Telomere dysfunction cooperates with epigenetic alterations to impair murine embryonic stem cell fate commitment

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 (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.

Histone demethylase complexes KDM3A and KDM3B cooperate with OCT4/SOX2 to define a pluripotency gene regulatory network

“…In addition, the expression of LIN28A also decreased in FD‐ treatment, while its expression increased significantly in F‐, indicating that it was also regulated by other factors. In previous study, OCT4 and LIN28A were also influenced by additional factors or chromatin conformation, such as H3K27ac or H3K4me 2,67,68 . Our study demonstrated that both were inhibited by H3K9me2 during pluripotency maintenance in piPSCs.…”

Understanding the role of telomere attrition and epigenetic signatures in COVID-19 severity

“…The exact relationship between telomere attrition and epigenetic alterations is still elusive. However, some evidence suggests that eroded telomeres lead to differentiation instability via DNA methylation ( Criqui et al, 2020 ).…”

Adapt to Persist: Glioblastoma Microenvironment and Epigenetic Regulation on Cell Plasticity

“…Normally, somatic cells have a limited proliferation capacity due to the shortening of telomeres (repetitive protective sequences located at the ends of chromosomes). In cancer cells, telomere attrition is partially prevented thanks to the addition of telomeric repeats by the enzyme telomerase, whose catalytic core is composed of a reverse transcriptase (TERT) and an RNA template [ 155 ]. Mutations in the TERT promoter are found in 60–80% of GBMs and have been associated with increased telomerase activity (TA).…”