Abstract
Cytosine methylation is a key mechanism of epigenetic regulation. CpG-dense loci, called "CpG islands", play a particularly important role in modulating gene expression. Methylation has long been suspected to alter the physical properties of DNA, but the full spectrum of the evoked changes is unknown. Here we measured the methylation-induced nanomechanical changes in a DNA molecule with the sequence of a CpG island. For the molecule under tension, contour length, bending rigidity and intrinsic stiffness decreased in hypermethylated dsDNA, pointing at structural compaction which may facilitate DNA packaging in vivo. Intriguingly, increased forces were required to convert hypermethylated dsDNA into an extended S-form configuration. The reduction of force hysteresis during mechanical relaxation indicated that methylation generates a barrier against strand unpeeling and melting-bubble formation. The high structural stability is likely to have significant consequences on the recognition, replication, transcription, and reparation of hypermethylated genetic regions.