Abstract
Cytosine methylation is one of the most important epigenetic marks that regulate the process of gene expression. Here, we have examined the effect of epigenetic DNA methylation on nucleosomal stability using molecular dynamics simulations and elastic deformation models. We found that methylation of CpG steps destabilizes nucleosomes, especially when these are placed in sites where the DNA minor groove faces the histone core. The larger stiffness of methylated CpG steps is a crucial factor behind the decrease in nucleosome stability. Methylation changes the positioning and phasing of the nucleosomal DNA, altering the accessibility of DNA to regulatory proteins, and accordingly gene functionality. Our theoretical calculations highlight a simple physical-based explanation on the foundations of epigenetic signaling.
Highlights
In eukaryotic cells gene function is modulated by a myriad of epigenetic marks and interactions with signal molecules that control synergistically the production of RNA and proteins
Author Summary In Eukaryotic cells, control of the patterns of DNA cytosine methylation – a mechanism that acts on top of the genetic code – plays a key role in the regulation of gene expression
In this work we investigate the physical implications of DNA methylation in nucleosomal DNA, in particular its preferred location with respect to the nucleosome core-particle and the consequences of DNA methylation for the accessibility of the genetic material
Summary
In eukaryotic cells gene function is modulated by a myriad of epigenetic marks and interactions with signal molecules that control synergistically the production of RNA and proteins. Several works suggest that methylated DNA increases nucleosome rigidity [28,29,30] and that it is less prone to wrap around nucleosomes than normal DNA [30,31,32], recent genomescale studies suggest that nucleosome-bound sequences are slightly enriched in methylated cytosines (MeC), which are placed in a subtle 10-base periodicity pattern [33] It is unclear whether methylation intrinsically favours or disfavours nucleosome formation, whether it leads or not to changes in nucleosome positioning or phasing, and what is the preferential location (if any) of MeC. Our study helps understand the important role of methylation in gene expression regulation
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