RT Journal Article
SR Electronic
T1 TET1 drives global DNA demethylation via DPPA3-mediated inhibition of maintenance methylation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 321604
DO 10.1101/321604
A1 Christopher B. Mulholland
A1 Joel Ryan
A1 Weihua Qin
A1 Michael D. Bartoschek
A1 Franziska R. Traube
A1 Edris Parsa
A1 Miha Modic
A1 Daniel Nixdorf
A1 Christoph Ziegenhain
A1 Thomas Carell
A1 Wolfgang Enard
A1 Sebastian Bultmann
A1 Heinrich Leonhardt
YR 2018
UL http://biorxiv.org/content/early/2018/05/15/321604.abstract
AB 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.