RNAseq of oncogene-induced senescent murine macrophages
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA642870 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12110227.fastq.gz | Fastqsanger.gz | |||
| SRR12110228.fastq.gz | Fastqsanger.gz | |||
| SRR12110229.fastq.gz | Fastqsanger.gz | |||
| SRR12110230.fastq.gz | Fastqsanger.gz | |||
| SRR12110231.fastq.gz | Fastqsanger.gz |
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Project description:Aging organisms accumulate senescent cells, which are the result of exposure to important stress such as telomere attrition, irradiation, oncogene activation, oxidative stress or cytotoxic drugs. These senescent cells are characterized by a stable cell cycle arrest and an important secretion of pro-inflammatory factors. This senescence-associated secretory phenotype (SASP) has been shown to promote chronic inflammation leading to age-associated diseases. While a lot of in vitro models of senescence focus on senescent fibroblasts, it has been shown that a major portion of the burden of senescent cells in old mice are macrophages. Senescent macrophages have been shown to contribute to atherosclerosis, neurodegenerative diseases and macular degeneration. Yet little is known about senescent macrophages. Considering their potential role in age-associated diseases, we think these senescent macrophages and their secretions need to be investigated. Here we aimed to establish and characterize an in vitro model for oncogene-induced senescence in macrophages, to characterize secretions of these senescent macrophages and to assess impacts of these secretions on recipient cells.
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Project description:Accumulation of senescent cells in the tumour microenvironment can drive tumourigenesis in a paracrine manner through the senescence-associated secretory phenotype (SASP). Using a new p16-FDR mouse line, we show that macrophages and endothelial cells are the predominant senescent cell types in murine KRAS-driven lung tumours. Single cell transcriptomics identify a population of tumour-associated macrophages, expressing a unique array of pro-tumourigenic SASP factors and surface proteins, that are also present in normal aged lungs. Genetic or senolytic ablation of senescent cells, and macrophage depletion, result in a significant reduction in tumour burden and increased mouse survival of KRAS-driven lung cancer models. Of translational relevance, we reveal the presence of macrophages with senescent features in human lung premalignant lesions, but not in adenocarcinomas. Together, our results have uncovered a population of senescent macrophages contributing to the initiation and progression of lung cancer, thus opening potential therapeutic avenues and cancer preventative strategies.
2023-06-02 | GSE230054 | GEO
Project description:Cellular senescence is a stable proliferation arrest that suppresses tumorigenesis. Histone chaperone HIRA deposits nucleosome-destabilizing histone variant H3.3 into chromatin in a DNA replication-independent manner. Histone H3.3 and a subset of other typically M-bM-^@M-^\replication-dependentM-bM-^@M-^] core histones were expressed in non-proliferating senescent cells, the latter linked to alternative mRNA splicing and polyadenylation. Senescent cells incorporated newly-synthesized histones into chromatin, partially dependent on HIRA. HIRA and newly-deposited histone H3.3 co-localized at promoters of expressed genes, and their distribution shifted between proliferating and senescent cells, paralleling changes in gene expression. In senescent cells, gene promoters showed exceptional enrichment of a histone acetylation linked to open and dynamic chromatin, H4K16ac. Abundance of H4K16ac depended on HIRA. In the mouse, inactivation of HIRA downregulated H4K16ac and dramatically enhanced oncogene-induced hyperplasia. To conclude, HIRA controls a previously undefined dynamic non-canonical H4K16ac-decorated chromatin landscape in senescence, and also plays an unanticipated role in suppression of oncogene-induced neoplasia. Examination of HIRA protein binding alongside histone modification H4K16ac and H3.3 in proliferating and senescent IMR90 cells
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Project description:DNA damage or other cellular stress can lead to an irreversible cell cycle arrest, known as cellular
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cells, and are enriched in human cirrhotic liver tissue. Using transcriptomic profiling we identified a unique
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Project description:Cellular senescence drives chronic sterile inflammation during aging via the senescence-associated secretory phenotype (SASP); however, the cell types responsible for this pathology remain poorly defined. Here, we identify p21⁺Trem2⁺ senescent macrophages as a major source of inflammaging. Using primary mouse and human macrophages, we developed a model of DNA damage and cholesterol-induced senescence and applied multi-omic profiling to fully characterize senescent macrophages. We found that senescent macrophages exhibit a distinctive p21-TREM2 expression profile and SASP, driven in part by type-I interferon signaling via secreted mitochondrial DNA. We also found that senescent macrophage accumulation occurs in aged and MASLD mouse livers and is enriched in human cirrhotic liver tissue. Finally, senolytic treatment targeting senescent macrophages reduced liver inflammation and steatosis in both aged and MASLD mice. Together, these findings establish macrophage senescence as a central driver of chronic inflammation in aging and metabolic liver disease, highlighting a promising, tractable therapeutic target.
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Project description:Metabolism is tightly coupled with the process of aging, and tumorigenesis. However, the mechanisms regulating metabolic properties in different contexts remain unclear. Cellular senescence is widely recognized as an important tumor suppressor function and accompanies metabolic remodeling characterized by increased mitochondrial oxidative phosphorylation (OXPHOS). Here we showed retinoblastoma (RB) is required for the increased OXPHOS in oncogene-induced senescent (OIS) cells. Combined metabolic and gene expression profiling revealed that RB mediated activation of the glycolytic pathway in OIS cells, causing upregulation of several glycolytic genes and concomitant increases in the levels of associated metabolites in the glycolytic pathway. Knockdown of these genes by small interfering RNAs (siRNAs) resulted in decreased mitochondrial respiration, suggesting that RB-mediated glycolytic gene activation promotes metabolic flux into the OXPHOS pathway. These results suggest that coordinate transcriptional activation of metabolic genes by RB enables OIS cells to maintain metabolically bivalent states that both glycolysis and OXPHOS are highly active. Collectively, our findings demonstrated a previously unrecognized function of RB in OIS cells. To understand the role of RB, we investigated the effect of RB1-knockdown in the transcription profile of oncogene-induced senescent (OIS) cells. IMR90 ER:Ras cells were treated with 100 nM 4-OHT for 6 days to induce senescence. RNA was isolated 6 days after OHT treatment and hybridized to Affymetrix microarrays. SiRNA transfection (control siRNA or siRB1) was performed 4 days before RNA isolation.
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Project description:Cellular senescence drives chronic sterile inflammation during aging via the senescence-associated secretory phenotype (SASP); however, the cell types responsible for this pathology remain poorly defined. Here, we identify p21⁺Trem2⁺ senescent macrophages as a major source of inflammaging. Using primary mouse and human macrophages, we developed a model of DNA damage and cholesterol-induced senescence and applied multi-omic profiling to fully characterize senescent macrophages. We found that senescent macrophages exhibit a distinctive p21-TREM2 expression profile and SASP, driven in part by type-I interferon signaling via secreted mitochondrial DNA. We also found that senescent macrophage accumulation occurs in aged and MASLD mouse livers and is enriched in human cirrhotic liver tissue. Finally, senolytic treatment targeting senescent macrophages reduced liver inflammation and steatosis in both aged and MASLD mice. Together, these findings establish macrophage senescence as a central driver of chronic inflammation in aging and metabolic liver disease, highlighting a promising, tractable therapeutic target.
2026-02-10 | GSE318651 | GEO
Project description:Cellular senescence drives chronic sterile inflammation during aging via the senescence-associated secretory phenotype (SASP); however, the cell types responsible for this pathology remain poorly defined. Here, we identify p21⁺Trem2⁺ senescent macrophages as a major source of inflammaging. Using primary mouse and human macrophages, we developed a model of DNA damage and cholesterol-induced senescence and applied multi-omic profiling to fully characterize senescent macrophages. We found that senescent macrophages exhibit a distinctive p21-TREM2 expression profile and SASP, driven in part by type-I interferon signaling via secreted mitochondrial DNA. We also found that senescent macrophage accumulation occurs in aged and MASLD mouse livers and is enriched in human cirrhotic liver tissue. Finally, senolytic treatment targeting senescent macrophages reduced liver inflammation and steatosis in both aged and MASLD mice. Together, these findings establish macrophage senescence as a central driver of chronic inflammation in aging and metabolic liver disease, highlighting a promising, tractable therapeutic target.
2026-02-10 | GSE318652 | GEO
Project description:Cellular senescence drives chronic sterile inflammation during aging via the senescence-associated secretory phenotype (SASP); however, the cell types responsible for this pathology remain poorly defined. Here, we identify p21⁺Trem2⁺ senescent macrophages as a major source of inflammaging. Using primary mouse and human macrophages, we developed a model of DNA damage and cholesterol-induced senescence and applied multi-omic profiling to fully characterize senescent macrophages. We found that senescent macrophages exhibit a distinctive p21-TREM2 expression profile and SASP, driven in part by type-I interferon signaling via secreted mitochondrial DNA. We also found that senescent macrophage accumulation occurs in aged and MASLD mouse livers and is enriched in human cirrhotic liver tissue. Finally, senolytic treatment targeting senescent macrophages reduced liver inflammation and steatosis in both aged and MASLD mice. Together, these findings establish macrophage senescence as a central driver of chronic inflammation in aging and metabolic liver disease, highlighting a promising, tractable therapeutic target.
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