (i) DNaseI cleavage rate varies over a thousand-fold range with the surrounding sequence, and (ii) cleavage near CpG dinucleotides is 10-20 fold higher when the cytosine is methylated. By combining computer simulations of DNA shape performed by the group of Remo Rohs at USC with statistical analysis of massively parallel sequencing data collected in the laboratory of collaborator John Stamatoyannopoulos at the University of Washington, they were able to find a unified explanation for these phenomena. It turns out that cytosine methylation narrows the DNA minor groove, which in turn strengthens interactions with positively charged amino-acid side chains. Such minor groove contacts occur for a wide range of transcription factors, as well as nucleosomes. The novel structural mechanism put forward in this study therefore has the potential to significantly deepen our understanding of how epigenetic information is "read" by the cell.
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