Folliculin regulates mTORC1/2 and WNT pathways in early human pluripotency
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ABSTRACT:
PROVIDER: PRJNA503630 | ENA |
REPOSITORIES: ENA
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Project description:Using co-immunoprecipitation and mass spectrometry analysis we identify unique FLCN binding partners. The interactions of FLCN with components of the mTOR pathway (mTORC1 and mTORC2) reveal a mechanism of FLCN function during exit from naïve pluripotency.
2019-02-13 | PXD011736 | Pride
Project description:It is important to understand how cells can maintain and exit human pluripotency. We exploited the metabolic and epigenetic differences between naïve and primed pluripotent cells to design a CRISPR-Cas9 screen for identifying genes that promote the exit from naïve pluripotency. Among the known and novel regulators of this early step of human development, we identified the tumor suppressor folliculin (FLCN). Flcn is important for implantation of the mouse embryo into the uterus and has been shown to regulate the exit of pluripotency in mouse through activation of Esrrb. However, the function of FLCN is unknown in human embryonic stem cells (hESC). Knock-out (KO) of FLCN revealed that it is not essential to maintain the naïve pluripotent state but is required for the exit of that state, in part by controlling the localization of the transcription factor TFE3. While mainly found in the cytoplasm of cells exiting the naïve state, FLCN KO resulted in TFE3 nuclear localization. TFE3 targets up-regulated in FLCN KO exit assay were members of Wnt pathway and ESRRB. Treatment of FLCN KO hESC with a Wnt inhibitor rescued the phenotype and allowed the cells to exit the naïve state. In contrast, the lack of rescue in ESRRB/FLCN double KO lines suggested that ESRRB was not responsible for the FLCN mutant phenotype. Using co-immunoprecipitation and mass spectrometry analysis we identified unique FLCN binding partners, in addition to known FLCN interactors, at various stages of pluripotency. The interactions of FLCN with components of the mTOR pathway (mTORC1 and mTORC2) revealed a mechanism of FLCN function during exit from naïve pluripotency.
2018-11-03 | GSE122118 | GEO
Project description:To reveal how cells exit human pluripotency, we designed a CRISPR-Cas9 screen exploiting the metabolic and epigenetic differences between naïve and primed pluripotent cells. We identify the tumor suppressor, Folliculin(FLCN) as a critical gene required for the exit from human pluripotency. Here we show that FLCN Knock-out (KO) hESCs maintain the naïve pluripotent state but cannot exit the state since the critical transcription factor TFE3 remains active in the nucleus. TFE3 targets up-regulated in FLCN KO exit assay are members of Wnt pathway and ESRRB. Treatment of FLCN KO hESC with a Wnt inhibitor, but not ESRRB/FLCN double mutant, rescues the cells, allowing the exit from the naïve state. Using co-immunoprecipitation and mass spectrometry analysis we identify unique FLCN binding partners. The interactions of FLCN with components of the mTOR pathway (mTORC1 and mTORC2) reveal a mechanism of FLCN function during exit from naïve pluripotency.
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Project description:The regulation of gene expression through histone post-translational modifications plays a crucial role in breast cancer progression. However, the molecular mechanisms underlying the contribution of histone modification to tumor initiation remain unclear. To gain a deeper understanding of the role of the histone modifier Enhancer of Zeste homology 2 (Ezh2) in the early stages of mammary tumor progression, we employed an inducible mammary organoid system bearing conditional Ezh2 alleles that faithfully recapitulates key events of Luminal B breast cancer initiation. We showed that the loss of Ezh2 severely impairs oncogene-induced organoid growth, with Ezh2-deficient organoids maintaining a polarized epithelial phenotype. Transcriptomic profiling showed that Ezh2-deficient mammary epithelial cells upregulated the expression of negative regulators of Wnt signaling and downregulated genes involved in mTORC1 (mechanistic target of rapamycin complex 1) signaling. We identified Sfrp1, a Wnt signaling suppressor, as an Ezh2 target gene that is de-repressed and expressed in Ezh2-deficient epithelium. Furthermore, an analysis of breast cancer data revealed that Sfrp1 expression was associated with favorable clinical outcomes in Luminal B breast cancer patients. Finally, we confirmed that targeting Ezh2 impairs mTORC1 activity through an indirect mechanism that upregulates the expression of the tumour suppressor Pten. These findings indicate that Ezh2 integrates the mTORC1 and Wnt signaling pathways during early mammary tumor progression, arguing that inhibiting Ezh2 or therapeutically targeting Ezh2-dependent programs could be beneficial for the treatment of early-stage Luminal B breast cancer.
2023-07-15 | GSE235144 | GEO
Project description:The regulation of gene expression through histone post-translational modifications plays a crucial role in breast cancer progression. However, the molecular mechanisms underlying the contribution of histone modification to tumor initiation remain unclear. To gain a deeper understanding of the role of the histone modifier Enhancer of Zeste homology 2 (Ezh2) in the early stages of mammary tumor progression, we employed an inducible mammary organoid system bearing conditional Ezh2 alleles that faithfully recapitulates key events of Luminal B breast cancer initiation. We showed that the loss of Ezh2 severely impairs oncogene-induced organoid growth, with Ezh2-deficient organoids maintaining a polarized epithelial phenotype. Transcriptomic profiling showed that Ezh2-deficient mammary epithelial cells upregulated the expression of negative regulators of Wnt signaling and downregulated genes involved in mTORC1 (mechanistic target of rapamycin complex 1) signaling. We identified Sfrp1, a Wnt signaling suppressor, as an Ezh2 target gene that is de-repressed and expressed in Ezh2-deficient epithelium. Furthermore, an analysis of breast cancer data revealed that Sfrp1 expression was associated with favorable clinical outcomes in Luminal B breast cancer patients. Finally, we confirmed that targeting Ezh2 impairs mTORC1 activity through an indirect mechanism that upregulates the expression of the tumour suppressor Pten. These findings indicate that Ezh2 integrates the mTORC1 and Wnt signaling pathways during early mammary tumor progression, arguing that inhibiting Ezh2 or therapeutically targeting Ezh2-dependent programs could be beneficial for the treatment of early-stage Luminal B breast cancer.
2023-07-15 | GSE235145 | GEO
Project description:Ezh2 promotes mammary tumor initiation through the epigenetic regulation of the Wnt and mTORC1 signaling pathways
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Project description:Ezh2 promotes mammary tumor initiation through epigenetic regulation of the Wnt and mTORC1 signaling pathways (ChIP-Seq)
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Project description:Ezh2 promotes mammary tumor initiation through the epigenetic regulation of the Wnt and mTORC1 signaling pathways (RNA-Seq)
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Project description:We report conditions for transgene-free reprogramming of human somatic cells to naïve pluripotency. We find that Wnt inhibition promotes RNA-mediated induction of naïve pluripotency.
2019-12-02 | GSE138304 | GEO
Project description:Embryonic stem cells can be maintained in a state of naive pluripotency by the use of 2 inhibitors, PD03 - a MEK inhibitor upstream of ERK, and CHIRON, a GSK3 b inhibitor, which acts as a Wnt agonist. The removal of these inhibitors allow embryonic stem cells to exit pluripotency. To determine if targets of transcriptional targets of these pathways are mechanosensitive such that their activation or suppression would be dependent on mechanical properties of substrate.
2021-08-31 | GSE125615 | GEO