The transcriptional co-activator Yap1 promotes adult hippocampal neural stem cell activation
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ABSTRACT:
PROVIDER: PRJNA605458 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11041800.fastq.gz | Fastqsanger.gz | |||
| SRR11041900.fastq.gz | Fastqsanger.gz | |||
| SRR11042000.fastq.gz | Fastqsanger.gz | |||
| SRR11042100.fastq.gz | Fastqsanger.gz | |||
| SRR11042200.fastq.gz | Fastqsanger.gz |
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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:Most adult hippocampal neural stem cells (NSCs) remain quiescent, with only a minor portion undergoing active proliferation and neurogenesis. The molecular mechanisms that trigger the transition from quiescence to activation are still poorly understood. Here, we found the activity of the transcriptional co-activator Yap1 to be enriched in active NSCs. Genetic deletion of Yap1 led to a significant reduction in the relative proportion of active NSCs, supporting a physiological role of Yap1 in regulating the transition from quiescence to activation. Overexpression of wild-type Yap1 in adult NSCs did not induce NSC activation, suggesting tight upstream control mechanisms, but overexpression of a gain-of-function mutant (Yap1-5SA) elicited cell cycle entry in NSCs and hilar astrocytes. Consistent with a role of Yap1 in NSC activation, single cell RNA sequencing revealed a partial induction of an activated NSC gene expression program. Furthermore, Yap1-5SA expression also induced expression of Taz and other key components of the Yap/Taz regulon that were previously identified in glioblastoma stem cell-like cells. Consequently, dysregulated Yap1 activity led to repression of hippocampal neurogenesis, aberrant cell differentiation, and partial acquisition of a glioblastoma stem cell-like signature.
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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: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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