Telomere dysfunction cooperates with epigenetic alterations to impair murine embryonic stem cell fate commitment
- University of Montreal, Canada
- University Health Network, Canada
- McGill University Health Centre, Canada
- University of Toronto, Canada
- University Heath Network, Canada
Abstract
The precise relationship between epigenetic perturbations and telomere dysfunction is an extant question. Previously, we showed that telomere dysfunction leads to differentiation instability in murine embryonic stem cells (mESCs) via perturbations in DNA methylation at pluripotency-factor promoters. Here, we uncovered that telomerase reverse transcriptase null (Tert-/-) mESCs exhibit genome-wide perturbations in chromatin accessibility and gene expression during differentiation. These changes were accompanied by an increase of H3K27me3 globally, an altered chromatin landscape at the Pou5f1/Oct4 pluripotency gene promoter, and impaired Tert-/- mESC differentiation. Inhibition of the Polycomb Repressive Complex 2 (PRC2), an H3K27 tri-methyltransferase, exacerbated the impairment in differentiation and pluripotency gene repression in Tert-/- mESCs but not wild-type mESCs, whereas inhibition of H3K27me3 demethylation led to a partial rescue of the Tert-/- phenotype. This data reveals a new interdependent relationship between H3K27me3 and telomere integrity in stem cell lineage commitment that may have implications in aging and cancer.
Data availability
ATAC-seq and ChIP-seq data has been deposited in GEO under accession number GSE130780 and GSE146322. The Metadata sheet accompanying this deposition is provided in Figure 4 - source data files 2 and 4.
Article and author information
Author details
Funding
Canadian Institutes of Health Research (367427)
- Lea Harrington
Canadian Institutes of Health Research (133573)
- Lea Harrington
Wellcome (084637)
- Lea Harrington
Ontario Genomics Institute (OGI-055)
- Cheryl H Arrowsmith
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Raymund Wellinger, Université de Sherbrooke, Canada
Version history
- Received: April 2, 2019
- Accepted: April 6, 2020
- Accepted Manuscript published: April 16, 2020 (version 1)
- Version of Record published: April 30, 2020 (version 2)
Copyright
© 2020, Criqui et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Telomere dysfunction cooperates with epigenetic alterations to impair murine embryonic stem cell fate commitment
eLife 9:e47333.
https://doi.org/10.7554/eLife.47333
Further reading
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