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Matrix stiffness modulates fibrogenesis in hepatic stellate cells through AP-1-induced chromatin priming [ATAC-Seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE240069 | GEO | 2023/08/05

REPOSITORIES: GEO

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Matrix stiffness regulate fibrotic phenotype through AP-1 contributing to chromatin accessibility dynamic [RNA-seq]

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

Matrix stiffness regulate fibrotic phenotype through AP-1 contributing to chromatin accessibility dynamic [Cut&Tag]

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Matrix stiffness regulate fibrotic phenotype through AP-1 contributing to chromatin accessibility dynamic [ATAC-seq]

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c-JUN is a pioneer factor safeguarding the primed state of pluripotency (RNA-Seq)

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c-JUN is a pioneer factor safeguarding the primed state of pluripotency (ChIP-Seq)

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2020-12-31 | GSE127920 | GEO

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2021-10-22 | PXD029277 | iProX

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Project description:In breast cancer, the increased stiffness of the extracellular matrix (ECM) is a key driver of malignancy. Yet little is known about the epigenomic changes that underlie the tumorigenic impact of ECM mechanics. Here, we show in a 3D culture model of breast cancer that stiff ECM induces a tumorigenic phenotype through changes in chromatin state. We found that increased stiffness yielded cells with more wrinkled nuclei and with increased lamina-associated chromatin, that cells cultured in stiff matrices displayed more accessible chromatin sites, which exhibited footprints of Sp1 binding, and that Sp1 acts along with histone deacetylases (HDAC) 3 and 8 to regulate the induction of stiffness-mediated tumorigenicity. Just as cell culture on soft environments or in them rather than on tissue-culture plastic better recapitulates the acinar morphology observed in mammary epithelium in vivo, mammary epithelial cells cultured on soft microenvironments or in them also more closely replicate the in vivo chromatin state. Our results emphasize the importance of culture conditions for epigenomic studies, and reveal that chromatin state is a critical mediator of mechanotransduction.

2019-05-31 | GSE131968 | GEO

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Evidence that c-JUN stabilizes chromatin architecture of EpiSCs

Project description:c-JUN is a transcription factor and the founding member of AP1 family. Here we present evidence that c-JUN stabilizes chromatin architecture. We first show that c-JUN is expressed and occupies chromatin loci both open and closed in primed mEpiSCs, but not naive mESCs. Interestingly, naive open loci undergo closing during naive to primed transition independent of c-JUN, but ~2500 of them become occupied by c-JUN immediately. These loci then open more readily during the reverse primed to naive transition (PNT) in the presence of c-JUN N-terminal Kinase inhibitor or by ectopically expressed Esrrb and Klf4 as both bind to them. Finally, we show that these loci become more open in c-Jun-/- EpiSCs which undergo PNT more efficiently than wild type cells. These results suggest that c-Jun is activated during naive to primed transition to stabilize chromatin architecture.

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