Sustained YAP1 signaling alters the fate of lutein and Müllerian mesenchymal cells in mice
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1185244 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31317586_1.fastq.gz | Fastqsanger.gz | |||
| SRR31317586_2.fastq.gz | Fastqsanger.gz | |||
| SRR31317587_1.fastq.gz | Fastqsanger.gz | |||
| SRR31317587_2.fastq.gz | Fastqsanger.gz | |||
| SRR31317588_1.fastq.gz | Fastqsanger.gz |
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Project description:Recent reports have suggested that the Hippo intracellular signaling pathway is required for homeostasis in a variety of tissues, including the ovary and female reproductive tract. To further define the role of the Hippo effector YAP1 in the female reproductive system, transgenic mouse models were designed to direct the expression of a dominant stable mutant of YAP1, termed YAP5SA, to the granulosa cells of antral follicles (R26YAP5SA;CYP19-cre) and Müllerian mesenchymal cells (R26YAP5SA;Amhr2cre/+). Unexpectedly, YAP5SA expression in the ovaries of R26YAP5SA;CYP19-cre mice was not detected in granulosa cells, but rather in a subset of lutein cells. This caused the lutein cells to transdifferentiate into cells having the morphologic and functional properties of myofibroblasts, including collagen deposition. These coalesced into roughly spherical lesions that persisted in the ovaries, but did not interfere with ovarian function or fertility. Seminiferous tubule-like structures also formed in the ovaries of adult R26YAP5SA;CYP19-cre mice, containing SOX9-positive Sertoli-like cells but no germ cells. Although multi-lineage transdifferentiation had been reported in mice lacking the Hippo kinases Lats1 and -2 in their granulosa cells, comparative RNAseq analyses of granulosa cells expressing YAP5SA vs granulosa cells lacking Lats1/2 showed few similarities in transcriptome alterations. R26YAP5SA;Amhr2cre/+ mice had severe developmental defects of their uterine horns and ovaries, which were attributed to transdifferentiation of Müllerian mesenchymal cells into myofibroblasts during embryogenesis. Together, these results indicate that sustained YAP1 signaling induces transdifferentiation in lutein and Müllerian mesenchymal cells, and further underscores the role of Hippo signaling in the maintenance of their fates.
2025-03-31 | GSE281696 | GEO
Project description:The Hippo pathway effector YAP1 controls stem cell fate in epithelial tissues, but its role in stem cells of non-epithelial tissues, such as skeletal muscle, is poorly documented. Here we show that sustained YAP1 activity in mouse activated satellite cells in vivo induces rhabdomyosarcoma (RMS) resembling human embryonal RMS (ERMS) with high penetrance and short latency. The transcriptional program of YAP1 in ERMS drives pro-proliferative pathways whilst decreasing MyoD1 and MEF2 pro-differentiation activity to globally maintain the myoblastic phenotype of ERMS. Normalization of YAP1 expression reduced tumor burden and allowed myogenic differentiation of YAP1-driven and RD ERMS xenografts in situ, thereby identifying YAP1 as a potent RMS-causing oncogene and potential target for differentiation therapy. A total of four samples were analyzed. Two ChIP-Seq datasets from RD human cells, containing reads connected to TEAD binding and IgG binding as control/background; two ChIP-Seq datasets from YAP-ERMS mouse cells, containing reads connected to TEAD binding and Input reads as control/background
2014-08-12 | E-GEOD-55186 | biostudies-arrayexpress
Project description:The transcriptional co-activator YAP1 oncogene is the downstream effector of the Hippo pathway, which regulates tissue homeostasis, organ size, regeneration and tumorigenesis. Multiple cancers are dependent on sustained expression of YAP1 for cell proliferation, survival and tumorigenesis, but the molecular basis of this oncogene dependency is not well understood. To identify genes that can functionally substitute for YAP1, we performed a genome-scale genetic rescue screen in YAP1-dependent colon cancer cells expressing an inducible YAP1-specific shRNA. We found that the transcription factor PRDM14 rescued cell proliferation and tumorigenesis upon YAP1 suppression in YAP1-dependent cells, xenografts, and colon cancer organoids. YAP1 and PRDM14 individually activated the transcription of calmodulin 2 (CALM2) and a glucose transporter SLC2A1 upon YAP1 suppression; and CALM2 or SLC2A1 expression was required for the rescue of YAP1 suppression. Together, these findings implicate PRDM14-mediated transcriptional upregulation of CALM2 and SLC2A1 as key components of oncogenic YAP1 signaling and dependency.
2022-01-05 | GSE182432 | GEO
Project description:Cancer cells that express oncogenic alleles of RAS typically require sustained expression of the mutant allele for survival, but the molecular basis of this oncogene dependency remains incompletely understood. To identify genes that can functionally substitute for oncogenic RAS, we systematically expressed 15,294 open reading frames in a human KRAS-dependent colon cancer cell line engineered to express an inducible KRAS-specific shRNA. We found 147 genes that promoted survival in the setting of KRAS suppression. In this model, the transcriptional co-activator YAP1 rescued cell viability in KRAS-dependent cells upon suppression of KRAS and was required for KRAS-induced cell transformation. Acquired resistance to Kras suppression in a Kras-driven murine lung cancer model also involved increased YAP1 signaling. KRAS and YAP1 converge on the transcription factor FOS and activate a transcriptional program involved in regulating the epithelial-mesenchymal transition (EMT). Together, these findings implicate transcriptional regulation of EMT by YAP1 as a significant component of oncogenic RAS signaling Three biological replicates of primary lung adenocarcinoma cells derived from the Kras Lox-STOP-Lox-G12D;p53flox/flox (KP) mouse lung cancer model into which a doxycycline-inducible shRNA targeting Kras expressed from the 3’UTR of GFP was introduced (KP-KrasA cells) were analyzed at timepoints (days) D0, D4, and D21.
2014-07-27 | E-GEOD-56175 | biostudies-arrayexpress
Project description:We report here high-throughput RNA sequencing (RNA-seq) to characterise the transcriptional landscape of the embryonic chicken Müllerian duct during development.
2020-10-07 | GSE153029 | GEO
Project description:To gain insight into the pathways accounting for the deleterious effects associated with severe mitochondrial dysfunction, we compared the transcriptomic profile in control L3 larvae with that of strong (arrested) nuo-5 RNAi. We also found that the natural compound lutein was able to rescue some of the defective phenotypes we characterized in nuo-5-depleted animals therefore we compared also the transcriptomic profile of stage-matched (L3) cohorts of C. elegans upon strong nuo-5 RNAi, treated and untreated with lutein, with that of animals fed empty vector control.
2020-01-31 | GSE144574 | GEO
Project description:The Hippo pathway effector YAP1 controls stem cell fate in epithelial tissues, but its role in stem cells of non-epithelial tissues, such as skeletal muscle, is poorly documented. Here we show that sustained YAP1 activity in mouse activated satellite cells in vivo induces rhabdomyosarcoma (RMS) resembling human embryonal RMS (ERMS) with high penetrance and short latency. The transcriptional program of YAP1 in ERMS drives pro-proliferative pathways whilst decreasing MyoD1 and MEF2 pro-differentiation activity to globally maintain the myoblastic phenotype of ERMS. Normalization of YAP1 expression reduced tumor burden and allowed myogenic differentiation of YAP1-driven and RD ERMS xenografts in situ, thereby identifying YAP1 as a potent RMS-causing oncogene and potential target for differentiation therapy.
2014-08-12 | GSE55186 | GEO
Project description:In order to define YAP1-specific gene expression patterns in gastric cancer, the constitutively active mutant YAP1 (YAP1-S127A) was over-expressed in MKN45 gastric cancer cells. Defined gene expression signature was later used to stratify gastric cancer patients according to the presence of the YAP1-activated signature. Three groups of samples are included: 1. Mock control; 2. Vector control; 3. YAP-S127A expression. Gene expression profiles of YAP-S127A mutant-expressing cells were compared to that of mock and vector control. Experiments were done in MKN45 gastric cancer cells.
2013-10-01 | E-GEOD-41387 | biostudies-arrayexpress
Project description:Doxycycline-inducible YAP1 S127A-driven rhabdomyosarcoma (RMS) tumors, control skeletal muscle and regressed tumors following YAP1 normalization by doxycycline withdrawal were compared to determine the YAP1-regulated gene expression profile relevant to RMS formation. To characterize the role of YAP1 in embryonal RMS at the molecular level and identify a gene signature for YAP1 activity readout, we compared the gene expression profiles of our YAP1-driven ERMS with control donor skeletal muscle (SKM) and doxycycline-withdrawn regressing tumors by microarray (doxycycline withdrawal for 3 or 6 days; OFF3 and OFF6, respectively). We next extracted a list of genes regulated by YAP1 in our YAP1-driven ERMS tumors (TUM) versus the 3 other conditions: skeletal muscle control (SKM), Doxycycline-withdrawn 3 days (OFF3) and 6 days (OFF6). The overlap between the 3 lists identified a subset of 633 common upregulated genes, named the YAP1-ERMS_UP signature, as well as 249 common downregulated genes, termed the YAP1-ERMS_DOWN signature. Proliferative pathways and transcriptional targets of E2F factors were highlighted in the YAP1-ERMS_UP genes, while muscle differentiation and trancriptional targets of myogenic factors Myod1 and Mef2 were highlighted in the YAP1-ERMS_DOWN genes. Tumor regression conditions (OFF3 days; OFF6 days) as well as control muscle (CTL) were compared with tumors at day 0 of doxycycline withdrawal (TUM). 3 samples for each conditions were used.
2014-08-12 | E-GEOD-47198 | biostudies-arrayexpress
Project description:Our study is based on the hypothesis that PCOS can be explained by an integrated, epigenetic model, whereby environmental factors modify the effect of susceptibility genes and influence the clinical heterogeneity that is characteristic of the syndrome during adult life. With the aim to understand the molecular mechanisms underlying PCOS, we report results from a case-control, genome-wide methylation study using human DNA from granulosa lutein cells.
2019-03-01 | E-MTAB-6672 | biostudies-arrayexpress