The Influence of Hydroxylation on Maintaining CpG Methylation Patterns: A Hidden Markov Model Approach

PLoS Comput Biol. 2016 May 25;12(5):e1004905. doi: 10.1371/journal.pcbi.1004905. eCollection 2016 May.

Abstract

DNA methylation and demethylation are opposing processes that when in balance create stable patterns of epigenetic memory. The control of DNA methylation pattern formation by replication dependent and independent demethylation processes has been suggested to be influenced by Tet mediated oxidation of 5mC. Several alternative mechanisms have been proposed suggesting that 5hmC influences either replication dependent maintenance of DNA methylation or replication independent processes of active demethylation. Using high resolution hairpin oxidative bisulfite sequencing data, we precisely determine the amount of 5mC and 5hmC and model the contribution of 5hmC to processes of demethylation in mouse ESCs. We develop an extended hidden Markov model capable of accurately describing the regional contribution of 5hmC to demethylation dynamics. Our analysis shows that 5hmC has a strong impact on replication dependent demethylation, mainly by impairing methylation maintenance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Methylcytosine / analogs & derivatives
  • 5-Methylcytosine / metabolism
  • Animals
  • Cell Division
  • Computational Biology
  • CpG Islands*
  • DNA Methylation*
  • DNA Replication
  • Embryonic Stem Cells / metabolism
  • Hydroxylation
  • Markov Chains
  • Mice
  • Models, Biological*
  • Stochastic Processes
  • Sulfites / metabolism

Substances

  • Sulfites
  • 5-hydroxymethylcytosine
  • 5-Methylcytosine
  • hydrogen sulfite

Grants and funding

This research has been partially funded by the German Research Council (DFG) as part of the Collaborative Research Center "Physical modeling of non-equilibrium processes in biological systems" (SFB 1027) and the Cluster of Excellence on Multimodal Computing and Interaction at Saarland University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.