Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Nuclear barrier induction as a new modality of cellular senescence

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE112530 | GEO | 2021/06/17

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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

Nuclear barrier induction as a new modality of cellular senescence

Project description:Nuclear barrier induction as a new modality of cellular senescence

| PRJNA448140 | ENA

Expression data from control infected and H-RASG12V infected IMR90 cells.

Project description:Cellular senescence is a stable proliferation arrest associated with an altered secretory pathway, the Senescence-Associated Secretory Phenotype (SASP). However, cellular senescence is initiated by diverse molecular triggers, such as activated oncogenes and shortened telomeres, and is associated with varied and complex physiological endpoints, such as tumor suppression and tissue aging. The extent to which distinct triggers activate divergent modes of senescence that might be associated with different physiological endpoints is largely unknown. To begin to address this, we performed gene expression profiling to compare the senescence programs associated with two different modes of senescence, oncogene-induced senescence (OIS) and replicative senescence (RS [in part caused by shortened telomeres]). While both OIS and RS are associated with many common changes in gene expression compared to control proliferating cells, they also exhibit substantial differences. These results are discussed in light of potential physiological consequences, tumor suppression and aging. We used microarrays to detail the global programme of gene expression after oncogene induced senescence.

2014-02-28 | E-GEOD-54402 | biostudies-arrayexpress

Unveiling E2F4, TEAD1 and AP-1 as regulatory transcription factors of the replicative senescence program by multi-omics analysis

Project description:Senescence, a stable state of growth arrest, affects many physiological and pathophysiological processes, especially aging. Previous work has indicated that transcription factors (TFs) play a role in regulating senescence. However, a systematic study of regulatory TFs during replicative senescence (RS) using multi-omics analysis is still lacking. Here, we generated time-resolved RNA-seq, reduced representation bisulfite sequencing (RRBS) and ATAC-seq datasets during RS of mouse skin fibroblasts, which demonstrated that an enhanced inflammatory response and reduced proliferative capacity were the main characteristics of RS in both the transcriptome and epigenome. Through integrative analysis and genetic manipulation, we found that transcription factors E2F4, TEAD1 and AP-1 are key regulators of RS. Overexpression of E2f4 improved cellular proliferative capacity, attenuated SA-β-Gal activity and changed RS-associated differentially methylated sites (DMSs). Moreover, knockdown of Tead1 attenuated SA-β-Gal activity and partially altered the RS-associated transcriptome. In addition, knockdown of Atf3, one member of AP-1 superfamily TFs, reduced Cdkn2a (P16) expression in pre-senescent fibroblasts. Taken together, results of this study identified transcription factors regulating the senescence program through multi-omics analysis, providing potential therapeutic targets for anti-aging.

2021-10-01 | GSE179880 | GEO

Unveiling E2F4, TEAD1 and AP-1 as regulatory transcription factors of the replicative senescence program by multiomics analysis

2021-10-08 | GSE185416 | GEO

Expression data from control infected and H-RASG12V infected IMR90 cells.

2014-02-28 | GSE54402 | GEO

Profiling nucleo/cytoplasmic distribution of mRNAs identifies a role for the Golgi-to-ER trafficking in C9orf72 toxicity

Project description:Compelling evidence indicates that defects in nucleocytoplasmic transport contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS). In particular, hexanucleotide (G4C2) repeat expansions in C9orf72, the most common cause of genetic ALS, have a widespread impact on the transport machinery that regulates the nucleocytoplasmic distribution of proteins and RNAs, thereby affecting their functions. We have previously reported that the expression of G4C2 hexanucleotide repeats in cultured human and mouse cells caused a marked accumulation of poly(A) mRNAs in cell nuclei, suggesting that mRNA trafficking is impaired by expanded C9orf72-ALS repeats. To further characterize the process, in this work we set out to systematically identify the specific mRNAs that are altered in their nucleocytoplasmic distribution in the presence of C9orf72-ALS repeats. Results from RNAseq profiling of nuclear and cytoplasmic RNA fractions obtained from cells expressing G4C231 repeats show a significant accumulation of mRNAs in the nuclei of G4C231 cells, further suggesting that nuclear retention of mRNAs is a major effect of C9orf72 expanded repeats expression. Interestingly, pathway analysis shows that mRNAs involved in ER-to-Golgi trafficking are particularly enriched among the identified mRNAs. Most importantly, functional studies in cultured cells and Drosophila indicate that the membrane trafficking route regulated by ARFGAP1, a GTPase-activating protein that associates with Golgi, is specifically affected by expanded C9orf72 repeats, as well as by C9orf72-related dipeptide repeat proteins (C9-DPRs), pointing to ER-to-Golgi vesicle-mediated transport as a target of C9orf72 toxicity.

2023-08-21 | GSE235448 | GEO

Revisiting the Hayflick Limit: Insights from an Integrated Analysis of Changing Transcripts, Proteins, Metabolites and Chromatin.

Project description:Replicative senescence (RS) as a model has become the central focus of research into cellular aging in vitro. Despite decades of study, this process through which cells cease dividing is not fully understood in culture, and even much less so in vivo during development and with aging. Here, we revisit Hayflick’s original observation of RS in WI-38 human fetal lung fibroblasts equipped with a battery of high dimensional modern techniques and analytical methods to deeply profile the process of RS across each aspect of the central dogma and beyond. We applied and integrated RNA-seq, proteomics, metabolomics, and ATAC-seq to a high resolution RS time course. We found that the transcriptional changes that underlie RS manifest early, gradually increase, and correspond to a concomitant global increase in accessibility in nucleolar and lamin associated domains. During RS WI-38 fibroblast gene expression patterns acquire a striking resemblance to those of myofibroblasts in a process similar to the epithelial to mesenchymal transition (EMT). This observation is supported at the transcriptional, proteomic, and metabolomic levels of cellular biology. In addition, we provide evidence suggesting that this conversion is regulated by the transcription factors YAP1/TEAD1 and the signaling molecule TGF-β2.

2022-04-04 | PXD028799 | Pride

Aging-regulated PNUTS maintains endothelial barrier function via SEMA3B suppression [PNUTS]

Project description:Age-related diseases pose great challenges to health care systems worldwide. During aging, endothelial senescence increases the risk for cardiovascular disease. Recently, it was described that Phosphatase 1 Nuclear Targeting Subunit (PNUTS) has a central role in cardiomyocyte aging and homeostasis. Here, we determined the role of PNUTS in endothelial cell aging. We confirmed that PNUTS is repressed in senescent endothelial cells (ECs). Moreover, PNUTS silencing elicits several of the hallmarks of endothelial aging: senescence, reduced angiogenesis and loss of barrier function. To validate our findings in vivo, we generated an endothelial-specific inducible PNUTS-deficient mouse line (Cdh5-CreERT2;PNUTSfl/fl), termed PNUTSEC-KO. Two weeks after PNUTS deletion, PNUTSEC-KO mice presented severe multiorgan failure and vascular leakage. Transcriptomic analysis of PNUTS-silenced HUVECs and lungs of PNUTSEC-KO mice revealed that the PNUTS-PP1 axis tightly regulates the expression of semaphorin 3B (SEMA3B). Indeed, silencing of SEMA3B completely restored barrier function after PNUTS loss-of-function. These results reveal a pivotal role for PNUTS in endothelial homeostasis through a SEMA3B downstream pathway that provides a potential target against the effects of aging in ECs.

2024-04-15 | GSE263742 | GEO

Aging-regulated PNUTS maintains endothelial barrier function via SEMA3B suppression

2024-04-14 | GSE263531 | GEO