MERVL/Zscan4 Network Activation Results in Transient Genome-wide DNA Demethylation of mESCs.
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.
Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, UK. Electronic address: eckersleym@babraham.ac.uk.
Mélanie A
MA
Eckersley-Maslin
EMBL-European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
Valentine
V
Svensson
Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, UK.
Christel
C
Krueger
Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, UK.
Thomas M
TM
Stubbs
Laboratory of EpiGenetics, Saarland University, Campus A2 4, 66123 Saarbrücken, Germany.
Pascal
P
Giehr
Bioinformatics Group, Babraham Institute, Cambridge CB22 3AQ, UK.
Felix
F
Krueger
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.
Ricardo J
RJ
Miragaia
Computer Science Department, Saarland University, Campus E1.3, 66123 Saarbrücken, Germany.
Charalampos
C
Kyriakopoulos
Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, UK.
Rebecca V
RV
Berrens
Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, UK.
Inês
I
Milagre
Laboratory of EpiGenetics, Saarland University, Campus A2 4, 66123 Saarbrücken, Germany.
Jörn
J
Walter
EMBL-European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
Sarah A
SA
Teichmann
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.
Wolf
W
Reik
D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D065150:Cellular Reprogramming; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000172:deficiency / Q000235:genetics; D020077:Endogenous Retroviruses / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D016678:Genome; D018392:Genomic Imprinting; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D005810:Multigene Family; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D059010:Single-Cell Analysis; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D059467:Transcriptome
D002843:Chromatin; D012333:RNA, Messenger; D014157:Transcription Factors; C000588925:Zscan4c protein, mouse; D015254:DNA Modification Methylases
DNA methylation; MERVL; Zscan4; chromatin; embryonic stem cell; endogenous retrovirus; imprint; preimplantation; reprogramming
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