Telomere dysfunction cooperates with epigenetic alterations to impair murine embryonic stem cell fate commitment.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 32297856.
- Also identified by DOI 10.7554/eLife.47333 and PMC identifier 7192583.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
The precise relationship between epigenetic alterations and telomere dysfunction is still an extant question. Previously, we showed that eroded telomeres lead to differentiation instability in murine embryonic stem cells (mESCs) via DNA hypomethylation at pluripotency-factor promoters. Here, we uncovered that telomerase reverse transcriptase null (<i>Tert<sup>-/-</sup></i>) mESCs exhibit genome-wide alterations in chromatin accessibility and gene expression during differentiation. These changes were accompanied by an increase of H3K27me3 globally, an altered chromatin landscape at the <i>Pou5f1/Oct4</i> promoter, and a refractory response to differentiation cues. Inhibition of the Polycomb Repressive Complex 2 (PRC2), an H3K27 tri-methyltransferase, exacerbated the impairment in differentiation and pluripotency gene repression in <i>Tert<sup>-/-</sup></i> mESCs but not wild-type mESCs, whereas inhibition of H3K27me3 demethylation led to a partial rescue of the <i>Tert<sup>-/-</sup></i> phenotype. These data reveal a new interdependent relationship between H3K27me3 and telomere integrity in stem cell lineage commitment that may have implications in aging and cancer.
Medical subject headings
- Cell Differentiation
- Embryonic Stem Cells
- Epigenesis, Genetic
- Histones
- Telomere