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 (Tert-/-) 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 Pou5f1/Oct4 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 Tert-/- mESCs but not wild-type mESCs, whereas inhibition of H3K27me3 demethylation led to a partial rescue of the Tert-/- 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.

Telomere maintenance is essential for maintaining genome integrity in both normal and cancer cells. Without functional telomeres, chromosomes lose their protective structure and undergo fusion and breakage events that drive further genome instability, including cell arrest or death. One means by which this loss can be overcome in stem cells and cancer cells is via re‐addition of G‐rich telomeric repeats by the telomerase reverse transcriptase (TERT). During aging of somatic tissues, however, insufficient telomerase expression leads to a proliferative arrest called replicative senescence, which is triggered when telomeres reach a critically short threshold that induces a DNA damage response. Cancer cells express telomerase but do not entirely escape telomere instability as they often possess short telomeres; hence there is often selection for genetic alterations in the TERT promoter that result in increased telomerase expression. In this review, we discuss our current understanding of the consequences of telomere instability in cancer and aging, and outline the opportunities and challenges that lie ahead in exploiting the reliance of cells on telomere maintenance for preserving genome stability.

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