FGF-WNT omic correlation project
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Orbitrap Fusion, Q Exactive
ORGANISM(S): Mus Musculus (ncbitaxon:10090)
SUBMITTER: 
Jeffrey M Rosen
PROVIDER: MSV000081730 | MassIVE | Wed Nov 22 11:24:00 GMT 2017
SECONDARY ACCESSION(S): PXD008268
REPOSITORIES: MassIVE
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Project description:Background & Aims: Hierarchical organization of intestine relies on their stem cells by self-renew and producing committed progenitors. Although signals like Wnt are known to animate the continued renewal by maintaining intestinal stem cells (ISCs) activity, molecular mechanisms especially E3 ubiquitin ligases that modulate ISCs ‘stemness’ and supportive niche have not been well understood. Here, we investigated the role of Cullin 4B (Cul4b) in regulating ISC functions. Methods: We generated mice with intestinal epithelial-specific disruption of Cul4b (pVillin-cre; Cul4bfn/Y), inducible disruption of Cul4b (Lgr5-creERT2; Cul4bfn/Y, CAG-creERT2; Cul4bfn/Y) and their control (Cul4bfn/Y). Intestinal tissues were analyzed by histology, immunofluorescence, RNA sequencing and mass spectrum. Intestinal organoids deprived from mice with pVillin-Cre; Cul4bfn/Y, Lgr5-Cre; Cul4bfn/Y, Tg-Cul4b and their controls were used in assays to measure intestinal self-renewal, proliferation and differentiation. Wnt signaling and intestinal markers were analyzed by immunofluorescence and immunoblot assays. Differential proteins upon Cul4b ablation or Cul4b-interacting proteins were identified by mass spectrometry. Results: Cul4b specifically located at ISCs zone. Block of Cul4b impaired intestinal homeostasis maintenance by reduced self-renewal and proliferation. Transcriptome analysis revealed that Cul4b-null intestine lose ISC characterization and showed disturbed ISC niche. Mechanistically, reactivated Wnt pathway could recover intestinal dysfunction of Cul4b knockout mice. Analysis of differential total and ubiquitylated proteins uncovered the novel targeting substrate of Cullin-Ring ubiquitin ligase 4b (CRL4b), immunity-related GTPase family M member 1 (Irgm1) in intestine. Decreased Irgm1 rescued abnormally interferon signaling, overemphasized autophagy and downstream phosphate proteins in Cul4b knockout mice. Conclusion: We conclude that Cul4b is essential for ISC self-renewal and Paneth cell function by targeting Irgm1 and modulating Wnt signaling. Our results demonstrate that Cul4b is a novel ISC stemness and niche regulator.
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Project description:Hierarchical organization of intestine relies on their stem cells by self-renew and producing committed progenitors. Although signals like Wnt are known to animate the continued renewal by maintaining intestinal stem cells (ISCs) activity, molecular mechanisms especially E3 ubiquitin ligases that modulate ISCs ‘stemness’ and supportive niche have not been well understood. Here, we investigated the role of Cullin 4B (Cul4b) in regulating ISC functions.We conclude that Cul4b is essential for ISC self-renewal and Paneth cell function by targeting Irgm1 and modulating Wnt signaling. Our results demonstrate that Cul4b is a novel ISC stemness and niche regulator.
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Project description:Breast cancer stem cells (bCSCs) have been implicated in tumor progression and therapeutic resistance; however, the molecular mechanisms that define bCSC-state are unclear. We have performed concurrent human miRNome-wide gain- and loss-of-function screens to identify switcher miRNAs controling the choice between bCSC self-renewal and differentiation. These analysis enlightened miR-600 whose silencing resulted in bCSC expansion. Mechanistically, miR-600 targets the stearoyl desaturase 1 (SCD1), an enzyme required to produce active, lipid-modified WNT proteins. To explore further miR-600 interactions and WNT-pathway, SUM159 cell line constructions were made and FACS-sorted to select the bCSCs. We compared gene expression profiles from native, miR-600 'over-expressed', miR-600'knock-down' and siSCD1 bCSCs. We showed that in the absence of miR-600, WNT signaling is maintained active and promotes self-renewal, whereas overexpression of miR-600 inhibits the production of active WNT proteins and promotes bCSC differentiation. These findings highlight a miR-600-centered signaling network that governs bCSC-fate decision and influences tumor progression.
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Project description:The partial EMT program drives breast cancer stemness and metastasis. This process is governed by transcriptional regulators that maintain the epithelial/mesenchymal (E/M) bipotent stem cell state and by differential growth factor signaling driving self-renewal vs differentiation. Here we show that TCF1/Wnt signaling stimulates transient ERK/CDK4/6 activation which upregulates FOXC2, and in turn TAp63 and ΔNp63 isoforms, thereby maintaining the partial EMT state. In parallel, ERK/CDK4/6 promotes FOXC2 expression and S-phase transition while activating FOXM1 to drive E/M cell self-renewal. Interestingly, transient ERK activation by Wnt3a inactivates EGFR, thus preventing EGF from causing a robust and sustained ERK phosphorylation that causes E/M to M differentiation, resulting in CSC exhaustion. Consistent with these data, ERK/CDK4/6 inhibition suppressed CSC organoid forming ability. Collectively, these findings illustrate an intricate mechanism integrating cancer stemness with self-renewal and differentiation via Wnt-stimulated ERK/CDK4/6 activation, underscoring the implication of these findings for cancer stem cell therapy.
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Project description:Hematopoietic stem cells (HSCs) have unique abilities to renew themselves and generate differentiated progenies of all blood cell lineages; however, how HSCs maintain the balance of self-renewal and lineage differentiation remains largely unknown. Herein, we showed that in mice the hematologic system deletion of Phosphatase, Mg2+/Mn2+ Dependent 1B (Ppm1b), a protein serine or threonine phosphatase highly expressed in HSCs, induces the suppression of phenotypic HSC expansion due to the blockage of cell cycle. Loss of Ppm1b impairs HSC self-renewal and hematopoietic reconstitution which were revealed by limiting dilution and BM transplantation assays. Through transcriptomic analysis, we observed that the Wnt/β-catenin pathway is downregulated in Ppm1b-deficient mice. Mechanistically, we provided evidence that Ppm1b interacted with β-catenin by performing a proximity ligation assay. Moreover, using an HN252 as a small molecule probe, we further found that Ppm1b inhibition suppressed the self-renewal of HSC and led to a decrease in common lymphoid progenitor cells, resulting in a reduction of B cells in the bone marrow and peripheral blood in turn. In the study we characterized an indispensable role of Ppm1b in regulating HSC self-renewal and B cell development via Wnt/β-catenin pathway.
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