Roles of Yap1 in mouse embryonic stem cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE69669 | GEO | 2016/03/04
SECONDARY ACCESSION(S): PRJNA286134
REPOSITORIES: GEO
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Project description:While Yap1, a Hippo pathway transcriptional effector, plays numerous roles in development and cancer, its functions in embryonic stem (ES) cell differentiation remain poorly characterized. It is known that approximately 30% of ES cells die after exiting self-renewal to differentiate, but upstream regulators of this process are not well known. We first observe that ES cells lacking Yap1 experience massive cell death upon the exit from self-renewal. We subsequently reveal that Yap1 contextually protects differentiating, but not self-renewing, mouse ES cells from hyperactivation of the apoptotic cascade. Mechanistically, Yap1 strongly activates anti-apoptotic genes via directly occupying their regulatory elements while mildly suppressing pro-apoptotic genes. Our demonstration of the pro-survival functions of Yap1 during ES cell differentiation expands our understanding of upstream regulators of the balance between survival and death during cell fate changes.
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Project description:Zinc finger and SCAN domain-containing 10 (Zscan10, also known as Zfp206) encodes a transcription factor that has been reported to be involved in the maintenance of pluripotency in mouse embryonic stem (ES) cells. Here we generated inducible knockout ES cells for Zscan10 using the Cre-loxP system and analyzed its function. We succeeded in establishing Zscan10-null ES cells and confirmed their pluripotency by the generation of chimeric embryos. Our results clearly indicate that Zscan10 is dispensable for the ability of self-renewal and differentiation in ES cells.
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Project description:Zinc finger and SCAN domain-containing 10 (Zscan10, also known as Zfp206) encodes a transcription factor that has been reported to be involved in the maintenance of pluripotency in mouse embryonic stem (ES) cells. Here we generated inducible knockout ES cells for Zscan10 using the Cre-loxP system and analyzed its function. We succeeded in establishing Zscan10-null ES cells and confirmed their pluripotency by the generation of chimeric embryos. Our results clearly indicate that Zscan10 is dispensable for the ability of self-renewal and differentiation in ES cells. An inducible knockout ES cell line of Zscan10 with the Cre-loxP system was generated and gene expression was measured without Zscan10 deletion or constitutive knocked out cells. Each sample was prepared in triplicate.
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Project description:Adult radial glia-like cells (RGLs) residing in the subgranular zone (SGZ) of the dentate gyrus (DG) are finely regulated to control the generation of new neurons. Quiescence is essential for the long-term maintenance of the RGL pool. Intrinsic factors as well as extrinsic niche signals orchestrate the balance between RGL quiescence and activation, but the mechanisms are still not completely understood. Yap1, a core factor of Hippo signaling, is very important for the proliferation of stem cells of various organs and species, such as intestinal stem cells of the mouse and neural stem cells in Drosophila brain. Here I addressed the role of Yap1 in adult hippocampal neurogenesis by gain- and loss-of-function studies. I found that the expression of Yap1 was enriched in adult RGLs, but was undetectable in other cell types such as neurons and cells of the oligodendroglial lineage. Through the analysis of conditional knock-out of Yap1 in adult RGLs and their lineage, I found that fewer RGLs became activated while a significantly higher proportion of RGLs remained in the quiescent state. Conversely, overexpression of constitutively active mutant variant of Yap1 (Yap1 5SA) induced the proliferation of quiescent RGLs in vitro and in vivo. This effect was dependent on functional interaction with the TEA Domain Transcription Factor (TEAD). Pharmacological blocking the interaction between endogenous Yap1 and TEAD by verteporfin reduced the rate of proliferation of neural progenitors in vitro, which indicates a physiological role of Yap1-TEAD interaction in regulating the transition between quiescence and activation. Interestingly, constitutive expression of Yap1 5SA in RGLs blocked adult neurogenesis and retained the cells in a progenitor-like (Sox2+) state. To further explore the molecular mechanisms of Yap1 in regulating the activation of quiescent RGLs, single-cell RNA sequencing analysis was performed at 3 and 7 days following Yap1 5SA overexpression. Yap1 5SA overexpressing cells exhibited increased signature of active NSCs but also displayed distinct features such as epithelial-to-mesenchymal transition (EMT). Importantly, we found that Catenin Beta 1 (CTNNB1) was upregulated suggesting a potential involvement of Wnt signaling in the proliferative effect of Yap1 5SA overexpression in adult NSCs. In sum, this work provides compelling evidence for regulation of the balance between activation and quiescence of adult hippocampal RGLs by Yap1.
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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.
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Project description:we found that CCHMC-DIPG1 cells express little OLIG2 and exhibit a mesenchymal phenotype, which raised a question regarding the role of OLIG2 in the growth of DIPG cells. Our results indicate that OLIG2 is dispensable for DIPG cell growth but is required for maintenance of the proneural tumor phenotype. Downregulation of OLIG2 leads to deregulation of adaptive YAP1 and EGFR signaling.
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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.
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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.
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