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Publication Detail
TET1 drives global DNA demethylation via DPPA3-mediated inhibition of maintenance methylation
  • Publication Type:
    Working discussion paper
  • Authors:
    Mulholland C, Ryan J, Qin W, Bartoschek M, Traube F, Parsa E, Modic M, Nixdorf D, Ziegenhain C, Carell T, Enard W, Bultmann S, Leonhardt H
  • Publication date:
  • Status:
SUMMARY DNA modifications undergo genome-wide changes during development, play a central role in epigenetic gene regulation, and preserve genome stability. Ten-eleven translocation (TET) proteins catalyze the oxidation of 5-methylcytosine (5mC) and are implicated in DNA demethylation and the regulation of gene expression (Chen et al., 2013; Ficz et al., 2011; Ito et al., 2011; Khoueiry et al., 2017; Koh et al., 2011; Pfaffeneder et al., 2011; Szwagierczak et al., 2010; Tahiliani et al., 2009; Vella et al., 2013; Williams et al., 2011; Wu et al., 2011; Xiong et al., 2016). However, the degree to which the gene regulatory effects of TET proteins depend on catalytic functions and the extent to which oxidative cytosine modifications represent intermediates of active DNA demethylation or serve as stable epigenetic marks still remains unclear. Here, we dissect the stage-specific catalytic and non-catalytic contributions of TET1 to the regulation of the methylome and transcriptome in the transition from naïve to primed pluripotency. Whereas non-catalytic functions of TET1 prevent the premature exit from pluripotency, we find that the catalytic activity of TET1 is necessary for the expression of the naïve pluripotency marker DPPA3 (STELLA/PGC7)(Hayashi et al., 2008). DPPA3 in turn binds and displaces UHRF1 from nuclear methylation sites to the cytoplasm, thereby impairing the recruitment and activity of the maintenance DNA methyltransferase DNMT1. Collectively, our work delineates catalytic and non-catalytic functions of TET1, uncovers the mechanism of TET1-governed DNA demethylation, and reveals the mechanistic basis by which DPPA3 antagonizes global DNA methylation.
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