RNA-sequencing of CCN2 knockout and wild type mice following 4 hours after IRI
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA773391 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16520762.fastq.gz | Fastqsanger.gz | |||
| SRR16520763.fastq.gz | Fastqsanger.gz | |||
| SRR16520764.fastq.gz | Fastqsanger.gz | |||
| SRR16520765.fastq.gz | Fastqsanger.gz | |||
| SRR16520766.fastq.gz | Fastqsanger.gz |
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Project description:In order to identify major regulatory events in the immediate phase of renal IRI associated with CCN2, we performed full transcriptome RNA-sequencing on a cDNA library constructed from RNA extracted from samples of kidney cortex.
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Project description:Differential gene expression of mouse cytokines and chemokines in Rag1 knockout (Rag1-/- or Rag1-KO) and Rag1-/- Tbx21-/- double knockout (Rag1-Tbet-DKO) was tested in fatty liver ischemic-reperfusion injury (IRI). C57BL/6 mice harboring Rag1-/- or Rag1-/- Tbx21-/- deletions were fed with a normal chow diet (ND, 4.09 kcal/gram,13.4% kJ/fat) or a high-fat diet (HFD, 5.10 kcal/gram, 60% kJ/fat). To induce liver ischemic-reperfusion injury in mice, an atraumatic micro clip was placed across the hepatic hilus, which interrupted the blood supply to the left and median lobes of the liver for 45-minutes of partial warm ischemia time. After 24 hours of liver IRI, the affected left lobe of the liver was harvested and stored in Allprotect Tissue Reagent (Qiagen). We used Qiagen RT² Profiler™ PCR Array for mouse cytokines & chemokines to distinguish immunologically related and diet-specific gene signatures specific to liver IRI in Rag1-KO and Rag1-Tbet-DKO mice.
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Project description:The cellular communication network (CCN) 2, also known as CTGF, is a secreted matricellular protein with regulatory functions in vasoproliferative and fibrotic diseases. Although CCN2 functions extend to developmental processes, the impact of CCN2/CTGF expression, or lack thereof, during retinogenesis is unknown. Herein, we used bulk RNA-sequencing to determine the transcriptomic changes associated with global deletion of CCN2 in E18.5 mouse retinas. we show that CCN2 signals act on intrinsic signal transduction pathway genes and induce genetic reprogramming of retinal progenitor cells endowing these cells with neurogenic and gliogenic potentials.
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Project description:GPX3 is primarily synthesized and secreted by renal tubular epithelial cells and serves as the main source of GPX3 in plasma. A portion of GPX3 adheres to the renal basement membrane, suggesting that GPX3 may also regulate renal cell physiological functions. Our previous work has found that GPX3 expression is downregulated in the renal tubular epithelial cells of mice that have undergone ischemia-reperfusion-induced acute kidney injury, but the specific impact of this downregulation remains unclear. To address this, we constructed mice with specific deletion of GPX3 in renal tubular epithelial cells and subjected them to ischemia-reperfusion modeling. We reported the protective role of native GPX3 in the kidneys under IRI-AKI conditions in mitigating oxidative stress and mitochondrial damage in tubular epithelial cells. The deletion of GPX3 in tubular epithelial cells exacerbated oxidative stress, apoptosis, and mitochondrial dysfunction in IRI-AKI. Renal cortex tissue from control and IRI-modeled mice was used for RNA sequencing. Overall, our data provide an overview of the genetic changes in the kidneys of mice with GPX3 knockout in both non-modeled and IRI-AKI-modeled conditions, laying the groundwork for studying the specific mechanisms by which GPX3 regulates renal function.
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Project description:To identify the direct m6A demethylation targets of ALKBH5 at the onset of renal IRI, we performed methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) using RNA isolated from IRI mouse kidney of WT and KO mice 24h after I/R (WT n=3 vs. KO n=3)
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Project description:Antiphospholipid syndrome (APS)-associated vasculopathy is heralded by abnormal proliferation of endothelial and smooth muscle cells, leading to small blood vessel occlusion in the skin, kidneys, and heart, amongst other organs. The underlying mechanisms remain unclear, and targeted treatment options for patients with APS are lacking. To identify and analyze APS microvascular endothelial cells (MVECs), skin biopsies of patients with APS complicated by livedo racemosa were characterized using single-cell RNA sequencing (scRNA-seq). Increased expression of CCN1 and CCN2 were discovered and further confirmed in APS skin by microscopy, and in APS plasma by ELISA. Exposure of healthy MVECs to patient IgG triggered CCN1 and CCN2 upregulation via yes-associated protein (YAP1)-mediated signaling. CCN2 originating from APS IgG-stimulated MVECs led to the proliferation and migration of vascular smooth muscle cells, which were blocked by the anti-CCN2 antibody, pamrevlumab. We further observed increased expression of CCN1 and CCN2, along with evidence of YAP1 nuclear translocation, in kidney vessels of APS nephropathy biopsies. Finally, CCN2 inhibition with pamrevlumab significantly reduced neointima thickening and cell proliferation in a mouse model of APS IgG-accelerated neointima formation. Together, this study revealed activation of YAP1-mediated signaling in APS dermal microvessels and demonstrated that the YAP1 target CCN2 plays a role in facilitating pro-proliferative communication between MVECs and VSMCs. These findings offer insights into the cellular and molecular mechanisms underlying APS vasculopathy and provide potential therapeutic targets for patients.
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Project description:TGF-β stimulates CCN2 expression which in turn amplifies TGF-β signaling. This process promotes extracellular matrix production and accelerates the pathological progression of fibrotic diseases. Alternative splicing plays an important role in multiple disease development, while U2 small nuclear RNA auxiliary factor 2 (U2AF2) is an essential factor in the early steps of pre-mRNA splicing. However, the molecular mechanism underlying abnormal CCN2 expression upon TGF-β stimulation remains unclear. This study elucidates that SIRT4 acts as a master regulator for CCN2 expression in response to TGF-β by modulating U2AF2-mediated alternative splicing. Analyses of renal biopsy specimens from patients with CKD and mouse fibrotic kidney tissues revealed marked nuclear accumulation of SIRT4. The tubulointerstitial fibrosis was alleviated by global deletion or tubular epithelial cell (TEC)-specific knockout of Sirt4, and aggravated by adeno-associated virus-mediated SIRT4 overexpression in TECs. Furthermore, SIRT4 was found to translocate from the mitochondria to the cytoplasm through the BAX/BAK pore under TGF-β stimulation. In the cytoplasm, TGF-β activated the ERK pathway and induced the phosphorylation of SIRT4 at Ser36, which further promoted its interaction with importin α1 and subsequent nuclear translocation. In the nucleus, SIRT4 was found to deacetylate U2AF2 at K413, facilitating the splicing of CCN2 pre-mRNA to promote CCN2 protein expression. Importantly, exosomes containing anti-SIRT4 antibodies were found to effectively mitigate the UUO-induced kidney fibrosis in mice. Collectively, these findings indicated that SIRT4 plays a role in kidney fibrosis by regulating CCN2 expression via the pre-mRNA splicing.
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Project description:Vascular smooth muscle cell (VSMC) phenotypic switching is widely recognized as a key mechanism responsible for the pathogenesis of several aortic diseases such as aortic aneurysm. Cellular communication network factor 2 (CCN2), often upregulated in human pathologies and animal disease models, exerts a myriad of context-dependent biological functions. However, current understanding of the role of SMC-CCN2 in SMC phenotypic switching and its function in the pathology of abdominal aortic aneurysm (AAA) is lacking. Here we report the effect of SMC-restricted CCN2 deficiency of hypercholesterolemic mice on gene expression in infrarenal aorta with or without angiotensin II (Ang II)-infusion.
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Project description:N-glycanase 1(NGLY1) catalyzes the removal of N-linked glycans from newly synthesized or misfolded protein to exert protein quality control function via the process of endoplasmic reticulum-associated degradation (ERAD). NGLY1 deficiency (OMIM 615273) is a newly diagnosed rare genetic disorder with ~60 patients worldwide to date. The affected individuals present a broad spectrum of clinical features, including developmental delay, seizures, muscle weakness, liver failure, and the reduced secretion of sweats and tears. Recent studies explored several possible molecular mechanisms of NGLY1 deficiency including in vivo proteostasis, mitochondrial homeostasis, innate immunity, water and ion transport, with the goal of linking these findings to the pathophysiology of the disease. This study focuses on the dysregulation of ERAD in NGLY1 deficiency. We demonstrate the abnormal accumulation of ERAD substrates in NGLY1 deficient cells. Comprehensive global quantitative proteomics discovered elevated levels of novel endogenous proteins in NGLY1 defective human and mouse cells. Further biological validation assays confirmed the altered abundance of several key candidates’ that were observed in the isobarically labeled proteomic experiments. CCN2 was selected for further analysis due to its high fold change in different cell models of NGLY1 deficiency. Functional assays show elevated CCN2 and over-stimulated TGF-β signaling in NGLY1 deficient cells. Given the important role of CCN2 and TGF-β pathway in mediating systemic fibrosis, we propose a potential link of increased CCN2 and TGF-β signaling to microscopic liver fibrosis in NGLY1 patients.
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Project description:Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Most patients are at an advanced stage at diagnosis, and are not eligible for curative therapy. Chemotherapy is an alternative treatment for advanced HCCs, but resistance is found in many patients. Understanding the underlying mechanisms in chemo-resistance is critical to further improve the efficacy of HCC treatment. In this study, we found that increased expression of Id-1 and CCN2 were closely related to oxaliplatin resistance in HCC. Upregulation of CCN2 and Id-1 was independently associated with shorter survival and increased recurrence in HCC patients, and significantly enhanced oxaliplatin resistance and promoted lung metastasis in vivo, whereas knock-down of their expression significantly reversed the chemo-resistance and inhibited HCC cell stemness. cDNA microarrays and PCR revealed that Id-1 and MAPK pathway were the downstream signaling of CCN2, and Id-1 could upregulate CCN2 in a positive feedback manner. Moreover, CCN2 significantly enhanced oxaliplatin resistance by activating the MAPK signaling pathway and upregulating Id-1 expression. Meanwhile, MAPK/Id-1 signaling was demonstrated as one of the most important autocrine signaling pathways regulated by CCN2 in oxaliplatin-resistant models, and combination with sorafenib could improve the efficacy of oxaliplatin in HCC. Conclusions: These findings suggest that CCN2-MAPK-Id-1 loop feedback amplification is involved in oxaliplatin-resistant HCC, and the combination of oxaliplatin with inhibitor of CCN2 or MAPK signaling could provide a promising approach to ameliorating HCC progression and oxaliplatin resistance.
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