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Transcriptome analysis of oxdative-stress induced senescence in human astrocytes

ABSTRACT: Purpose: Cellular senescence is a cell stress response resulting in permanent growth arrest and the production of an altered pro-inflammatory secretory profile known as the senescecnce-associated secretory phenotype (SASP). The induction of senescence in astrocytes, a cell type responsible for maintaining homeostasis within the central nervous system (CNS) and responding to CNS insults, has been implicated in neurodegenerative disease. However, little is known about the senescent transcriptome in CNS-derived cell types including astrocytes. Methods: To better understand senescence-associated gene expression changes in astrocytes, we investigated global changes in the astrocyte transcriptome using RNA-seq following the induction of oxidative stress-induced senescence with hydrogen peroxide. Results: During senescence, we find evidence of a loss of brain expressed transcripts involved in diverse CNS processes including neuronal differentiation and development, gliogenesis, axonogenesis, and learning and memory as well as a loss of transcripts involved in MHC class II antigen processing and presentation. In addition, we find evidence for induction of the senescent phenotype including a loss of transcripts involved in cell division and an increase in the mRNA level of inflammatory mediators suggestive of a SASP. Conclusions: Overall, our findings suggest a loss of differentiated function in senescent astrocytes and a gain in neuroinflammatory function as part of the SASP as a potential mechanisms for dysfunction in the aging brain.

ORGANISM(S): Homo sapiens

PROVIDER: GSE58910 | GEO | 2014/12/27

SECONDARY ACCESSION(S): PRJNA253866

REPOSITORIES: GEO

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Oxylipin biosynthesis reinforces cellular senescence through a RAS/p53 feedback loop and allows detection of senolysis

Project description:Cellular senescence is a stress or damage response that causes a permanent proliferative arrest and secretion of numerous factors with potent biological activities. This senescence-associated secretory phenotype (SASP) has been characterized largely for secreted proteins that participate in embryogenesis, wound healing, inflammation and many age-related pathologies. By contrast, lipid components of the SASP are understudied. We show that senescent cells activate the biosynthesis of several oxylipins that promote segments of the SASP and reinforce the proliferative arrest. Notably, senescent cells synthesize and accumulate an unstudied intracellular prostaglandin, 1a,1b-dihomo-15-deoxy-delta-12,14-prostaglandin J2. Released 15-deoxy-delta-12,14-prostaglandin J2 is a biomarker of senolysis in culture and in vivo. This and other prostaglandin D2-related lipids promote the senescence arrest and SASP by activating RAS signaling. These data identify an important aspect of cellular senescence and a method to detect senolysis

2021-02-20 | ST001708 | MetabolomicsWorkbench

Transcriptional profiling of growing and senescent WT and IL-1R-depleted IMR90 cells

Project description:Senescent cells no longer divide, but remain metabolically active and secrete an array of cytokines, growth factors, and proteases termed the senescence-associated secretory phenotype (SASP). Previous studies have indicated that the SASP factor IL-1α may be an upstream regular of the SASP. We show here that knockdown of the IL-1α receptor IL-1R results in a sizable reduction of SASP expression late in senescence induction. Our results suggest that targeting the IL-1 signaling pathway is a reliable method to dissociate the SASP from cell-cycle exit.

2019-04-16 | GSE108278 | GEO

Notch signalling mediates secondary senescence

Project description:Oncogene induced senescence (OIS) is a tumour suppressive response to oncogene activation that can be transmitted to neighbouring cells through secreted factors of the senescence associated secretory phenotype (SASP). Using single-cell transcriptomics we observed two distinct endpoints, a primary marked by Ras and a secondary by Notch. We find that secondary senescence in vitro and in vivo requires Notch, rather than SASP alone as previously thought. Currently, primary and secondary senescent cells are not thought of as functionally distinct endpoints. A blunted SASP response and the induction of fibrillar collagens in secondary senescence compared to OIS point towards a functional diversification.

2019-04-23 | GSE115301 | GEO

ChIP-Seq data from IMR90 Control and IMR90 HRAS-G12V using an H3K79me3 antibody

Project description:Oncogene-induced senescent cells display a robust change in their epigenome and have increased transcription and secretion of numerous pro-inflammatory cytokines and chemokines termed the senescence-associated secretory phenotype (SASP). Therefore, understanding how and if the epigenome is involved in regulating the transcription of the SASP is critical to understanding how to restrain the harmful effects of the SASP. The active histone marks H3K79me2 and H3K79me3 and their methyltransferase DOT1L are increased during oncogene-induced senescence. Whether H3K79 methylation and DOT1L expression are involved in the transcriptional regulation of the SASP is unknown.

2020-08-21 | GSE156591 | GEO

Gene expression data from IMR90 Control, IMR90 HRAS-G12V, IMR90 HRAS-G12V+shDOT1L, IMR90 DOT1L Overexpression

2020-08-21 | GSE156648 | GEO

GNPS - Exosomes Released from Senescent Cells and Isolated from Human Plasma Reveal Aging-associated Proteomic Signatures

Project description:Senescence emerged as a significant mechanism of aging and age-related diseases, offering an attractive target for clinical intervention. Senescent cells release senescence-associated secretory phenotype (SASP), including exosomes that may act as signal transducers between distal tissues, propagating secondary senescence and signaling throughout the body. However, the composition of exosome SASP remains underexplored, presenting an opportunity for novel unbiased discovery. Here, we present a detailed lipidomic analysis of exosome SASP using mass spectrometry from senescent primary human lung fibroblasts and human plasma from young and older individuals.

2024-03-15 | MSV000094326 | GNPS

A novel histone variant H2A.J accumulates in senescent human cell with persistent DNA damage and promote inflammatory gene expression

Project description:The senescence of mammalian cells is characterized by a proliferative arrest in response to stress and the expression of an inflammatory phenotype. We discovered that H2A.J, a poorly studied H2A variant found only in mammals, accumulates in human fibroblasts in senescence with persistent DNA damage. Knock-down of H2A.J interfered with the derepression of a set of inflammatory genes that contribute to the senescent-associated secretory phenotype (SASP), and over-expression of H2A.J increased the expression of some of these genes in proliferating cells. H2A.J accumulation may thus promote the signaling of senescent cells to the immune system. 41 samples analysed

2016-07-04 | E-GEOD-62701 | biostudies-arrayexpress

Exosomes Released from Senescent Cells and Isolated from Human Plasma Reveal Aging-associated Proteomic Signatures

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Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence

Project description:Cellular senescence is triggered by various distinct stresses and characterized by a permanent cell cycle arrest. Senescent cells secrete a variety of inflammatory factors, collectively referred to as the senescence-associated secretory phenotype (SASP). The mechanism(s) underlying the regulation of the SASP remains incompletely understood. Here we define a role for innate DNA sensing in the regulation of senescence and the SASP. We find that cyclic GMP-AMP synthase (cGAS) recognizes cytosolic chromatin fragments (CCFs) in senescent cells. The activation of cGAS, in turn triggers the production of SASP factors via Stimulator of interferon genes (STING), thereby promoting paracrine senescence. We demonstrate that diverse stimuli of cellular senescence engage the cGAS-STING pathway in vitro and we show cGAS-dependent regulation of senescence upon irradiation and oncogene activation in vivo. Our findings provide insights into the mechanisms underlying cellular senescence by establishing the cGAS-STING pathway as a crucial regulator of senescence and the SASP.

2017-06-20 | GSE100102 | GEO

Amphiregulin mediates non-cell-autonomous effect of senescence on reprogramming

Project description:Cellular senescence is an irreversible growth arrest with a highly dynamic secretome, termed the senescence-associated secretory phenotype (SASP). Senescence has been implicated in somatic reprogramming to pluripotency. The cell-intrinsic proliferation arrest is a barrier for reprogramming, whereas the SASP facilitates the cell fate conversion in nonsenescent cells. However, the mechanisms by which reprogramming-induced senescence regulates cell plasticity are not well understood. Here, we have further investigated how the heterogeneity of paracrine senescence impacts reprogramming. We show that senescence promotes in vitro reprogramming in a stress-dependent manner. We identified a catalog of SASP factors and pathways potentially involved in the cell fate conversion using an unbiased proteomic analysis. Amphiregulin (AREG), a growth factor frequently secreted by the senescent cells, promotes in vitro reprogramming by accelerating proliferation and MET via the EGFR signaling pathway. Of note, AREG treatment diminished the negative effect of donor age on reprogramming. Finally, AREG enhances in vivo reprogramming in the skeletal muscle. Hence, senescence could facilitate cellular plasticity via various SASP factors to promote reprogramming and tissue repair.

2022-07-28 | PXD028590 | Pride

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