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Exosomes packaged chromatin with dynamic H3R26me2s modification prevents cellular inflammation by blocking the cGAS-STING pathway [CUT&Tag-seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE239628 | GEO | 2024/07/31

REPOSITORIES: GEO

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Exosomes packaged chromatin with dynamic H3R26me2s modification prevents cellular inflammation by blocking the cGAS-STING pathway [RNA-seq]

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

Exosomes packaged chromatin with dynamic H3R26me2s modification prevents cellular inflammation by blocking the cGAS-STING pathway.

Project description:Exosomes packaged chromatin with dynamic H3R26me2s modification prevents cellular inflammation by blocking the cGAS-STING pathway.

| PRJNA1000450 | ENA

Exosomes packaged chromatin with dynamic H3R26me2s modification prevents cellular inflammation by blocking the cGAS-STING pathway [RNA-seq]

Project description:Exosomes packaged chromatin with dynamic H3R26me2s modification prevents cellular inflammation by blocking the cGAS-STING pathway [RNA-seq]

| PRJNA1000453 | ENA

Exosomes packaged chromatin with dynamic H3R26me2s modification prevents cellular inflammation by blocking the cGAS-STING pathway [CUT&Tag-seq]

Project description:Exosomes packaged chromatin with dynamic H3R26me2s modification prevents cellular inflammation by blocking the cGAS-STING pathway [CUT&Tag-seq]

| PRJNA1000452 | ENA

Neddylation modification on cGAS of human and mouse

Project description:The cytosolic DNA sensor cyclic GMP-AMP (cGAMP) synthetase (cGAS) has emerged as a fundamental component fueling the anti-pathogen immunity. Because of its pivotal role in initiating innate immune response, the activity of cGAS must be tightly fine-tuned to maintain immune homeostasis in antiviral response. Here, we reported that neddylation modification was indispensable for appropriate cGAS-STING signaling activation. Blocking neddylation pathway using neddylation inhibitor MLN4924 substantially impaired the induction of type I interferon and proinflammatory cytokines, which was selectively dependent on Nedd8 E2 enzyme Ube2m. We further found that deficiency of the Nedd8 E3 ligase Rnf111 greatly attenuated DNA-triggered cGAS activation while not affecting cGAMP induced activation of STING, demonstrating that Rnf111 was the Nedd8 E3 ligase of cGAS. We further identified Lys231 and Lys421 as the key neddylation sites in human cGAS. Mechanistically, Rnf111 interacted with and polyneddylated cGAS, which in turn promoted its dimerization and enhanced the DNA-binding ability, leading to proper cGAS-STING pathway activation. In the same line, the Ube2m or Rnf111 deficiency mice exhibited severe defects in innate immune response and were susceptible to HSV-1 infection. Collectively, our study uncovered a vital role of the Ube2m-Rnf111 neddylation axis in promoting the activity of the cGAS-STING pathway and highlighted the importance of neddylation modification in antiviral defense.

2021-02-22 | PXD024088 | Pride

METTL3-Mediated N6-methyladenosine mRNA Modification and cGAS-STING Pathway Activity in Kidney Fibrosis

Project description:Background Chemical modifications on RNA profoundly impact RNA function and regulation. m6A, the most abundant RNA modification in eukaryotes, plays a pivotal role in diverse cellular processes and disease mechanisms. However, its importance is understudied in human chronic kidney disease (CKD) samples regarding its influence on pathological mechanisms. Methods LC-MS/MS and Methylated RNA Immunoprecipitation (MeRIP) sequencing were utilized to examine alterations in m6A levels and patterns in CKD samples. Overexpression of the m6A writer METTL3 in cultured kidney tubular cells was performed to confirm the impact of m6A in tubular cells and explore the biological functions of m6A modification on target genes. Additionally, tubule-specific deletion of Mettl3 (Ksp-Cre Mettl3f/f) mice and the use of anti-sense oligonucleotides inhibiting Mettl3 expression were utilized to reduce m6A modification in an animal kidney disease model. Results By examining 127 human CKD samples, we observed a significant increase in m6A modification and METTL3 expression in diseased kidneys. Epitranscriptomic analysis unveiled an enrichment of m6A modifications in transcripts associated with the activation of inflammatory signaling pathways, particularly the cGAS-STING pathway. m6A hypermethylation increased mRNA stability in cGAS and STING1, as well as elevated the expression of key proteins within the cGAS-STING pathway. Both the tubule-specific deletion of Mettl3 and the use of anti-sense oligonucleotides to inhibit Mettl3 expression protected mice from inflammation, reduced cytokine expression, decreased immune cell recruitment, and attenuated kidney fibrosis. Conclusions Our research revealed heightened METTL3-mediated m6A modification in fibrotic kidneys, particularly enriching the cGAS-STING pathway. This hypermethylation increased mRNA stability for cGAS and STING1, leading to sterile inflammation and fibrosis.

2024-07-03 | GSE271143 | GEO

ARF1 prevents aberrant type I IFN induction by regulating STING activation and recycling

Project description:Type I interferon (IFN) signalling is tightly controlled. Upon recognition of DNA by cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING) translocates along the endoplasmic reticulum (ER)-Golgi axis to induce IFN signalling. Afterwards, signal termination is achieved through autophagic degradation of STING, or STING recycling by retrograde COPI-mediated transport. Here we identify the GTPase ARF1 as a negative regulator of cGAS-STING signaling. Heterozygous ARF1 missense mutations cause a novel type I interferonopathy associated with enhanced IFN stimulated gene production. Expression of patient-derived, GTPase-defective, ARF1 in cell lines and primary cells results in increased cGAS-STING dependent type I IFN signalling. Mechanistically, mutated ARF1 both induces activation of cGAS by aberrant mitochondrial DNA, and promotes accumulation of active STING at the Golgi/ERGIC due to defective COPI retrograde transport. Our data establish ARF1 as a key factor in cGAS-STING homeostasis, which is required to maintain mitochondrial integrity and promote STING recycling.

2022-06-23 | MSV000089711 | MassIVE

Transcriptome changes after the transfection of cGAS specific agonist G3-YSD

Project description:The cGAS-STING signalling has been well recognized as the major pathway response to self and non-self DNA molecule in cytoplasm. Here, we measured the temporal transcriptome dynamic changes after cGAS-STING signalling activation based on cGAS specific agonist G3-YSD transfection

2022-12-09 | GSE207458 | GEO

cGAS Senses Translation Stress Through Direct Binding to Ribosomes

Project description:The cGAS-STING pathway, a central component of the innate immune system, senses cytosolic DNA and induces interferon-stimulated genes (ISGs) to mediate inflammation. Here we report the unexpected discovery that cGAS senses dysfunctional protein production. Purified ribosomes interact with and stimulate the catalytic activity of recombinant cGAS in vitro. Disruption of the ribosome-associated protein quality control pathway, which detects and resolves ribosome collisions, results in cGAS- and STING-dependent ISG expression, and causes the re-localization of cGAS from the nucleus to the cytosol. Indeed, cGAS preferentially binds collided ribosomes in vitro, and other orthogonal perturbations that lead to elevated levels of collided ribosomes cause re-localization of cGAS as well. Thus, the cGAS-STING pathway senses and responds to translation stress. These findings have implications for the inflammatory responses to viral infection and tumorigenesis, both of which substantially reprogram cellular protein synthesis.

2021-09-09 | PXD019359 | Pride

Gene expression profiles in BMDM cells of Trex1-KO and wild-type mice after treatment of STING antagonists

Project description:Mounting evidence demonstrates that cGAS-STING signaling is the major pathway in sensing cytosolic DNAs. However, aberrant accumulation of self DNA molecules in Trex1 (a 3'-to-5' DNA exonuclease) deficient cells usually causes over-activation of cGAS-STING signaling, which is associated with the pathology of several autoimmune diseases. Here, we investigated gene expression changes in BMDM cells of Trex1 knockout mice after manipulating cGAS-STING signaling activity via treatment of two STING antagonists (SN-011 and H151) .

2021-05-26 | GSE143830 | GEO

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