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.
Highlights
DNA methylation is an epigenetic modification essential for the regulation of genome stability and genome function [1, 2]
Oxidation of 5mC by Ten-eleven translocation (Tet) enzymes leads to the formation of 5-hydroxymethyl cytosine (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
Summary
DNA methylation is an epigenetic modification essential for the regulation of genome stability and genome function [1, 2]. The palindromic nature of a CpG sequence in which 5mC occurs allows a recognition of the 5mC hemimethylated state after semi-conservative replication and a copying of the parental methylation pattern to the newly synthesized DNA strand (see Fig 1). A series of experiments revealed that Dnmt in conjunction with Uhrf are responsible for this copying referred to as maintenance methylation. Dnmt and Uhrf have a high preference for binding to hemimethylated CpG substrates [7,8,9]. Together they assure the maintenance symmetric CpG methylation patterns after each round of replication
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