Abstract
SummaryMouse 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.
Highlights
It is well known that mouse embryonic stem cells (ESCs) contain extensive epigenetic and transcriptional heterogeneities, yet the mechanistic details of how cells enter and exit these different states and their importance for stem cell potency and maintenance are only beginning to be understood
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
The MERVL/Zscan4 transcriptional network was upregulated during induced pluripotent stem cell reprogramming
Summary
It is well known that mouse embryonic stem cells (ESCs) contain extensive epigenetic and transcriptional heterogeneities, yet the mechanistic details of how cells enter and exit these different states and their importance for stem cell potency and maintenance are only beginning to be understood (reviewed in De Los Angeles et al, 2015; Lee et al, 2014; Torres-Padilla and Chambers, 2014). A rare group of ESCs express early-embryonic transcripts, including the Zscan cluster (Zalzman et al, 2010) and MERVL endogenous retrovirus (Macfarlan et al, 2012). Expression of MERVL is normally restricted to the two-cell mouse preimplantation embryo and occurs transiently in rare ESCs (Macfarlan et al, 2012). The Zscan cluster of zinc-finger proteins, normally restricted to the two-cell embryo (Falco et al, 2007), is expressed in a subset of ESCs (Zscan4+ cells), where it has been proposed to have a role in telomere elongation and genomic stability (Zalzman et al, 2010). The dynamics of transcriptional network activation and any epigenetic consequences in these cells remain unclear
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