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Transcriptomic profiling of oncogenic RIT1 and activated YAP1 in lung epithelial cells

ABSTRACT: Based on xenograft data, we have found that YAP1 activation synergizes with RIT1M90I to promote lung cancer. To investigate the molecular basis for the observed functional synergy, we performed whole-genome RNA-seq in SALE cells expressing RIT1M90I and YAP15SA individually or in combination. We find that RIT1M90I and YAP15SA induced very different transcriptional states with little correlation. And, that transcripts altered by RIT1M90I were not enriched for a YAP1 gene signature, whereas YAP15SA drove activation of this signature. In addition, we find that when RIT1M90I and YAP15SA w co-expressed, YAP1-regulated gene expression was enhanced by RIT1M90I compared to YAP15SA alone, with known YAP1 targets such as TNNT2, ITGB2, and COL4A3 showing 2.5-3.6 fold increased expression compared to YAP15SA alone. These data suggest that RIT1M90I on its own does not trigger YAP1 target transcription but may instead enhance activation of YAP1 targets in settings of YAP1 activation, such as tumors with Hippo pathway loss.

ORGANISM(S): Homo sapiens

PROVIDER: GSE165631 | GEO | 2021/05/31

REPOSITORIES: GEO

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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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Transcriptomic profiling of oncogenic RIT1 and activated YAP1 in lung epithelial cells

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