O-GlcNAcylation controls pro-fibrotic transcriptional regulatory signaling in hepatic stellate cells
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ABSTRACT:
PROVIDER: PRJNA1016361 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26050800.fastq.gz | Fastqsanger.gz | |||
| SRR26051900_1.fastq.gz | Fastqsanger.gz | |||
| SRR26051900_2.fastq.gz | Fastqsanger.gz | |||
| SRR26050801.fastq.gz | Fastqsanger.gz | |||
| SRR26050802.fastq.gz | Fastqsanger.gz |
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Project description:Liver injury causes “transdifferentiation” of quiescent hepatic stellate cells (Q-HSCs) into wound repairing myofibroblasts (MF-HSCs), whose uncontrolled activation leads ultimately to liver fibrosis. Although this process is triggered by deep metabolic and transcriptional reprogramming, functional links between these two key events are not yet understood. Here, using a compendium of in vitro, ex vivo and in vivo models of fibrogenic liver injuries in addition to human liver samples, we report that O-linked β D N acetylglucosaminylation (O GlcNAcylation), a post-translational modification (PTM) considered as nutritional sensor, is increased during myofibroblastic activation of HSCs and is required for their pro-fibrotic activities. Mechanistically, a multi omics approach combining proteomic, epigenomic and transcriptomic data mining revealed that O GlcNAcylation controls the transcriptional program of MF-HSCs by targeting the key fibrogenic transcription factors Basonuclin 2 (BNC2) and TEA domain transcription factor 4 (TEAD4) together with the Yes associated protein 1 (YAP1) co-activator. Indeed, inhibition of protein O GlcNAcylation impedes their stability leading to decreased functionality of the BNC2/TEAD4/YAP1 complex towards promoting activation of fibrogenic transcriptional regulatory elements. Altogether, this study unravels the fibrogenic role of protein O-GlcNAcylation identifying a vulnerable regulatory process in activated HSCs.
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Project description:O-GlcNAcylation controls pro-fibrotic transcriptional regulatory signaling in hepatic stellate cells (HSCs)
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Project description:ZNF469 is a novel pro-fibrotic regulator of extracellular matrix in hepatic stellate cells
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Project description:Comparison of longitudinal transcriptomic profiles of activated human primary hepatic stellate cells to activated human primary hepatic stellate cells that are treated with anti-fibrotic inhibitor reveals inflammatory signaling as a key pathway that is modulated during pro-fibrotic activation and repressed during attenuation of fibrotic response.
2019-12-18 | GSE117329 | GEO
Project description:Activation of quiescent hepatic stellate cells (HSCs) into proliferative myofibroblasts drives extracellular cellular matrix (ECM) accumulation and liver fibrosis; nevertheless, transcriptional network that promotes such the process remains elusive. ZNF469, a putative C2H2 zinc finger protein, is found to be upregulated upon HSC activation; however, the molecular function of ZNF469 is completely unknown. Here, we show that knockdown of ZNF469 in primary human HSCs impaired proliferation, migration, and collagen production. Conversely, overexpression of ZNF469 in HSCs yielded the opposite results. TGFb promoted expression of ZNF469 in a Smad3-dependent manner where the binding of Smad3 was confirmed at the ZNF469 promoter. RNA-seq data of ZNF469-knockdown HSCs revealed the ECM-receptor interaction as the top affected pathway, and significant downregulation of various collagen and proteoglycan genes was observed. To explore the function of ZNF469, we cloned a full-length open reading frae (ORF) of ZNF469 with an epitope tag and identified a nuclear localization of the protein. ChIP assays revealed the presence of ZNF469 at the promoter of ECM genes, supporting its function as a transcription factor. Analysis of human fibrotic and cirrhotic tissues showed increased expression of ZNF469 and a positive correlation between expression levels of ZNF469 and ECM genes. Moreover, this observation was similar in other fibrotic organs, including heart, lung, and skin. Together, this study is the first to reveal the roles of ZNF469 as a pro-fibrotic factor in HSCs and suggests ZNF469 as a novel target for antifibrotic therapy.
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Project description:Background/Aims: Sept4, a subunit of the septin cytoskeleton specifically expressed in quiescent hepatic stellate cells (HSCs), is downregulated through transdifferentiation to fibrogenic and contractile myofibroblastic cells. Since Sept4?/? mice are prone to liver fibrosis, we examined the unknown molecular network underlying liver fibrosis by probing the association between loss of Sept4 and accelerated transdifferentiation of HSCs. Methods: We compared the transcriptomes of Sept4+/+ and Sept4?/? HSCs by differential DNA microarray analysis and quantitative RT-PCR. Based on reduced dickkopf2 (Dkk2) gene expression in Sept4?/? HSCs, we tested whether supplementing Dkk2 could suppress myofibroblastic transformation of Sept4?/? HSCs. We used a lymphoid enhancer-binding factor/transcription factor-luciferase reporter assay to test whether Dkk2 can exert anti-fibrotic effects by interfering with the canonical Wnt pathway. Results: We observed consistent upregulation of Dkk2 in primary cultured HSCs and in a carbon tetrachloride hepatitis model in mice, which decreased with loss of Sept4. Supplementing Dkk2 suppressed the induction of pro-fibrotic genes (?-smooth muscle actin and 2 collagen genes) and induced an anti-fibrotic gene (Smad7) in Sept4?/? HSCs. In human liver specimens with inflammation and fibrosis, Dkk2 immunoreactivity appeared to be positively correlated with the degree of fibrotic changes. Conclusions: Pro-fibrotic transformation of HSCs through the loss of Sept4 is partly due to reduced expression of Dkk2 and its homologues, and the resulting disinhibition of the canonical Wnt pathway. We induced Liver Cirrhosis to SEPT4-KO or wild type mouse by CCl4, and examined mRNA expression profiling in hepatic stellate cell of these mouse.
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Project description:Characterization of Pro-Fibrotic Signaling Pathways in Human Hepatic Organoids
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Project description:Objective: To evaluate gene expression profiles in patients with advanced cirrhosis compared with healthy controls (HC). Results: Patients with advanced cirrhosis exhibit an unbalanced systemic response involving pro-fibrotic / protective signatures that could be contributing to the pathogenesis of cirrhosis and also to that of the extra-hepatic complications of this disease.
2016-02-14 | E-MTAB-3338 | biostudies-arrayexpress
Project description:Liver fibrosis, characterized by excessive extracellular matrix deposition, is driven by activated hepatic stellate cells (HSCs). Due to the limited availability of anti-fibrotic drugs, research con-tinues to explore potential therapeutic agents. Moringa oleifera Lam. (MO), known for its various bioactive properties, is being investigated for its anti-fibrotic potential. This study focused on 1-phenyl-2-pentanol (1-PHE), a compound derived from MO leaves, and its impact on LX-2 hu-man hepatic stellate cell activation. TGF-β1-stimulated LX-2 cells were treated with MO extract or 1-PHE, and liver fibrosis markers were assessed at both gene and protein levels. Proteomic analysis and molecular docking were employed to identify potential protein targets and signaling pathways affected by 1-PHE. 1-PHE treatment downregulated fibrosis markers, including colla-gen type I alpha 1 chain (COL1A1), collagen type IV alpha 1 chain (COL4A1), mothers against decapentaplegic homolog 2 and 3 (SMAD2/3), and matrix metalloproteinase-2 (MMP2), and re-duced the secretion of matrix metalloproteinase-9 (MMP9). Proteomic analysis revealed the pos-sible mechanism of 1-PHE in modulating the Wnt/β-catenin pathway. These findings suggest that 1-PHE may suppress HSCs activation by inhibiting the TGF-β1 and Wnt/β-catenin signaling pathways, indicating its potential as an anti-liver fibrosis agent. Further research is warranted to validate these findings.
2024-10-17 | PXD052809 | Pride
Project description:Liver fibrosis is a reversible wound-healing response to liver injury and hepatic stellate cells (HSCs) are central cellular players that mediate hepatic fibrogenesis. However, the molecular mechanisms that govern this process remain unclear. Here, we reveal a novel cistromic circuit in HSCs comprising the vitamin D receptor (VDR) and SMAD transcription factors that restrains the intensity of hepatic fibrogenesis. Ligand-activated VDR suppresses TGFβ1-induced pro-fibrotic gene expression in HSCs. Administration of a vitamin D analogue, calcipotriol, diminishes the fibrotic response in a mouse model of liver fibrosis, while VDR knockout mice spontaneous develop extensive hepatic fibrosis by age 6 months. Using ChIP-Seq, we find that the anti-fibrotic properties of VDR are due to crosstalk with SMAD, mediated by their co-occupancy of DNA-binding sites on pro-fibrotic genes. Specifically, SMAD binding potentiates local chromatin accessibility to enhance VDR recruitment at the same cis-regulatory elements, which reciprocally antagonizes the interaction between SMAD3 and chromatin and limits the assembly of transcriptional activation complexes at fibrotic genes, a process that is enhanced by the presence of VDR agonists. These results not only establish this coordinated VDR/SMAD cistromic circuit as a master regulator of hepatic fibrogenesis, but also support VDR as a potential drug target to ameliorate liver fibrosis. Identification of VDR, SMAD3 and H3 binding sites in human stellate LX2 cells that were pre-treated with calcipotriol (100nM) for 16 hrs (where calcipotriol treatment is indicated) followed by incubation of calcipotriol (100nM) or TGFβ1 (1ng/ml) for another 4 hours (where indicated).
2013-04-29 | E-GEOD-38103 | biostudies-arrayexpress