Understanding the connection between epigenetic DNA methylation and nucleosome positioning from computer simulations

PLoS Comput Biol. 2013;9(11):e1003354. doi: 10.1371/journal.pcbi.1003354. Epub 2013 Nov 21.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Computational Biology
  • Cytosine / chemistry
  • Cytosine / metabolism
  • DNA Methylation*
  • Epigenesis, Genetic*
  • Models, Genetic*
  • Molecular Dynamics Simulation
  • Nucleosomes / genetics*
  • Thermodynamics

Substances

  • Nucleosomes
  • Cytosine

Grants and funding

This work was supported by a Sara Borrell fellowship to GP, by MINECO-Spain BIO2012-32868, the European Research Council (ERC-Advanced Grant, MO), and the Fundación Botín. MO is an ICREA Academia Researcher. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.