Next Generation Sequencing Facilitates Quantitative Analysis of Transcriptomes of Murine Fibroblast Fibroproliferative Response with TGFβ
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE131253 | GEO | 2020/02/20
REPOSITORIES: GEO
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Project description:Next Generation Sequencing Facilitates Quantitative Analysis of Transcriptomes of Murine Fibroblast Fibroproliferative Response with TGFβ
| PRJNA543065 | ENA
Project description:Triple-negative breast cancer (TNBC) is an aggressive subtype with few treatment options for chemo-resistant disease. In both preclinical models and patient circulating tumor cells, androgen receptor (AR) expression is increased in anchorage independent TNBC. The AR inhibitor enzalutamide (Enza) leads to reduced TNBC growth in soft agar, invasion, mammosphere formation in vitro, and reduced tumorigenicity and recurrence when combined with chemotherapy in vivo pre-clinical models. Transforming growth factor β (TGFβ) pathway gene signatures are also increased during TNBC anchorage independent survival both in vitro and in vivo in pre-clinical models and CTC from patients during relapse while on chemotherapy. We hypothesized that a positive loop between AR and TGFβ signaling facilitates TNBC anchorage independent survival (anoikis resistance). We previously published that AR protein levels and transcriptional activity increased during anchorage independent conditions and we now find that that multiple components of the TGFβ pathway, including TGFβ1 and 3, as well as pathway activity, as measured by nuclear localization and transcriptional activity of pSmad3, are enhanced in anchorage independent conditions. Indeed, exogenous TGFβ increased AR protein and TGFβ inhibition decreased AR and TNBC viability, particularly under anchorage independent culture conditions. ChIP-Seq experiments revealed AR binding to genomic regions near the TGFB1 and SMAD3. TGFB3 and AR expression were positively correlated in clinical datasets and high levels of co-expression correspond to significantly worse recurrence-free and overall survival in both ER- and basal-like breast cancer. Finally, combining Enza with a TGFβ inhibitor decreased cell survival more than either drug alone, particularly under anchorage independent conditions, where the effect was more than additive. These findings warrant further investigations into whether combined inhibition of AR and TGFβ pathways might decrease metastatic recurrence rates and mortality from TNBC.
2021-11-10 | GSE157862 | GEO
Project description:Systemic sclerosis (SSc) is an autoimmune connective tissue disease involving multiple organs. The most common clinical symptom of SSc is progressive fibrosis of the skin, and the pathologically manifestations of skin were activation and proliferation of fibroblasts and continuous proliferation of extracellular matrix. Transforming growth factor β (TGFβ) can promote the proliferation and activation of fibroblasts, causing excessive deposition of collagen and structural proteins, and thereby causing fibrosis and dysfunction of tissues and organs. In this study, human cysteine-rich secreted protein LCCL domain protein 2 (CRISPLD2) was found increased reactivity in TGFβ induced fibroblasts, and we further confirmed that CRISPLD2 can participate in TGFβ induced fibroblast fibrosis from multiple perspectives and levels, and investigated the mechanism of CRISPLD2 in fibrosis, providing evidence for CRISPLD2 to become a clinical potential therapeutic target and a new biomarker.
2024-04-23 | GSE264288 | GEO
Project description:Tissue fibrosis is a chronic disease driven by persistent fibroblast activation that has recently been linked to epigenetic modifications. Here, we screened a small library of epigenetic small-molecule modulators to identify compounds capable of inhibiting or reversing TGFβ-mediated fibroblast activation. We identified pracinostat, an HDAC inhibitor, as a potent attenuator of lung fibroblast activation and confirmed its efficacy in patient-derived fibroblasts isolated from fibrotic lung tissue. Mechanistically, we found that HDAC-dependent transcriptional repression was an early and essential event in TGFβ-mediated fibroblast activation. Treatment of lung fibroblasts with pracinostat broadly attenuated TGFβ-mediated epigenetic repression and promoted fibroblast quiescence. We confirmed a specific role for HDAC-dependent histone deacetylation in the promoter region of the anti-fibrotic gene PPARGC1A (PGC1α) in response to TGFβ stimulation. Finally, we identified HDAC7 as a key factor whose RNAi-mediated knockdown attenuates fibroblast activation without altering global histone acetylation. Together these results provide novel mechanistic insight into the essential role HDACs play in TGFβ-mediated fibroblast activation via targeted gene repression.
2019-08-29 | GSE136534 | GEO
Project description:Transforming growth factor β (TGFβ) signaling is a core pathway of fibrosis, but the molecular regulation of the activation of latent TGFβ remains incompletely understood. Here, we demonstrate a crucial role of WNT5A/JNK/ROCK signaling that rapidly coordinates the activation of latent TGFβ in fibrotic diseases. WNT5A was identified as predominant non-canonical WNT ligand in fibrotic diseases such as systemic sclerosis, sclerodermatous chronic graft-versus-host disease and idiopathic pulmonary fibrosis, stimulating fibroblast-to-myofibroblast transition and tissue fibrosis by activation of latent TGFβ. The activation of latent TGFβ requires rapid JNK- and ROCK-dependent cytoskeletal rearrangements and integrin αV (ITGAV). Conditional Knockout of WNT5A or its downstream targets prevented activation of latent TGFβ, rebalanced TGFβ signaling and ameliorated experimental fibrosis. We thus uncovered a novel mechanism for the aberrant activation of latent TGFβ in fibrotic diseases and provided evidence for targeting WNT5A/JNK/ROCK signaling in fibrotic diseases as a new therapeutic approach.
2024-02-29 | GSE222916 | GEO
Project description:Overall goal: To elucidate fibroblast-specific role of TGFβ-Smad2/3 signaling in fibroblast activation and their differentiation to myofibroblasts. Purpose of analysis: To generate transcriptional profile of Smad2/3 and TGFβreceptors1/2-deficient fibroblasts in the context of pathological cardiac fibrosis.
2017-10-25 | GSE101772 | GEO
Project description:Glioblastoma stem cells (GSCs) fate is controlled by environmental cues, among which cytokines play a crucial role. The transforming growth factor β (TGFβ) family signaling pathways controls GSCs. On one hand, TGFβ promotes cell proliferation in GBM, it induces the expression of platelet-derived growth factor-B (PDGFB). Moreover, TGFβ, via its signaling mediators Smad2/3, induces the expression of the cytokine leukemia inhibitory factor (LIF) and Sox4, which in turn enhances the expression of the stem cell transcription factor Sox2; this increases the self-renewal capacity of the GSCs and their stemness characteristics, and enhances the GSC tumor-initiating potential. On the other hand, Bone morphogenic proteins (BMPs) are known to promote GSC differentiation towards the astrocytic phenotype. To further understand which genes are regulated by TGFβ and BMP7 in GSCs we performed a microarray in the Affymetrix HTA2 platform in three different glioblastoma cell line, U2987, and two patient-derived glioblastoma stem cells, U3031MG and U3034MG, in the presence or absence of 5 ng/ml of TGFβ or 30 ng/ml BMP7 for 24 h, three biological replicates per condition.
2020-09-01 | E-MTAB-9076 | biostudies-arrayexpress
Project description:Cholangiocarcinoma (CCA) is a devastating liver cancer characterized by high aggressiveness and resistance to therapy, which results to poor prognosis. Signals imposed by oncogenic pathways, such as transforming growth factor β (TGFβ) frequently contribute to CCA development. In this study, we explored novel effectors of the TGFβ pathway in CCA by gene expression profiling. We identified the long non-coding RNA LINC00313 as a novel target gene of TGFβ signalling in CCA cells. TGFβ induced LINC00313 expression in a TβRI/Smad-dependent manner. Subcellular fractionation showed that LINC00313 is a predominantly nuclear lncRNA. By integrating RNA-seq and ATAC-seq data from LINC00313 over-expressing cells, we observed that LINC00313 regulates the expression of several genes involved in the Wnt signalling pathway. As a proof of concept, we focused on the gene encoding transcription factor 7 (TCF7), a major effector that drives transcription of Wnt-target genes. LINC00313 gain of function resulted in increased TCF7 expression, while its loss of function diminished basal or TGFβ-induced TCF7 expression levels. Interestingly, LINC00313 enhanced basal or chemically induced TCF/LEF-dependent transcriptional responses, promoted colony-forming capacities of CCA cells in vitro and accelerated tumor growth in vivo. We also report that genes associated with LINC00313 over-expression recapitulate poor prognosis human CCA associated with a reduced overall survival and KRAS mutations. To decipher the underlying molecular functions of LINC00313, we identified its interacting proteins by performing an unbiased RNA pull-down assay followed by mass spectrometry. We demonstrated that actin-like 6A (ACTL6A), a subunit of the SWI/SNF chromatin remodelling complex specifically binds to LINC00313 and impacts TCF7 expression and TCF/LEF signalling output. Thus, we propose a model whereby TGFβ induces LINC00313, in order to regulate the expression of a subset of target genes, such as TCF7 possibly in co-operation with the SWI/SNF chromatin remodelling complex, via establishing direct interaction with ACTL6A. By regulating key genes of the Wnt pathway, LINC00313 fine-tunes Wnt/TCF/LEF-dependent transcriptional responses and boosts cholangiocarcinogenesis.
2024-02-05 | E-MTAB-12879 | biostudies-arrayexpress
Project description:Cholangiocarcinoma (CCA) is a devastating liver cancer characterized by high aggressiveness and resistance to therapy, which results to poor prognosis. Signals imposed by oncogenic pathways, such as transforming growth factor β (TGFβ) frequently contribute to CCA development. In this study, we explored novel effectors of the TGFβ pathway in CCA by gene expression profiling. We identified the long non-coding RNA LINC00313 as a novel target gene of TGFβ signalling in CCA cells. TGFβ induced LINC00313 expression in a TβRI/Smad-dependent manner. Subcellular fractionation showed that LINC00313 is a predominantly nuclear lncRNA. By integrating RNA-seq and ATAC-seq data from LINC00313 over-expressing cells, we observed that LINC00313 regulates the expression of several genes involved in the Wnt signalling pathway. As a proof of concept, we focused on the gene encoding transcription factor 7 (TCF7), a major effector that drives transcription of Wnt-target genes. LINC00313 gain of function resulted in increased TCF7 expression, while its loss of function diminished basal or TGFβ-induced TCF7 expression levels. Interestingly, LINC00313 enhanced basal or chemically induced TCF/LEF-dependent transcriptional responses, promoted colony-forming capacities of CCA cells in vitro and accelerated tumor growth in vivo. We also report that genes associated with LINC00313 over-expression recapitulate poor prognosis human CCA associated with a reduced overall survival and KRAS mutations. To decipher the underlying molecular functions of LINC00313, we identified its interacting proteins by performing an unbiased RNA pull-down assay followed by mass spectrometry. We demonstrated that actin-like 6A (ACTL6A), a subunit of the SWI/SNF chromatin remodelling complex specifically binds to LINC00313 and impacts TCF7 expression and TCF/LEF signalling output. Thus, we propose a model whereby TGFβ induces LINC00313, in order to regulate the expression of a subset of target genes, such as TCF7 possibly in co-operation with the SWI/SNF chromatin remodelling complex, via establishing direct interaction with ACTL6A. By regulating key genes of the Wnt pathway, LINC00313 fine-tunes Wnt/TCF/LEF-dependent transcriptional responses and boosts cholangiocarcinogenesis.
2024-02-05 | E-MTAB-12030 | biostudies-arrayexpress
Project description:Idiopathic pulmonary fibrosis (IPF) is a chronic and often fatal pulmonary disorder characterized by fibroblast proliferation and the excess deposit of extracellular matrix proteins. The etiology of IPF is unknown, but a central role for microRNAs (miRNAs), a class of small non-coding regulatory RNAs, has been recently suggested. We report the upregulation of miR-199a-5p in mouse lungs undergoing bleomycin-induced fibrosis and also in human biopsies from IPF patients. Levels of miR-199a-5p were increased selectively in myofibroblasts and putative profibrotic effects of miR-199a-5p were further investigated in cultured lung fibroblasts. MiR-199a-5p expression was induced upon TGFβ exposure and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts. CAV1, a critical mediator of pulmonary fibrosis, was established as a bona fide target of miR-199a-5p. Finally, we also found an aberrant expression of miR-199a-5p in mouse models of kidney and liver fibrosis, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. We propose miR-199a-5p as a major regulator of fibrosis that represents a potential therapeutic target to treat fibroproliferative diseases. This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-02-01 | E-GEOD-34818 | biostudies-arrayexpress