High Yap and Mll1 promote a persistent regenerative cell state induced by Notch signaling and loss of p53
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ABSTRACT:
PROVIDER: PRJEB40157 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR4557820_1.fastq.gz | Fastqsanger.gz | |||
| ERR4557820_2.fastq.gz | Fastqsanger.gz | |||
| ERR4557821_1.fastq.gz | Fastqsanger.gz | |||
| ERR4557821_2.fastq.gz | Fastqsanger.gz | |||
| ERR4557812_1.fastq.gz | Fastqsanger.gz |
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Project description:Specified intestinal epithelial cells reprogram and contribute to the regeneration and renewal of the epithelium upon injury. Mutations that deregulate such renewal processes may contribute to tumorigenesis. Using intestinal organoids, we show that concomitant activation of Notch signaling and ablation of p53 induce a highly proliferative and regenerative cell state, which is associated with increased levels of Yap and the histone methyltransferase Mll1. The induced signaling system orchestrates high proliferation, self-renewal, and niche-factor-independent growth, and elevates the trimethylation of histone 3 at lysine 4 (H3K4me3). We demonstrate that Yap and Mll1 are also elevated in patient-derived colorectal cancer (CRC) organoids and control growth and viability. Our data suggest that Notch activation and p53 ablation induce a signaling circuitry involving Yap and the epigenetic regulator Mll1, which locks cells in a proliferative and regenerative state that renders them susceptible for tumorigenesis.
| S-EPMC8179171 | biostudies-literature
Project description:Chronic cutaneous wounds remain a persistent unmet medical need that decrease expectancy and quality of life. Here, we report that topical application of PY-60, a small molecule activator of the transcriptional coactivator YAP, promotes regenerative repair of cutaneous wounds in pig and human models. Pharmacological YAP activation enacts a reversible pro-proliferative transcriptional program in keratinocytes and dermal cells that results in accelerated re-epithelization and regranulation of the wound bed. These results demonstrate that transient topical administration of a YAP activating agent may represent a generalizable therapeutic approach to treating chronic wounds.
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Project description:Notch signaling and Muller glia's regenerative response
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Project description:Murine small intestinal crypts of six independent mice were isolated and cultured as 3D-Organoids. Expression of NICD and loss of p53 mutagenesis was induced by 24h treatment with 4OH-tamoxifen in three of the cultures, resulting in three mutant organoid lines. The other three organoid lines were not exposed to tamoxifen and served as controls. Of each organoid line a duplicate was taken resulting in six control and six mutant samples that were compared in the analysis.
2021-06-04 | E-MTAB-6588 | biostudies-arrayexpress
Project description:YAP is a transcriptional co-activator of the hippo signaling pathway and is known for its oncogenic and regenerative activity across numerous tissue types. In particular, high YAP levels in patients with gastric cancer (GC) confer a lower survival rate and poor prognosis for these individuals. Therefore, there is a great need to develop targeted therapies against these aggressive tumors. However, the role of YAP and its underlying molecular mechanisms during gastric tumorigenesis are still poorly understood. Using genetic models, we demonstrate the oncogenic function of YAP in CLU+ gastric cells in vivo. YAP over-expression in CLU+ cells induced atrophy, metaplasia and hyperproliferation in the gastric corpus, while its deletion in a Notch activated gastric tumor model rescued metaplasia. Furthermore, we defined the YAP1 targetome in YAP activated gastric tumors, and showed that YAP1 binds to the active chromatin elements of spasmolytic polypeptide-expressing metaplasia (SPEM) related genes and activates their expressions in gastric tumors and ulcers. Together, these results reveal YAP1 as a critical regulator of metaplasia in the gastric corpus, and highlights YAP signaling as a possible therapeutic target to inhibit the progression of gastric tumors.
2023-11-07 | GSE199171 | GEO
Project description:YAP is a transcriptional co-activator of the hippo signaling pathway and is known for its oncogenic and regenerative activity across numerous tissue types. In particular, high YAP levels in patients with gastric cancer (GC) confer a lower survival rate and poor prognosis for these individuals. Therefore, there is a great need to develop targeted therapies against these aggressive tumors. However, the role of YAP and its underlying molecular mechanisms during gastric tumorigenesis are still poorly understood. Using genetic models, we demonstrate the oncogenic function of YAP in CLU+ gastric cells in vivo. YAP over-expression in CLU+ cells induced atrophy, metaplasia and hyperproliferation in the gastric corpus, while its deletion in a Notch activated gastric tumor model rescued metaplasia. Furthermore, we defined the YAP1 targetome in YAP activated gastric tumors, and showed that YAP1 binds to the active chromatin elements of spasmolytic polypeptide-expressing metaplasia (SPEM) related genes and activates their expressions in gastric tumors and ulcers. Together, these results reveal YAP1 as a critical regulator of metaplasia in the gastric corpus, and highlights YAP signaling as a possible therapeutic target to inhibit the progression of gastric tumors.
2023-11-07 | GSE199170 | GEO
Project description:siRNA-mediated inhibition compared to untreated cells and cells transfected with nonsense siRNA. Loss of contact inhibition and anchorage-independent growth are hallmarks of cancer cells. In this context, frequent inactivation of the Hippo pathway and subsequent nuclear enrichment of the transcriptional coactivator yes-associated protein (YAP) uncouple cell proliferation and anti-apoptosis from contact inhibition, associated with uncontrolled tumor growth and tumor cell dissemination. However, general molecular mechanisms of tumor-supporting YAP activity remain unclear. In this study, we show that overexpression and nuclear accumulation of YAP in hepatocytes and hepatocellular carcinoma (HCC) cells leads to an induction of the Notch pathways through transcriptional activation of the Notch ligand jagged-1 (Jag-1). This induction of Jag-1 strictly depends on binding of YAP to TEAD4 and does not rely on WNT/β-catenin pathway activity. Co-activation of YAP, TEAD4, Jag-1, and the Notch target gene Hes-1 was significantly higher in HCC from patients with poor prognosis. High-level expression and nuclear accumulation of YAP correlates with Jag-1/Notch activation not only in human HCC tissues, but also in colon and pancreatic cancer tissues. Thus, our data demonstrate that YAP-driven co-activation of the Jag-1/Notch pathway in part facilitates oncogenic properties of the oncogene YAP not only in HCC but also in different gastrointestinal malignancies. Expression profiling of untreated HCC cell lines (control 1), cells transfected with scrambled/nonsense siRNA (control 2), and after siRNA-mediated YAP inhibition.
2012-11-01 | E-GEOD-35004 | biostudies-arrayexpress
Project description:Pharmacological YAP activation promotes regenerative repair of cutaneous wounds.
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Project description:The Notch pathway is a conserved cell-cell communication pathway that controls cell fate decisions. Here we sought to determine how Notch pathway activation inhibits the neuroendocrine cell fate in the lungs, an archetypal process for cell fate decisions orchestrated by Notch signaling that has remained poorly understood at the molecular level. Using heterogeneity in small cell lung cancer as a model system, we uncovered a role for the transcriptional regulators REST and YAP as promoters of the neuroendocrine to non-neuroendocrine transition. We further identified the specific neuroendocrine gene programs repressed by REST downstream of Notch in this process. Importantly, we validated the importance of REST and YAP in neuroendocrine to non-neuroendocrine cell fate switches in both developmental and tissue repair processes in the lungs. Altogether, these experiments identify conserved roles for REST and YAP in Notch-driven inhibition of the neuroendocrine cell fate in embryonic lungs, adult lungs, and lung cancer.
2022-02-07 | GSE171917 | GEO
Project description:The Notch pathway is a conserved cell-cell communication pathway that controls cell fate decisions. Here we sought to determine how Notch pathway activation inhibits the neuroendocrine cell fate in the lungs, an archetypal process for cell fate decisions orchestrated by Notch signaling that has remained poorly understood at the molecular level. Using heterogeneity in small cell lung cancer as a model system, we uncovered a role for the transcriptional regulators REST and YAP as promoters of the neuroendocrine to non-neuroendocrine transition. We further identified the specific neuroendocrine gene programs repressed by REST downstream of Notch in this process. Importantly, we validated the importance of REST and YAP in neuroendocrine to non-neuroendocrine cell fate switches in both developmental and tissue repair processes in the lungs. Altogether, these experiments identify conserved roles for REST and YAP in Notch-driven inhibition of the neuroendocrine cell fate in embryonic lungs, adult lungs, and lung cancer.
2022-02-07 | GSE171918 | GEO