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Author Spotlight: High-Sensitivity Tissue Factor Activity Assay for Plasma Diagnosis
Published on: December 29, 2023
Epigenetic regulation of tissue factor inducibility in endothelial cell senescence
David J Kurz1, Sravan Payeli2, Helen Greutert2
1Center for Molecular Cardiology, Institute of Physiology, University of Zurich, Switzerland; Cardiology, Triemli Hospital, Zurich, Switzerland.
Abstract:
Cellular senescence, a programmed state induced by multiple deleterious triggers, is characterised by permanent cell-cycle exit and altered gene expression and cell morphology. In humans it is considered a tumor suppressor mechanism, mediating removal of damaged or mutated cells from the cell-cycle pool, and may also contribute to the ageing process. In this study, we show that senescent human umbilical vein endothelial cells lose their ability to induce tissue factor (TF), a transmembrane protein with important roles in hemostasis and cancer progression, in response to thrombin or - independently of cell-surface receptors - phorbol-12-myristate-13-acetate. This phenomenon could not be explained by senescence-related alterations in the downstream signal transduction cascade or by accelerated TF mRNA degradation. Rather, using chromatin immuno-precipitation we could show that loss of TF gene inducibility during senescence occurs following chromatin remodelling of the TF promoter resulting from hypo-acetylation of histone H3. These findings were reversible after transduction of presenescent cultures with telomerase reverse transcriptase, enabling late-passage cultures to escape senescence. These results extend the involvement of heterochromatic gene silencing in senescence beyond cell cycle-related genes and suggest a novel anti-cancer mechanism of senescence through inhibition of TF inducibility.
Insights
Cellular senescence, a state of permanent cell-cycle exit, inhibits tissue factor (TF) gene induction in endothelial cells. This occurs via chromatin remodeling, suggesting a novel anti-cancer mechanism for senescence.
Area of Science:
- Cell Biology
- Molecular Biology
- Oncology
Background:
- Cellular senescence is a state of irreversible cell cycle arrest with implications for tumor suppression and aging.
- Tissue Factor (TF) is crucial in hemostasis and cancer progression.
- Senescence involves altered gene expression, but its impact on TF inducibility is unclear.
Purpose of the Study:
- To investigate the effect of cellular senescence on tissue factor (TF) gene induction in human umbilical vein endothelial cells.
- To elucidate the molecular mechanisms underlying changes in TF expression during senescence.
- To explore the potential anti-cancer role of senescence-induced TF inhibition.
Main Methods:
- Induction of cellular senescence in human umbilical vein endothelial cells.
- Stimulation with thrombin and phorbol-12-myristate-13-acetate to assess TF induction.
- Analysis of downstream signaling pathways and TF mRNA stability.
- Chromatin immunoprecipitation (ChIP) to examine TF promoter chromatin structure.
- Reversal of senescence using telomerase reverse transcriptase (TERT) transduction.
Main Results:
- Senescent endothelial cells exhibited a significant loss of TF gene inducibility.
- This loss was not due to altered signaling or mRNA degradation.
- ChIP analysis revealed chromatin remodeling and histone H3 hypoacetylation at the TF promoter in senescent cells.
- TERT transduction reversed senescence and restored TF inducibility.
Conclusions:
- Cellular senescence silences TF gene expression through epigenetic modifications (chromatin remodeling and histone hypoacetylation).
- This epigenetic silencing of TF is a novel mechanism contributing to the tumor-suppressive function of senescence.
- Senescence-induced inhibition of TF offers a potential anti-cancer strategy by limiting pro-tumorigenic pathways.
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