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Transcription termination safeguards quiescent chromatin for faithful cell-cycle re-entry.

ABSTRACT: Quiescence is a conserved program of endurance and readiness in non-cycling cells that is fundamental to the longevity of eukaryotic lineages, from clonal microbial populations to human regenerative tissues. While this G₀ state is universally associated with a compact chromatin organization, the active safeguards that preserve this structural template—and their necessity for future division competence and fidelity—remain unknown. Here we show, using fission yeast as a model, that chromatin structural maintenance in quiescence requires the enforcement of transcription termination by the conserved factor Ppn1PNUTS/Ref2. We identify a minimal disordered region in Ppn1 that resolves a physical conflict in the quiescent genome by preventing the transcriptional “eviction” of cohesin. Loss of this safeguard drives a progressive structural erosion that deregulates cyclin dependent kinase (CDK) dynamics and causes lethal aneuploidy upon cell-cycle re-entry. Notably, this deterioration is not an inevitable terminal state; re-establishing termination via a brief Ppn1 pulse resets division fidelity by stabilizing a core de novo cohesin landscape. These findings redefine quiescent chromatin as an actively maintainable blueprint rather than a passive standby state established at G₀ entry. We propose that "quiescence exhaustion" is driven by transcriptional stress eroding genomic organization, defining a structural limit to cellular longevity.

ORGANISM(S): Schizosaccharomyces pombe

PROVIDER: GSE348149 | GEO | 2026/09/25

REPOSITORIES: GEO

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Project description:Background: Although quiescence—reversible cell-cycle arrest—is a key part in the life history and fate of many mammalian cell types, the mechanisms of gene regulation in quiescent cells are poorly understood. We sought to clarify the role of microRNAs as regulators of the cellular functions of quiescent human fibroblasts. Results: Using microarrays, we discovered that the expression of the majority of profiled microRNAs differed between proliferating and quiescent fibroblasts. Fibroblasts induced into quiescence by contact inhibition or serum starvation had similar microRNA profiles, indicating common changes induced by distinct quiescence signals. By analyzing the gene expression patterns of microRNA target genes with quiescence, we discovered a strong regulatory function for miR-29, which is downregulated with quiescence. Using microarrays and immunoblotting, we confirmed that miR-29 targets genes encoding collagen and other extracellular matrix proteins and that those target genes are induced in quiescence. In addition, overexpression of miR-29 resulted in more rapid cell cycle re-entry from quiescence. We also found that let-7 and miR-125 were upregulated in quiescent cells. Overexpression of either one alone resulted in slower cell cycle re-entry from quiescence, while the combination of both together slowed cell cycle re-entry even further. Conclusions: microRNAs regulate key aspects of fibroblast quiescence including the proliferative state of the cells as well as their gene expression profiles, in particular, the induction of extracellular matrix proteins in quiescent fibroblasts. microRNAs in human neonatal dermal fibroblasts in 3 cell cycle conditions (proliferating, 4 days serum starved, 7 days contact inhibited) were analyzed by one color microarray. 3 separate fibroblast cell lines from different human donors were analyzed for each condition, with two separate labeling and hybridization samples for each cell line. In total, 18 samples were hybridized to the microRNA microarray.

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Transcription termination safeguards quiescent chromatin for faithful cell-cycle re-entry.

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