Matrix stiffness modulates fibrogenesis in hepatic stellate cells through AP-1-induced chromatin priming [ATAC-Seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1002239 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Matrix stiffness modulates fibrogenesis in hepatic stellate cells through AP-1-induced chromatin priming
| PRJNA911197 | ENA
Project description:The increased stiffness of the extracellular matrix is a key driver of liver fibrosis. The activated hepatic stellate cell (HSC) is the major producer of extracellular matrix (ECM) components. While little is known about the epigenomic changes that underlie the fibrogenic impact of ECM mechanics. In this study, we utilized a reliable in vitro system to mimic liver cirrhosis and integrated multi-omics analysis, which includes time-series RNA-seq and ATAC-seq as well as histone modification Cut&Tag, with imaging and biochemical essays to study the mechanism underlying the biomechanics function on fibrotic phenotype. We found that cells cultured in stiff matrix displayed more accessible chromatin sites, consisting of amount regions became accessible before stable fibrotic phenotype. We defined these regions as primed chromatin that chromatin accessibility foreshadows changes in gene expression. This kind of chromatin enriched in cytoskeleton organization and responding to mechanical stimulus biological process. Here, we depicted the AP-1 transcription factor family as being responsible for driving the construction of primed chromatin. Among AP-1 transcription factors, we confirmed JUN was critical to reconstruct chromatin accessibility to promote fibrogenic genotype. In addition, we described ERK contribute to the activation of JUN resulting in its binding on chromatin. Our results profiled a dynamic landscape of chromatin accessibility and defined the primed chromatin that contribute to fibrosis during responding to stiff matrix. We identified that AP-1 was capable of reorganizing the chromatin accessibility in mechanotransduction.
2023-08-05 | GSE240069 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-05-01 | GSE220703 | GEO
Project description:Hepatic fibrosis is a wound-healing response to chronic liver injury, which may result in cirrhosis and liver failure. The c-Jun N-terminal kinase-1 (JNK1) gene has been shown to be involved in liver fibrosis. Here, we aimed to investigate the molecular mechanism and identify the cell-type involved in mediating the JNK1-dependent effect on liver fibrogenesis Wild-type (WT), JNK1−/− and JNK1Δhepa (hepatocyte-specific deletion of JNK1) mice were subjected to bile duct ligation (BDL). Additionally, we performed bone marrow transplantations (BMT), isolated primary hepatic stellate cells (HSCs) and studied their activation in vitro. Serum markers of liver damage (liver transaminases, alkaline phosphatase and bilirubin) and liver histology revealed reduced injury in JNK1−/− compared to WT and JNK1Δhepa mice. Hepatocyte cell death and proliferation was reduced in JNK1−/− compared to WT and JNK1Δhepa. Parameters of liver fibrosis such as Sirius Red staining as well as Collagen IA1 and αSMA expression were down-regulated in JNK1−/− compared to WT and JNK1Δhepa livers, 4 weeks after BDL. To delineate the essential cell-type, we performed BMT of WT and JNK1-/- into JNK1-/- and WT mice, respectively. BMT experiments excluded bone marrow derived cells from having a major impact on the JNK1-dependent effect on fibrogenesis. Hence, we investigated primary HSCs from JNK1−/− livers showing reduced transdifferentiation compared with WT and JNK1Δhepa-derived HSCs. We conclude that JNK1 in HSCs plays a crucial role in hepatic fibrogenesis and thus represents a promising target for cell-directed treatment options for liver fibrosis. Control (JNK1f/f), JNK1 null (JNK1-/-) and hepatocyte-specific JNK1 null (JNK1Δhepa) mice were subjected to control, acute and chronic injury, i.e. sham or bile-duct ligation for 48h or 28 days resp., whereafter gene expression profiles were determined.
2013-11-27 | E-GEOD-40041 | biostudies-arrayexpress
Project description:The increased stiffness of the extracellular matrix is a key driver of liver fibrosis. The activated hepatic stellate cell (HSC) is the major producer of extracellular matrix (ECM) components. While little is known about the epigenomic changes that underlie the fibrogenic impact of ECM mechanics. In this study, we utilized a reliable in vitro system to mimic liver cirrhosis and integrated multi-omics analysis, which includes time-series RNA-seq and ATAC-seq as well as histone modification Cut&Tag, with imaging and biochemical essays to study the mechanism underlying the biomechanics function on fibrotic phenotype. We found that cells cultured in stiff matrix displayed more accessible chromatin sites, consisting of amount regions became accessible before stable fibrotic phenotype. We defined these regions as primed chromatin that chromatin accessibility foreshadows changes in gene expression. This kind of chromatin enriched in cytoskeleton organization and responding to mechanical stimulus biological process. Here, we depicted the AP-1 transcription factor family as being responsible for driving the construction of primed chromatin. Among AP-1 transcription factors, we confirmed JUN was critical to reconstruct chromatin accessibility to promote fibrogenic genotype. In addition, we described ERK contribute to the activation of JUN resulting in its binding on chromatin. Our results profiled a dynamic landscape of chromatin accessibility and defined the primed chromatin that contribute to fibrosis during responding to stiff matrix. We identified that AP-1 was capable of reorganizing the chromatin accessibility in mechanotransduction.
2023-05-01 | GSE220701 | GEO
Project description:The increased stiffness of the extracellular matrix is a key driver of liver fibrosis. The activated hepatic stellate cell (HSC) is the major producer of extracellular matrix (ECM) components. While little is known about the epigenomic changes that underlie the fibrogenic impact of ECM mechanics. In this study, we utilized a reliable in vitro system to mimic liver cirrhosis and integrated multi-omics analysis, which includes time-series RNA-seq and ATAC-seq as well as histone modification Cut&Tag, with imaging and biochemical essays to study the mechanism underlying the biomechanics function on fibrotic phenotype. We found that cells cultured in stiff matrix displayed more accessible chromatin sites, consisting of amount regions became accessible before stable fibrotic phenotype. We defined these regions as primed chromatin that chromatin accessibility foreshadows changes in gene expression. This kind of chromatin enriched in cytoskeleton organization and responding to mechanical stimulus biological process. Here, we depicted the AP-1 transcription factor family as being responsible for driving the construction of primed chromatin. Among AP-1 transcription factors, we confirmed JUN was critical to reconstruct chromatin accessibility to promote fibrogenic genotype. In addition, we described ERK contribute to the activation of JUN resulting in its binding on chromatin. Our results profiled a dynamic landscape of chromatin accessibility and defined the primed chromatin that contribute to fibrosis during responding to stiff matrix. We identified that AP-1 was capable of reorganizing the chromatin accessibility in mechanotransduction.
2023-05-01 | GSE220700 | GEO
Project description:The increased stiffness of the extracellular matrix is a key driver of liver fibrosis. The activated hepatic stellate cell (HSC) is the major producer of extracellular matrix (ECM) components. While little is known about the epigenomic changes that underlie the fibrogenic impact of ECM mechanics. In this study, we utilized a reliable in vitro system to mimic liver cirrhosis and integrated multi-omics analysis, which includes time-series RNA-seq and ATAC-seq as well as histone modification Cut&Tag, with imaging and biochemical essays to study the mechanism underlying the biomechanics function on fibrotic phenotype. We found that cells cultured in stiff matrix displayed more accessible chromatin sites, consisting of amount regions became accessible before stable fibrotic phenotype. We defined these regions as primed chromatin that chromatin accessibility foreshadows changes in gene expression. This kind of chromatin enriched in cytoskeleton organization and responding to mechanical stimulus biological process. Here, we depicted the AP-1 transcription factor family as being responsible for driving the construction of primed chromatin. Among AP-1 transcription factors, we confirmed JUN was critical to reconstruct chromatin accessibility to promote fibrogenic genotype. In addition, we described ERK contribute to the activation of JUN resulting in its binding on chromatin. Our results profiled a dynamic landscape of chromatin accessibility and defined the primed chromatin that contribute to fibrosis during responding to stiff matrix. We identified that AP-1 was capable of reorganizing the chromatin accessibility in mechanotransduction.
2023-05-01 | GSE220702 | GEO
Project description:Hepatic fibrosis is a wound-healing response to chronic liver injury, which may result in cirrhosis and liver failure. The c-Jun N-terminal kinase-1 (JNK1) gene has been shown to be involved in liver fibrosis. Here, we aimed to investigate the molecular mechanism and identify the cell-type involved in mediating the JNK1-dependent effect on liver fibrogenesis Wild-type (WT), JNK1−/− and JNK1Δhepa (hepatocyte-specific deletion of JNK1) mice were subjected to bile duct ligation (BDL). Additionally, we performed bone marrow transplantations (BMT), isolated primary hepatic stellate cells (HSCs) and studied their activation in vitro. Serum markers of liver damage (liver transaminases, alkaline phosphatase and bilirubin) and liver histology revealed reduced injury in JNK1−/− compared to WT and JNK1Δhepa mice. Hepatocyte cell death and proliferation was reduced in JNK1−/− compared to WT and JNK1Δhepa. Parameters of liver fibrosis such as Sirius Red staining as well as Collagen IA1 and αSMA expression were down-regulated in JNK1−/− compared to WT and JNK1Δhepa livers, 4 weeks after BDL. To delineate the essential cell-type, we performed BMT of WT and JNK1-/- into JNK1-/- and WT mice, respectively. BMT experiments excluded bone marrow derived cells from having a major impact on the JNK1-dependent effect on fibrogenesis. Hence, we investigated primary HSCs from JNK1−/− livers showing reduced transdifferentiation compared with WT and JNK1Δhepa-derived HSCs. We conclude that JNK1 in HSCs plays a crucial role in hepatic fibrogenesis and thus represents a promising target for cell-directed treatment options for liver fibrosis.
2013-11-27 | GSE40041 | GEO
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
Project description:Background & Aims: Rapid induction of beta-PDGF receptor (beta-PDGFR) is a core feature of hepatic stellate cell activation, the hallmark of liver fibrogenesis. However, biological consequences of the induction are not well characterized. We aimed to determine the involvement of beta-PDGFR-mediated molecular pathway activation on hepatic stellate cells in liver injury, fibrogenesis, and carcinogenesis in vivo. Methods: Loss and constitutive activation of beta-PDGFR were assessed in mouse models with either a stellate cell-specific beta-PDGFR knockout or the expression of an autoactivating mutation respectively. Liver injury and fibrosis were induced in two mechanistically distinct models: carbontetrachloride (CCl4) treatment and ligation of the common bile duct. Hepatocarcinogenesis with underlying liver injury/fibrosis was assessed by a single dose of diethylnitrosamine (DEN) followed by repeated injections of CCl4. Genome-wide expression profiling was performed isolated stellate cells from these models to determine deregulated pathways. Results: Depletion of beta-PDGFR in hepatic stellate cells led to decreased histological liver injury, serum transaminases, collagen alpha 1(I) and alpha smooth muscle actin expression, and collagen deposition. Stellate cell proliferation was significantly reduced after acute hepatic injury in vivo. In contrast, autoactivation of beta-PDGFR in stellate cells accelerated liver fibrosis, most prominently after 6 weeks of CCl4 induced injury. There was no difference in development of DEN-induced pre-neoplastic loci according to the status of beta-PDGFR. Conclusions: Depletion of beta-PDGFR in hepatic stellate cells attenuated the development of liver injury, fibrosis, and stellate cell proliferation in multiple animal models, whereas the constitutive activation of beta-PDGFR enhanced fibrosis. However, manipulation of beta-PDGFR alone did not reduce development of dysplastic nodules. These findings indicate that titration of receptor beta-PDGFR expression on stellate cells parallels fibrosis and injury, but may not impact the development of hepatic neoplasia alone. Hepatic stellate cells were isolated from liver of beta-PDGFR-wild-type or knockout mice, and treated with beta-PDGF ligand or vehicle control.
2015-02-19 | E-GEOD-52253 | biostudies-arrayexpress