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Nuclear barrier induction as a new modality of cellular senescence

ABSTRACT: Nuclear barrier induction as a new modality of cellular senescence

PROVIDER: PRJNA448140 | ENA |

REPOSITORIES: ENA

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Nuclear barrier induction as a new modality of cellular senescence

Project description:Blocking of nucleocytoplasmic trafficking is an essential feature of replicative senescence (RS). However, whether nuclear barrier per se causes cellular senescence still remains elusive. Here, we show that nuclear barrier induced by blocking nucleocytoplasmic trafficking, especially nuclear export, elicits RS-like changes in SA-β-gal activity, DNA damage, and expression of cell cycle regulators. Comparative transcriptome analysis revealed that nuclear barrier-induced senescence (NBIS) was most similar in gene expression changes to RS compared to senescence induced by stresses (oxidative stress, DNA damage and oncogene), implying that nuclear barrier induces RS-like physiological senescence-associated changes. Shared senescence-related processes between NBIS and RS included lysosomal degradation, nuclear transport, and translation, resulting in coordinated reduction in transmission of extrinsic signals to nucleus and intracellular protein supply from nucleus. Notably, these processes were conserved in yeast aging. Therefore, we propose NBIS as a novel modality of cellular senescence, representing the fundamental nature of physiological aging in eukaryotes.

2021-06-17 | GSE112530 | GEO

Blocking Nuclear Receptor Nr4a3 Unlocks the Senescence Barrier to Promote Direct Cardiac Reprogramming

Project description:Direct reprogramming of scar-forming fibroblasts into induced cardiomyocytes (iCMs) offers a regenerative strategy to repair injured myocardium. However, reprogramming efficiency remains low in fibroblasts from adult and aged hearts, and the molecular barriers underlying this resistance remain poorly understood. Here, we used transcriptomic and epigenetic profiling to uncover cellular senescence as a key obstacle limiting fibroblast plasticity and cardiogenic conversion. Fibroblasts from post-neonatal stages exhibited impaired activation of cardiac gene programs and persistent expression of fibrotic and inflammatory signatures. A loss of function screen identified Nr4a3 as a key repressor of cardiac reprogramming, particularly in senescent and aged cardiac fibroblasts (CFs). Nr4a3 overexpression promoted senescence and suppressed iCM reprogramming, whereas Nr4a3 knockdown significantly enhanced iCM induction from both murine and human senescent CFs. Mechanistically, Nr4a3 depletion remodeled the chromatin landscape by shifting it from a fibrotic and inflammatory state to a regenerative cardiac program. We further identified Cxcl14, a senescence-associated secretory phenotype (SASP) factor upregulated by Nr4a3, as a key downstream effector. Blocking Cxcl14 restored reprogramming in otherwise refractory fibroblasts. In vivo, Nr4a3 knockdown enhanced reprogramming-based improvement of heart function following myocardial infarction. These findings demonstrated that cellular senescence is a major barrier to direct cardiac reprogramming and identified Nr4a3 as a central regulator of this block. Targeting Nr4a3 and its downstream effectors may represent a promising therapeutic avenue to enhance cardiac regeneration in aged individuals following injury.

2025-10-11 | GSE305089 | GEO

Synergistic induction of blood-brain barrier properties

Project description:Synergistic induction of blood-brain barrier properties

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Disruption of nucleocytoplasmic trafficking as a cellular senescence driver

Project description:Senescent cells exhibit a reduced response to intrinsic and extrinsic stimuli. This reduction could be explained by disrupted nuclear transmission of signals. However, this hypothesis required more evidence to complete as a new modality of cellular senescence. Proteomic analysis of the cytoplasmic and nuclear fractions from young and senescent cells revealed disruption of nucleocytoplasmic trafficking (NCT) as an essential feature of replicative senescence (RS) at the global level. Blocking NCT either chemically or genetically induced RS-like senescence phenotypes, named as nuclear barrier-induced senescence (NBIS). Transcriptomic analysis revealed that NBIS had the most similar gene expression pattern to RS, compared with other stress-induced types of cellular senescence. Core proteomic and transcriptomic shared patterns between RS and NBIS included upregulation of endocytosis-lysosome network and downregulation of NCT in senescent cells, which were also conserved in yeast aging model. These results implicate an aging-dependent coordinated reduction in the transmission of extrinsic signals to the nucleus and in the nucleus-to-cytoplasm supply of proteins/RNAs. We further showed that the aging-associated decrease in Sp1 transcription factor expression was responsible for downregulation of NCT. Our results suggest that NBIS is a modality of cellular senescence that can represent the nature of physiological aging in eukaryotes.

2021-06-18 | PXD025618 | Pride

Inhibiting or depleting AHCY prevents senescence induction

Project description:Inhibiting or depleting AHCY prevents senescence induction

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Cancer immune control needs senescence induction by Stat1 dependent cell cycle regulator pathways in tumours

Project description:Immune checkpoint bloackade (ICB)-based or natural cancer immune responses largely eliminate tumours. Yet, they require additional mechanisms to arrest those cancer cells that are not rejected. Cytokine-induced senescence (CIS) can stably arrest cancer cells, suggesting that interferon-dependent induction of senescence-inducing cell cycle regulators is needed to control those cancer cells that escape from killing. Here we report in two different cancers sensitive to T cell-mediated rejection, we show that deletion of the senescence-inducing cell cycle regulators p16Ink4a/p19Arf (Cdkn2a) or p21Cip1 (Cdkn1a) in the tumour cells abrogated both, the natural and the ICB-induced cancer immune control. Also in humans, melanoma metastases that progressed rapidly during ICB have losses of senescence-inducing genes and amplifications of senescence inhibitors. Metastatic cells also resist CIS. Such genetic and functional alterations are infrequent in metastatic melanomas regressing during ICB. Thus, activation of tumour-intrinsic, senescence-inducing cell cycle regulators is required to stably arrest those cancer cells that escape from eradication.

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Blocking Nuclear Receptor Nr4a3 Unlocks the Senescence Barrier to Promote Direct Cardiac Reprogramming

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Blocking Nuclear Receptor Nr4a3 Unlocks the Senescence Barrier to Promote Direct Cardiac Reprogramming

Project description:Blocking Nuclear Receptor Nr4a3 Unlocks the Senescence Barrier to Promote Direct Cardiac Reprogramming

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Blocking Nuclear Receptor Nr4a3 Unlocks the Senescence Barrier to Promote Direct Cardiac Reprogramming

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Project description:Blocking Nuclear Receptor Nr4a3 Unlocks the Senescence Barrier to Promote Direct Cardiac Reprogramming