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

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  • Pascal Giehr
  • Charalampos Kyriakopoulos
  • Gabriella Ficz
  • Verena Wolf
  • Jörn Walter

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.Author Summary: Oxidation of 5mC by Ten-eleven translocation (Tet) enzymes leads to the formation of 5hmC and other higher oxidized forms in the DNA. Several findings indicate that oxidation induces demethylation processes, but the mechanistic contribution of 5hmC to this process remains unclear. Using an innovative combination of 5hmC detection chemistry and high resolution sequencing, we generate data that can be used for a novel hidden Markov modeling approach. This new model for the first time incorporates 5hmC dynamics and allows to test certain scenarios of demethylation mechanisms. Our findings support the conclusion that 5mC oxidation compromises the copying of DNA methylation patterns across generations in ES-cells.

Suggested Citation

  • Pascal Giehr & Charalampos Kyriakopoulos & Gabriella Ficz & Verena Wolf & Jörn Walter, 2016. "The Influence of Hydroxylation on Maintaining CpG Methylation Patterns: A Hidden Markov Model Approach," PLOS Computational Biology, Public Library of Science, vol. 12(5), pages 1-16, May.
    • Handle: RePEc:plo:pcbi00:1004905
    DOI: 10.1371/journal.pcbi.1004905
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    References listed on IDEAS

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    1. Julia Arand & David Spieler & Tommy Karius & Miguel R Branco & Daniela Meilinger & Alexander Meissner & Thomas Jenuwein & Guoliang Xu & Heinrich Leonhardt & Verena Wolf & Jörn Walter, 2012. "In Vivo Control of CpG and Non-CpG DNA Methylation by DNA Methyltransferases," PLOS Genetics, Public Library of Science, vol. 8(6), pages 1-11, June.
    2. Mark Wossidlo & Toshinobu Nakamura & Konstantin Lepikhov & C. Joana Marques & Valeri Zakhartchenko & Michele Boiani & Julia Arand & Toru Nakano & Wolf Reik & Jörn Walter, 2011. "5-Hydroxymethylcytosine in the mammalian zygote is linked with epigenetic reprogramming," Nature Communications, Nature, vol. 2(1), pages 1-8, September.
    3. Déborah Bourc'his & Timothy H. Bestor, 2004. "Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L," Nature, Nature, vol. 431(7004), pages 96-99, September.
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