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.
Highlights
Cellular processes crucial for development, tissue regeneration or cancer progression depend on the presence of cells that retain the capacity to commit to multiple lineages, called pluripotent or multipotent cells
Since the repression of Nanog and Pou5f1 during differentiation rely upon H3K27me3 deposition via the Polycomb Repressive Complex 2 (PRC2) (Obier et al, 2015; Villasante et al, 2011), and Dnmt3 and PRC2 are critical to Murine embryonic stem cells (mESCs) neural differentiation (Liu et al, 2018), we investigated whether perturbation of H3K27me3 levels, genome-wide, could further impact the cell differentiation defect associated with dysfunctional telomeres
Murine ESCs with critically short telomeres fail to consolidate a differentiated state To address the role of telomere shortening on stem cell differentiation, we analyzed late-passage telomerase reverse transcriptase (Tert)-/- mESCs that possess significantly shorter telomeres and an increase in end-to-end fusions compared to WT mESCs (Figure 1—figure supplement 1A,B; Liu et al, 2000)
Summary
Cellular processes crucial for development, tissue regeneration or cancer progression depend on the presence of cells that retain the capacity to commit to multiple lineages, called pluripotent or multipotent cells. Murine embryonic stem cells (mESCs) are pluripotent and can form all tissues in the body, whereas multipotent cells can form numerous, but not all, tissue types. The capacity of these cells to replenish committed cell lineages deteriorates with age due to intrinsic and extrinsic factors (Liu and Rando, 2011; Waterstrat and Van Zant, 2009). Stem cell aging directly impacts tissue function through perturbations in the stem cell reservoir or the function of their lineage-committed progeny. The gradual attrition of chromosome ends, called telomeres, is observed in human cells in culture and in vivo, and is an established hallmark of aging that is often referred to as the ‘telomere clock’
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