Publication — IRIC
Telomere dysfunction cooperates with epigenetic alterations to impair murine embryonic stem cell fate commitment.
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.