MERVL/Zscan4 Network Activation Results in Transient Genome-wide DNA Demethylation of mESCs

Mélanie A. Eckersley-Maslin*, Valentine Svensson, Christel Krueger, Thomas M. Stubbs, Pascal Giehr, Felix Krueger, Ricardo J. Miragaia, Charalampos Kyriakopoulos, Rebecca V. Berrens, Inês Milagre, Jörn Walter, Sarah A. Teichmann, Wolf Reik

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

113 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)179-192
Number of pages14
JournalCell Reports
Volume17
Issue number1
DOIs
Publication statusPublished - 27 Sep 2016
Externally publishedYes

Keywords

  • chromatin
  • DNA methylation
  • embryonic stem cell
  • endogenous retrovirus
  • imprint
  • MERVL
  • preimplantation
  • reprogramming
  • Zscan4

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