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Cell Rep. 2016 Sep 27;17(1):179-192. doi: 10.1016/j.celrep.2016.08.087.

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

Author information

1
Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, UK. Electronic address: eckersleym@babraham.ac.uk.
2
EMBL-European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
3
Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, UK.
4
Laboratory of EpiGenetics, Saarland University, Campus A2 4, 66123 Saarbrücken, Germany.
5
Bioinformatics Group, Babraham Institute, Cambridge CB22 3AQ, UK.
6
EMBL-European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK; Centre of Biological Engineering, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal.
7
Computer Science Department, Saarland University, Campus E1.3, 66123 Saarbrücken, Germany.
8
Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, UK; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. Electronic address: wolf.reik@babraham.ac.uk.

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:

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

PMID:
27681430
PMCID:
PMC5055476
DOI:
10.1016/j.celrep.2016.08.087
[Indexed for MEDLINE]
Free PMC Article

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