Regulation of Primary Cilia Disassembly Through HUWE1-Mediated TTBK2 Degradation Plays a Crucial Role in Cerebellar Development and Medulloblastoma Growth
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1117916 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29224972_1.fastq.gz | Fastqsanger.gz | |||
| SRR29224972_2.fastq.gz | Fastqsanger.gz | |||
| SRR29224973_1.fastq.gz | Fastqsanger.gz | |||
| SRR29224973_2.fastq.gz | Fastqsanger.gz | |||
| SRR29224974_1.fastq.gz | Fastqsanger.gz |
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Project description:Development of the cerebellum requires precise regulation of granule neuron progenitor (GNP) proliferation. Although it is known that primary cilia are necessary to support GNP proliferation, the exact molecular mechanism governing primary cilia dynamics within GNPs remains elusive. Here, we establish the pivotal roles for the centrosomal kinase TTBK2 (Tau tubulin kinase-2) and the E3 ubiquitin ligase HUWE1 in GNP proliferation. We show that TTBK2 is highly expressed in proliferating GNPs under Sonic Hedgehog (SHH) signaling, coinciding with active GNP proliferation and the presence of primary cilia. TTBK2 stabilizes primary cilia by inhibiting their disassembly, thereby promoting GNP proliferation in response to SHH. Mechanistically, we identify HUWE1 as a novel centrosomal E3 ligase that facilitates primary cilia disassembly by targeting TTBK2 degradation. Disassembly of primary cilia serves as a trigger for GNP differentiation, allowing their migration from the external granule layer (EGL) of the cerebellum to the internal granule layer (IGL) for subsequent maturation. Moreover, we have established a link between TTBK2 and SHH-type medulloblastoma (SHH-MB), a tumor characterized by uncontrolled GNP proliferation. TTBK2 depletion inhibits SHH-MB proliferation, indicating that TTBK2 may be a potential therapeutic target for this cancer type. In summary, our findings reveal the mechanism governing cerebellar development and highlight a potential anti-cancer strategy for SHH-MB.
2024-06-03 | GSE268621 | GEO
Project description:Development of the cerebellum requires precise regulation of granule neuron progenitor (GNP) proliferation. Although it is known that primary cilia are necessary to support GNP proliferation, the exact molecular mechanism governing primary cilia dynamics within GNPs remains elusive. Here, we establish the pivotal roles for the centrosomal kinase TTBK2 (Tau tubulin kinase-2) and the E3 ubiquitin ligase HUWE1 in GNP proliferation. We show that TTBK2 is highly expressed in proliferating GNPs under Sonic Hedgehog (SHH) signaling, coinciding with active GNP proliferation and the presence of primary cilia. TTBK2 stabilizes primary cilia by inhibiting their disassembly, thereby promoting GNP proliferation in response to SHH. Mechanistically, we identify HUWE1 as a novel centrosomal E3 ligase that facilitates primary cilia disassembly by targeting TTBK2 degradation. Disassembly of primary cilia serves as a trigger for GNP differentiation, allowing their migration from the external granule layer (EGL) of the cerebellum to the internal granule layer (IGL) for subsequent maturation. Moreover, we have established a link between TTBK2 and SHH-type medulloblastoma (SHH-MB), a tumor characterized by uncontrolled GNP proliferation. TTBK2 depletion inhibits SHH-MB proliferation, indicating that TTBK2 may be a potential therapeutic target for this cancer type. In summary, our findings reveal the mechanism governing cerebellar development and highlight a potential anti-cancer strategy for SHH-MB.
| S-EPMC11445238 | biostudies-literature
Project description:Aim: To determine the major protein kinase pathways altered upon serum- or LPA-induced cilia disassembly Primary cilia are dynamic structures which must disassemble for a cell to go through mitosis and re-assemble in G0 to transduce essential signals. Also, in non-cycling cells (such as renal epithelial cells), there is evidence to suggest that deregulated cilia disassembly is of critical importance, for example in instances with an excess of a cilia disassembly stimuli (such as Aurora kinase A expression and activation, a key disassembly factor) which is associated with ciliopathy phenotypes and a net loss of ciliated cells. Serum, growth factor or lysophosphatidic acid (LPA) stimulation of ciliated cells are well established experimental paradigms for the induction of cilia disassembly. The signalling network activated by these stimuli that culminates in cilia disassembly is complex and poorly understood. Studies have generally focused on a single or small group of proteins of interest to define their roles in cilia disassembly and the key pathways and kinases activated upon serum stimulation to induce cilia disassembly have not been defined. Moreover, to the best of our knowledge an unbiased analysis of the major pathways activated during cilia disassembly has not been performed. Ciliated hTERT-RPE1 cells were treated with 10% serum or 2 M LPA for 15’ or 2 h to initiate cilia disassembly + pan-class I PI3K inhibitor GDC-0941, followed by label-free phosphoproteomics.
2024-07-25 | PXD046462 | Pride
Project description:Cilia are important subcellular organelles and are regulated by transcription factors including Foxj1 and Rfx proteins. Whether and how are cilia regulated at epigenetic level remains unknown. We addressed this question by knocking down or knocking out of chromatin remodeling genes. Interestingly, depletion of multiple components of the switch/sucrose non-fermentable (SWI/SNF) complexes lead to ciliopathy-like phenotypes in zebrafish embryos. Specifically, depletion of Actl6a, one of the components of the SWI/SNF complexes lead cilia disassembly and cystic kidney, but do not affect cilia motility. Omics studies show that in Actl6a-depleted embryos, a set of cilia genes including Foxj1a and Rfx2, the master regulators of cilia assembly, were downregulated at transcriptional level, chromatin accessibility and the SWI/SNF complexes binding. Thus, our study reveals that the SWI/SNF complexes regulate cilia stability and kidney development by direct modulating the expression Foxj1a and Rfx2.
2026-01-01 | GSE277562 | GEO
Project description:Cilia are important subcellular organelles and are regulated by transcription factors including Foxj1 and Rfx proteins. Whether and how are cilia regulated at epigenetic level remains unknown. We addressed this question by knocking down or knocking out of chromatin remodeling genes. Interestingly, depletion of multiple components of the switch/sucrose non-fermentable (SWI/SNF) complexes lead to ciliopathy-like phenotypes in zebrafish embryos. Specifically, depletion of Actl6a, one of the components of the SWI/SNF complexes lead cilia disassembly and cystic kidney, but do not affect cilia motility. Omics studies show that in Actl6a-depleted embryos, a set of cilia genes including Foxj1a and Rfx2, the master regulators of cilia assembly, were downregulated at transcriptional level, chromatin accessibility and the SWI/SNF complexes binding. Thus, our study reveals that the SWI/SNF complexes regulate cilia stability and kidney development by direct modulating the expression Foxj1a and Rfx2.
2026-01-01 | GSE277564 | GEO
Project description:Background: Whereas cilia damage and reduced cilia beat frequency have been implicated as causative of reduced mucociliary clearance in smokers, theoretically mucociliary clearance could also be affected by cilia length. Based on models of mucociliary clearance predicting cilia length must exceed the 6 -7 μm airway surface fluid depth to generate force in the mucus layer, we hypothesized cilia height may be decreased in airway epithelium of normal smokers compared to nonsmokers. Methodology/Principal Findings: Cilia length in normal nonsmokers and smokers was evaluated in aldehyde-fixed, paraffin-embedded endobronchial biopsies, and air-dried and hydrated samples brushed from human airway epithelium via fiberoptic bronchoscopy. In 28 endobronchial biopsies, healthy smoker cilia length was reduced 15% compared to nonsmokers (p<0.05). In 47 air-dried samples of airway epithelial cells, smoker cilia length was reduced 13% compared to nonsmokers (p<0.0001). Analysis of the length of individual, detached cilia in 17 samples, smoker cilia length was reduced 9% compared to nonsmokers (p<0.05). Finally, in 16 fully hydrated, unfixed samples, smoker cilia length was reduced 7% compared to nonsmokers (p<0.05). Conclusions/significance: Models predict that a reduction in cilia length would reduce mucociliary clearance, suggesting that smoking-associated shorter airway epithelial cilia plays a significant role in the pathogenesis of smoking-induced lung disease.
2012-12-13 | E-GEOD-16696 | biostudies-arrayexpress
Project description:Cilia are important subcellular organelles and are regulated by transcription factors including Foxj1 and Rfx proteins. Whether and how are cilia regulated at epigenetic level remains unknown. We addressed this question by knocking down or knocking out of chromatin remodeling genes. Interestingly, depletion of multiple components of the switch/sucrose non-fermentable (SWI/SNF) complexes lead to ciliopathy-like phenotypes in zebrafish embryos. Specifically, depletion of Actl6a, one of the components of the SWI/SNF complexes lead cilia disassembly and cystic kidney, but do not affect cilia motility. Omics studies show that in Actl6a-depleted embryos, a set of cilia genes including Foxj1a and Rfx2, the master regulators of cilia assembly, were downregulated at transcriptional level, chromatin accessibility and the SWI/SNF complexes binding. Thus, our study reveals that the SWI/SNF complexes regulate cilia stability and kidney development by direct modulating the expression Foxj1a and Rfx2.
2026-01-01 | GSE274957 | GEO
Project description:Cilia are important subcellular organelles and are regulated by transcription factors including Foxj1 and Rfx proteins. Whether and how are cilia regulated at epigenetic level remains unknown. We addressed this question by knocking down or knocking out of chromatin remodeling genes. Interestingly, depletion of multiple components of the switch/sucrose non-fermentable (SWI/SNF) complexes lead to ciliopathy-like phenotypes in zebrafish embryos. Specifically, depletion of Actl6a, one of the components of the SWI/SNF complexes lead cilia disassembly and cystic kidney, but do not affect cilia motility. Omics studies show that in Actl6a-depleted embryos, a set of cilia genes including Foxj1a and Rfx2, the master regulators of cilia assembly, were downregulated at transcriptional level, chromatin accessibility and the SWI/SNF complexes binding. Thus, our study reveals that the SWI/SNF complexes regulate cilia stability and kidney development by direct modulating the expression Foxj1a and Rfx2.
2026-01-01 | GSE274953 | GEO
Project description:Deregulated expression of MYC is a driver of colorectal carcinogenesis, necessitating novel strategies to inhibit MYC function. The ubiquitin ligase HUWE1 (HECTH9, ARFBP1, MULE) associates with both MYC and the MYC-associated protein MIZ1. We show here that HUWE1 is required for growth of colorectal cancer cells in culture and in orthotopic xenograft models. Using high throughput screening, we identify small molecule inhibitors of HUWE1, which inhibit MYC-dependent transactivation in colorectal cancer cells, but not in stem and normal colon epithelial cells. Inhibition of HUWE1 stabilizes MIZ1. MIZ1 globally accumulates on MYC target genes and contributes to repression of MYC-activated target genes upon HUWE1 inhibition. Our data show that transcriptional activation by MYC in colon cancer cells requires the continuous degradation of MIZ1 and identify a novel principle that allows for inhibition of MYC function in tumor cells. MIZ1 and MYC ChIPseq experiments in HUWE1 inhibitor-treated Ls174T cells as well as RNAseq experiments in HUWE1- or MIZ1-depleted Ls174T cells after HUWE1 inhibitor treatment. Sequencing was performed on an Illumina Genome Analyzer IIx.
2014-10-21 | E-GEOD-59223 | biostudies-arrayexpress
Project description:HUWE1 was depleted in Ls174T cells with an shRNA and the expression changes relative to a control shRNA were analyzed with microarray. Ls174T cells were treated with two separate HUWE1 inhibitor compounds (BI8622/BI8626) at concentrations of 20 uM and expression profiles relative to DMSO treated control were monitored via microarray. HUWE1-depleted Ls174T cells were treated with BI8622 (20uM) and expression profiles relative to BI8622-treated non-depleted cells were analyzed.
2014-10-22 | E-MTAB-1890 | biostudies-arrayexpress