Hepatic NcoR1 deletion exacerbates ischemia and reperfusion (IR) induced liver injury regulated by NF-kB p65 [sham-IR]
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ABSTRACT:
PROVIDER: PRJNA1258914 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR33440381_1.fastq.gz | Fastqsanger.gz | |||
| SRR33440381_2.fastq.gz | Fastqsanger.gz | |||
| SRR33440382_1.fastq.gz | Fastqsanger.gz | |||
| SRR33440382_2.fastq.gz | Fastqsanger.gz | |||
| SRR33440383_1.fastq.gz | Fastqsanger.gz |
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Project description:Background & Aims: Liver ischemia-reperfusion (IR) injury is a common and serious complication in liver transplantation surgery. Disturbances of mitochondrial function, altered lipid metabolism, and insulin resistance are pathways shown to participate in acute and chronic liver diseases. NcoR1 was previously shown to integrate in all these damage pathways in liver, adipose tissue, and muscle, whereby its mechanistic role is not fully understood. Here, we delineated hepatocytic NcoR1 in liver ischemia-reperfusion injury. Methods: We established an IR model in mice, measured liver function related enzymes in serum, SOD, and combined these data with HE staining and PCR assays from liver sections and lysates, respectively to determine the extent of liver injury. We used mice with albumin-Cre/LoxP system mediated hepatocyte-specific NcoR1 depletion (NcoR1△Hep) to investigate the role of NcoR1 in the etiopathogenesis of liver IR and to delineate potential related mechanisms. We also analysed the impact of NcoR1 on oxidative stress mediated cell damage, including activation of NFB signaling activation in hepatocytes in gain and loss of function studies, using immunoblotting and immunofluorescence. Results: Upon ischemia and reperfusion injury (IR), as evidenced by increased levels of liver enzymes (ALT, AST), and inflammatory cytokines (Tnf, Mcp1 et al), NcoR1 expression levels decreased at both, mRNA and protein levels in total liver lysates. To discriminate cell type specific effects, we successfully established NcoR1△Hep mice, and found that depletion of Ncor1 in hepacotytes exhibited more severe liver injury from IR, as compared to NcoR1fl/fl control mice, as evidenced by the aforementioned parameters. Silencing NcoR1 or Ncor1 deficiency promoted both, parameters of inflammatory and oxidative stress such as Gclc, Gclm, Hmox1, and Ccl2, et, al. in AML12 cells and primary mouse hepatocytes, while NcoR1 over-expression shows the opposite results. Further, IR treated NcoR1△Hep mice displayed increased phosphorylation of p65, an essential parameter of the NFB signaling pathway, a critical mediator of stress signals in hepatocytes. Gene silencing of p65 in primary hepatocytes increased NcoR1 expression, suggesting that NFkB/p65 signaling is a negative regulator of NcoR1 expression. Conclusion: Our results indicate that damage mediated activation of NFB/p65 signaling decreases NcoR1 expression in hepatocytes, which is required for IR aggravation.
2025-05-10 | GSE296317 | GEO
Project description:Background & Aims: Liver ischemia-reperfusion (IR) injury is a common and serious complication in liver transplantation surgery. Disturbances of mitochondrial function, altered lipid metabolism, and insulin resistance are pathways shown to participate in acute and chronic liver diseases. NcoR1 was previously shown to integrate in all these damage pathways in liver, adipose tissue, and muscle, whereby its mechanistic role is not fully understood. Here, we delineated hepatocytic NcoR1 in liver ischemia-reperfusion injury. Methods: We established an IR model in mice, measured liver function related enzymes in serum, SOD, and combined these data with HE staining and PCR assays from liver sections and lysates, respectively to determine the extent of liver injury. We used mice with albumin-Cre/LoxP system mediated hepatocyte-specific NcoR1 depletion (NcoR1△Hep) to investigate the role of NcoR1 in the etiopathogenesis of liver IR and to delineate potential related mechanisms. We also analysed the impact of NcoR1 on oxidative stress mediated cell damage, including activation of NFB signaling activation in hepatocytes in gain and loss of function studies, using immunoblotting and immunofluorescence. Results: Upon ischemia and reperfusion injury (IR), as evidenced by increased levels of liver enzymes (ALT, AST), and inflammatory cytokines (Tnf, Mcp1 et al), NcoR1 expression levels decreased at both, mRNA and protein levels in total liver lysates. To discriminate cell type specific effects, we successfully established NcoR1△Hep mice, and found that depletion of Ncor1 in hepacotytes exhibited more severe liver injury from IR, as compared to NcoR1fl/fl control mice, as evidenced by the aforementioned parameters. Silencing NcoR1 or Ncor1 deficiency promoted both, parameters of inflammatory and oxidative stress such as Gclc, Gclm, Hmox1, and Ccl2, et, al. in AML12 cells and primary mouse hepatocytes, while NcoR1 over-expression shows the opposite results. Further, IR treated NcoR1△Hep mice displayed increased phosphorylation of p65, an essential parameter of the NFB signaling pathway, a critical mediator of stress signals in hepatocytes. Gene silencing of p65 in primary hepatocytes increased NcoR1 expression, suggesting that NFkB/p65 signaling is a negative regulator of NcoR1 expression. Conclusion: Our results indicate that damage mediated activation of NFB/p65 signaling decreases NcoR1 expression in hepatocytes, which is required for IR aggravation.
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Project description:Hepatic NcoR1 deletion exacerbates ischemia and reperfusion (IR) induced liver injury regulated by NF-kB p65
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Project description:The transcription factor NF-κB p65 plays a key role in innate and adaptive immunity. It functions as a master regulator of the inflammatory response by inducing the expression of pro-inflammatory genes including secreted cytokines (IL6), chemokines (IL8, CXCL2), and multiple regulatory intracellular proteins (NFKBIA). NF-κB is activated by the so-called canonical, noncanonical and atypical signalling pathways. In the canonical pathway, activation of the Interleukin-1 receptor complex triggers degradation of the cytosolic p65 inhibitor IBα followed by nuclear translocation of p65 where it is directed by unknown pathways to the enhancers and promoters of pro-inflammatory genes. Despite its pleiotropic functions in adaptive and innate immunity or stress reactions, the entire repertoire of p65 interacting factors that contribute to its general or stimulus-specific functions within the nucleus or other cell compartments is still elusive. We identified the p65 interactomes in intact cells by BioID pulldowns under inflammatory condition (+IL-α). Extensive bioinformatics analysis of the proximity labeling data sets revealed several hundred high confidence interactors including multiple novel factors that have not been reported in the literature. We investigated which of our 38 high-confidence interactors have an impact on IL-1 NF-kB gene expression by siRNA screening. We found 5 interesting hits in the context of inflammation which will be further assessed by microarray analysis.
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Project description:To explore the effects on the NF-kB transcriptome after knockdown of RPS3 in stimulated T cells, we performed microarray assays comparing RPS3-silenced versus NS-treated samples on the same chip. p65-silenced versus NS-treated samples were used as a control. Keywords: time series design Jurkat cells transfected with control siRNA versus RPS3 or p65-siRNA were stimuated with TCR for 1, 3, or 6 hours for a total of 6 arrays.
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Project description:Aberrant regulation of NF-kB pathway is believed to be a major event contributing to malignant transformation and progression of prostate cancer (PCa). P65 consists of a DNA-binding and dimerization domain (RHD), nuclear localization signal (NLS) and transactivation domains (TA1 and TA2). The c-terminal 30 amino acids (TA1 domain) comprise the most important transactivation domain and NF-kB transactivation may be regulated by multiple phosphorylation in this domain. This p536 is located in TA1 domain and is conserved in human, mouse, chicken. We previously discovered that p536 is present in majority of PCa and associated with ERG expression indicating that ERG can significantly enhance phosphorylation of p65 at Ser536 in vivo. We have successfully generated a dominant negative (DN) p65 which has been mutated (S536A) such that it cannot be phosphorylated at Ser 536 and cannot carry out Ser536 phosphorylation dependent functions. We also generated two mutants S536D and S536E which are the phosphomimetic mutant that resembles phospho-p65 and can be detected by anti-phospho-p65 antibody. We carried out microarray studies and discovered a set of p536 regulated genes compared with wild type p65 regulated gene set.
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Project description:The inflammatory gene response requires activation of the protein kinase TAK1, but it is currently unknown how TAK1-derived signals coordinate transcriptional programs in the genome. We determined the genome-wide binding of the TAK1-controlled NF-?B subunit p65 in relation to active enhancers and promoters of transcribed genes by ChIP-seq experiments. Out of 35,000 active enhancer regions, 410 H3K4me1-positive enhancers show interleukin (IL)-1-induced H3K27ac and p65 binding. Inhibition of TAK1, IKK2 or depletion of p65 blocked inducible enhancer activation and gene expression. As exemplified by the CXC chemokine cluster located on chromosome 4, the TAK1-p65 pathway also regulates the recruitment kinetics of the histone acetyltransferase CBP, of NF-?B p50 and of AP-1 transcription factors to both, promoters and enhancers. This study provides a high resolution view of epigenetic changes occurring during the IL-1 response and allows the first genome-wide identification of a novel class of inducible p65 NF-?B-dependent enhancers in epithelial cells. RNA-seq of KB cells either untreated or treated with IL-1 alpha
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