@article{d2df030f7ea847f2946c26bdc64503ac,
title = "MERVL/Zscan4 Network Activation Results in Transient Genome-wide DNA Demethylation of mESCs",
abstract = "Mouse embryonic stem cells are dynamic and heterogeneous. For example, rare cells cycle through a state characterized by decondensed chromatin and expression of transcripts, including the Zscan4 cluster and MERVL endogenous retrovirus, which are usually restricted to preimplantation embryos. Here, we further characterize the dynamics and consequences of this transient cell state. Single-cell transcriptomics identified the earliest upregulated transcripts as cells enter the MERVL/Zscan4 state. The MERVL/Zscan4 transcriptional network was also upregulated during induced pluripotent stem cell reprogramming. Genome-wide DNA methylation and chromatin analyses revealed global DNA hypomethylation accompanying increased chromatin accessibility. This transient DNA demethylation was driven by a loss of DNA methyltransferase proteins in the cells and occurred genome-wide. While methylation levels were restored once cells exit this state, genomic imprints remained hypomethylated, demonstrating a potential global and enduring influence of endogenous retroviral activation on the epigenome.",
keywords = "chromatin, DNA methylation, embryonic stem cell, endogenous retrovirus, imprint, MERVL, preimplantation, reprogramming, Zscan4",
author = "Eckersley-Maslin, {M{\'e}lanie A.} and Valentine Svensson and Christel Krueger and Stubbs, {Thomas M.} and Pascal Giehr and Felix Krueger and Miragaia, {Ricardo J.} and Charalampos Kyriakopoulos and Berrens, {Rebecca V.} and In{\^e}s Milagre and J{\"o}rn Walter and Teichmann, {Sarah A.} and Wolf Reik",
note = "Funding Information: The authors thank all members of the W.R. laboratory for helpful discussions. We also thank Ferdinand von Meyenn and Mario Iurlaro for serum-2i transcriptome data, Simon Andrews for bioinformatics support, Simon Walker for imaging support, Nathalie Smerdon for high-throughput sequencing assistance, David Oxley for mass spectrometry, Rachael Walker for flow cytometry assistance, Ruslan Strogantsev for genomic imprinting discussions, Minoru Ko for the Zscan4c::EGFP plasmid, Samuel Pfaff for the MERVL::tdTomato plasmid, and Haruhiko Koseki for Dnmt1 fl/fl ESCs. M.A.E.-M. is supported by an EMBO Fellowship (ALTF938-2014) and Marie Sklodowska-Curie Individual Fellowship. P.G. was supported by DFG grant WA1029 within the SFB1027. Research in W.R.{\textquoteright}s lab is supported by the BBSRC (grant BB/K010867/1), Wellcome Trust (grant 095645/Z/11/Z), EU EpiGeneSys, and BLUEPRINT. Publisher Copyright: {\textcopyright} 2016 The Author(s)",
year = "2016",
month = sep,
day = "27",
doi = "10.1016/j.celrep.2016.08.087",
language = "English",
volume = "17",
pages = "179--192",
journal = "Cell reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "1",
}
