Similar Datasets
Project description:Exosomes DNA derived from genomic and mitochondrial could modulate type I IFN expression by triggering the cGAS-STING pathway. However, the chromatin modification of secreted exosomes involved in this process is largely unknown. Here, we could detect the histone H3R26me and H3K27ac in the components of secreted exosomes, meanwhile, a global decrease of H3R26 symmetric dimethylation (H3R26me2s) accompanied by the lowering enrichment of H3K27ac, and this distribution pattern was able to be verified by decreased H3R26me2s leading to the reduction of H3K27ac. Furthermore, these fragmented chromatins trans-located into cytoplasmic could repress cGAS-STING induction of IFNβ1 expression, which is further packaged into the exosomes. Collectively, our findings elucidate a novel pathway that which cells can actively transport the chromatin fragments of altered histone arginine methylation to alleviate the stimulation by damaged DNA. We perform RNA-seq to analysis the changes of gene expression in cells treated with bleomycin.
2024-07-31 | GSE239629 | GEO
Project description:Exosomes DNA derived from genomic and mitochondrial could modulate type I IFN expression by triggering the cGAS-STING pathway. However, the chromatin modification of secreted exosomes involved in this process is largely unknown. Here, we could detect the histone H3R26me and H3K27ac in the components of secreted exosomes, meanwhile, a global decrease of H3R26 symmetric dimethylation (H3R26me2s) accompanied by the lowering enrichment of H3K27ac, and this distribution pattern was able to be verified by decreased H3R26me2s leading to the reduction of H3K27ac. Furthermore, these fragmented chromatins trans-located into cytoplasmic could repress cGAS-STING induction of IFNβ1 expression, which is further packaged into the exosomes. Collectively, our findings elucidate a novel pathway that which cells can actively transport the chromatin fragments of altered histone arginine methylation to alleviate the stimulation by damaged DNA. We perform ChIP-seq to analysis the changes of histone modification in cells treated with bleomycin.
2024-07-31 | GSE239628 | GEO
Project description:Exosomes packaged chromatin with dynamic H3R26me2s modification prevents cellular inflammation by blocking the cGAS-STING pathway.
| PRJNA1000450 | ENA
Project description:Exosomes packaged chromatin with dynamic H3R26me2s modification prevents cellular inflammation by blocking the cGAS-STING pathway [RNA-seq]
| PRJNA1000453 | ENA
Project description:Exosomes packaged chromatin with dynamic H3R26me2s modification prevents cellular inflammation by blocking the cGAS-STING pathway [CUT&Tag-seq]
| PRJNA1000452 | ENA
Project description:Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease1. Multiple factors can contribute to ageing-associated inflammation2; however, the molecular pathways that transduce aberrant inflammatory signalling and their impact in natural ageing remain unclear. Here we show that the cGAS-STING signalling pathway, which mediates immune sensing of DNA3, is a critical driver of chronic inflammation and functional decline during ageing. Blockade of STING suppresses the inflammatory phenotypes of senescent human cells and tissues, attenuates ageing-related inflammation in multiple peripheral organs and the brain in mice, and leads to an improvement in tissue function. Focusing on the ageing brain, we reveal that activation of STING triggers reactive microglial transcriptional states, neurodegeneration and cognitive decline. Cytosolic DNA released from perturbed mitochondria elicits cGAS activity in old microglia, defining a mechanism by which cGAS-STING signalling is engaged in the ageing brain. Single-nucleus RNA-sequencing analysis of microglia and hippocampi of a cGAS gain-of-function mouse model demonstrates that engagement of cGAS in microglia is sufficient to direct ageing-associated transcriptional microglial states leading to bystander cell inflammation, neurotoxicity and impaired memory capacity. Our findings establish the cGAS-STING pathway as a driver of ageing-related inflammation in peripheral organs and the brain, and reveal blockade of cGAS-STING signalling as a potential strategy to halt neurodegenerative processes during old age.
| S-EPMC10412454 | biostudies-literature
Project description:Chronic inflammation in adipose tissue plays a key role in obesity-induced insulin resistance. However, the mechanisms underlying obesity-induced inflammation remain elusive. Here we show that obesity promotes mtDNA release into the cytosol, where it triggers inflammatory responses by activating the DNA-sensing cGAS-cGAMP-STING pathway. Fat-specific knockout of disulfide-bond A oxidoreductase-like protein (DsbA-L), a chaperone-like protein originally identified in the mitochondrial matrix, impaired mitochondrial function and promoted mtDNA release, leading to activation of the cGAS-cGAMP-STING pathway and inflammatory responses. Conversely, fat-specific overexpression of DsbA-L protected mice against high-fat diet-induced activation of the cGAS-cGAMP-STING pathway and inflammation. Taken together, we identify DsbA-L as a key molecule that maintains mitochondrial integrity. DsbA-L deficiency promotes inflammation and insulin resistance by activating the cGAS-cGAMP-STING pathway. Our study also reveals that, in addition to its well-characterized roles in innate immune surveillance, the cGAS-cGAMP-STING pathway plays an important role in mediating obesity-induced metabolic dysfunction.
| S-EPMC5699051 | biostudies-literature
Project description:Hutchinson Gilford progeria syndrome (HGPS) is a devastating accelerated aging disease caused by LMNA gene mutation. The truncated lamin A protein produced "progerin" has a dominant toxic effect in cells, causing disruption of nuclear architecture and chromatin structure, genomic instability, gene expression changes, oxidative stress, and premature senescence. It was previously shown that progerin-induced genomic instability involves replication stress (RS), characterized by replication fork stalling and nuclease-mediated degradation of stalled forks. RS is accompanied by activation of cGAS/STING cytosolic DNA sensing pathway and STAT1-regulated interferon (IFN)-like response. It is also found that calcitriol, the active hormonal form of vitamin D, rescues RS and represses the cGAS/STING/IFN cascade. Here, the mechanisms underlying RS in progerin-expressing cells and the rescue by calcitriol are explored. It is found that progerin elicits a marked downregulation of RAD51, concomitant with increased levels of phosphorylated-RPA, a marker of RS. Interestingly, calcitriol prevents RS and activation of the cGAS/STING/IFN response in part through maintenance of RAD51 levels in progerin-expressing cells. Thus, loss of RAD51 is one of the consequences of progerin expression that can contribute to RS and activation of the IFN response. Stabilization of RAD51 helps explain the beneficial effects of calcitriol in these processes.
| S-EPMC7117971 | biostudies-literature
Project description:Ageing is intimately connected to the induction of cell senescence1,2, but why this is so remains poorly understood. A key challenge is the identification of pathways that normally suppress senescence, are lost during ageing and are functionally relevant to oppose ageing3. Here we connected the structural and functional decline of ageing tissues to attenuated function of the master effectors of cellular mechanosignalling YAP and TAZ. YAP/TAZ activity declines during physiological ageing in stromal cells, and mimicking such decline through genetic inactivation of YAP/TAZ in these cells leads to accelerated ageing. Conversely, sustaining YAP function rejuvenates old cells and opposes the emergence of ageing-related traits associated with either physiological ageing or accelerated ageing triggered by a mechano-defective extracellular matrix. Ageing traits induced by inactivation of YAP/TAZ are preceded by induction of tissue senescence. This occurs because YAP/TAZ mechanotransduction suppresses cGAS-STING signalling, to the extent that inhibition of STING prevents tissue senescence and premature ageing-related tissue degeneration after YAP/TAZ inactivation. Mechanistically, YAP/TAZ-mediated control of cGAS-STING signalling relies on the unexpected role of YAP/TAZ in preserving nuclear envelope integrity, at least in part through direct transcriptional regulation of lamin B1 and ACTR2, the latter of which is involved in building the peri-nuclear actin cap. The findings demonstrate that declining YAP/TAZ mechanotransduction drives ageing by unleashing cGAS-STING signalling, a pillar of innate immunity. Thus, sustaining YAP/TAZ mechanosignalling or inhibiting STING may represent promising approaches for limiting senescence-associated inflammation and improving healthy ageing.
| S-EPMC7613988 | biostudies-literature
Project description:The cGAS/STING signaling pathway plays a pivotal role in regulating innate immunity. Emerging novel drugs aim to regulate the anti-tumor immune response by activating innate immunity. The anti-diabetic drug metformin has been reported to exhibit anti-cancer effect against various types of cancer. However, the role of metformin in regulating the cGAS/STING signaling pathway in gastric cancer remains unknown. In our study, we first used bioinformatic analysis to detect that metformin is closely related to tumor immunity in multiple tumors. Next, we validated the function of metformin in activating the cGAS/STING signaling pathway in gastric cancer cell lines. In addition, KEGG pathway enrichment analysis showed that metformin is negatively correlated with the PI3K/AKT signaling pathway in gastric cancer. We further verified that metformin activates the cGAS/STING signaling pathway by blocking AKT phosphorylation. Moreover, we found that metformin regulates the AKT signaling pathway by mediating the transcription factor SOX2. Thus, our study indicates that metformin activates the cGAS/STING signaling pathway by suppressing SOX2/AKT and has promising potential in gastric cancer immunotherapy.
| S-EPMC10432977 | biostudies-literature