Primary cilia control translation and the cell cycle in medulloblastoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA853310 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19866093_1.fastq.gz | Fastqsanger.gz | |||
| SRR19866093_2.fastq.gz | Fastqsanger.gz | |||
| SRR19866094_1.fastq.gz | Fastqsanger.gz | |||
| SRR19866094_2.fastq.gz | Fastqsanger.gz | |||
| SRR19866095_1.fastq.gz | Fastqsanger.gz |
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Project description:The primary cilium, a signaling organelle projecting from the surface of a cell, controls cellular physiology and behavior. The presence or absence of primary cilia is a distinctive feature of a given tumor type; however, whether and how the primary cilium contributes to tumorigenesis is unknown for most tumors. Medulloblastoma (MB) is a common pediatric brain cancer comprising four groups: SHH, WNT, group 3 (G3), and group 4 (G4). From 111 cases of MB, we show that primary cilia are abundant in SHH and WNT MBs but rare in G3 and G4 MBs. Using WNT and G3 MB mouse models, we show that primary cilia promote WNT MB by facilitating translation of mRNA encoding β-catenin, a major oncoprotein driving WNT MB, whereas cilium loss promotes G3 MB by disrupting cell cycle control and destabilizing the genome. Our findings reveal tumor type–specific ciliary functions and underlying molecular mechanisms. Moreover, we expand the function of primary cilia to translation control and reveal a molecular mechanism by which cilia regulate cell cycle progression, providing new frameworks for studying cilia function in normal and pathologic conditions.
2022-07-04 | GSE207008 | GEO
Project description:The primary cilium, a signaling organelle projecting from the surface of a cell, controls cellular physiology and behavior. The presence or absence of primary cilia is a distinctive feature of a given tumor type; however, whether and how the primary cilium contributes to tumorigenesis are unknown for most tumors. Medulloblastoma (MB) is a common pediatric brain cancer comprising four groups: SHH, WNT, group 3 (G3), and group 4 (G4). From 111 cases of MB, we show that primary cilia are abundant in SHH and WNT MBs but rare in G3 and G4 MBs. Using WNT and G3 MB mouse models, we show that primary cilia promote WNT MB by facilitating translation of mRNA encoding β-catenin, a major oncoprotein driving WNT MB, whereas cilium loss promotes G3 MB by disrupting cell cycle control and destabilizing the genome. Our findings reveal tumor type-specific ciliary functions and underlying molecular mechanisms. Moreover, we expand the function of primary cilia to translation control and reveal a molecular mechanism by which cilia regulate cell cycle progression, thereby providing new frameworks for studying cilium function in normal and pathologic conditions.
| S-EPMC9296008 | biostudies-literature
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:Primary cilia have been considered tumor-suppressing organelles in cholangiocarcinoma (CCA), though the mechanisms behind their protective role are not fully understood. This study investigates how the loss of primary cilia affects DNA damage response (DDR) and DNA repair processes. Human cholangiocyte cell lines were used to examine the colocalization of DNA repair proteins at the cilia and assess the impact of experimental deciliation on DNA repair pathways. Deciliation was induced using shRNA knockdown or CRISPR knockout of IFT20, IFT88, or KIF3A, followed by exposure to the genotoxic agents cisplatin, methyl methanesulfonate (MMS), or irradiation. Cell survival, cell cycle progression, and apoptosis rates were evaluated, and DNA damage was assessed using comet assays and γH2AX quantification. An in vivo liver-specific IFT88 knockout model, generated using Albumin-Cre/Lox recombination, was used to study the loss of primary cilia in the liver. Results showed that RAD51 localized predominantly at the base of the cilium, while ATR, PARP1, CHK1, and CHK2 were also detected within the ciliary shaft. Deciliated cells displayed dysregulation in critical DNA repair pathways. These cells also showed reduced survival and increased S-phase arrest after genotoxic challenges as compared to ciliated cells. Enhanced DNA damage was observed via increased γH2AX signals and comet assay results. An increase in γH2AX expression was also observed in our in vivo model, indicating elevated DNA damage. Additionally, key DDR proteins such as ATM, p53, and p21, were downregulated in deciliated cells after irradiation. This study underscores the crucial role of primary cilia in regulating DNA repair and suggests that targeting cilia-related mechanisms could present a novel therapeutic approach for CCA.
2025-07-31 | GSE280249 | GEO
Project description:Profiling RNA translation in pediatric medulloblastoma
| PRJNA1028779 | ENA
Project description:Profiling RNA translation in pediatric medulloblastoma
| PRJNA1028780 | ENA
Project description:RNA-seq technology was used to reveal the transcriptome changes of tubular epithelia in response to fluid flow and determine the role of primary cilia in this process. Many fluid flow-sensitive genes were identified, among which are those regulated by primary cilia sensing of fluid flow. These genes were further validated by RT-qPCR.
2018-01-27 | GSE109701 | GEO
Project description:Drug addiction represents a pathological form of learning and memory with profound implications for individuals and society. The serotonin receptor 5-HT6R, uniquely expressed on primary cilia, is associated with neurological development, cognitive impairments, emotional disorders, and reward memory for cocaine and nicotine. However, its role in morphine-related reward memory remains unclear. This study demonstrated that 5-HT6R expression was downregulated during the early stage of morphine-induced conditioned place preference (CPP) extinction but returned to baseline levels later, with no significant changes observed during CPP establishment or reinstatement. Knocking down 5-HT6R accelerated CPP extinction, while overexpression prolonged the process. Furthermore, primary cilia defects within the mPFC were noted during the early stage of CPP extinction, and the removal of primary cilia expedited this process. Finally, ATR was identified as a novel target molecule of 5-HT6R, and the 5-HT6R-ATR-primary cilia network was found to regulate morphine-induced CPP extinction, offering new insights for opioid addiction therapy.
2025-09-03 | GSE273842 | GEO
Project description:Biliary complications are disabling conditions that arise in up to 25% of liver transplanted patients, resulting in additional surgical procedures, re-transplantation or, in the absence of a suitable regraft, death. Here, we investigate the role of the primary cilia, a highly-specialised sensory organelle, in biliary injury leading to biliary complications. Human biopsies were used to study the structure and function of primary cilia in liver transplant recipients that develop biliary complications (N=7), compared to successful transplants (N=12). To study the biological effects of the primary cilia during transplantation, we used murine models that recapitulate liver procurement and cold storage conditions, and the K19CreERT Kif3a flox/flox mouse model to conditionally eliminate primary cilia in cholangiocytes. Microarray and RNA-seq analysis were used to study these biological effects at the transcriptional level. To explore the molecular mechanisms responsible for the observed phenotypes, we used in vitro models of ischemia, cellular senescence and primary cilia ablation. Pharmacological and genetic approaches were used to target cellular senescence and the primary cilia, in mouse models and human donor livers. Prolonged ischemic periods pre-transplantation result in ciliary shortening and cellular senescence. Primary cilia damage results in biliary injury and a loss of regenerative potential. Initiation of senescence negatively primary cilia structure, establishing a negative feedback loop that further impairs regeneration. We conclude that primary cilia play an essential role in biliary regeneration; we demonstrate that senolytics and cilia-stabilising treatments provide a potential therapeutic opportunity to reduce the rate of biliary complications and improve the outcome of the liver transplanted patient.
2024-07-12 | GSE220718 | GEO
Project description:The transcription factor OTX2 has been implicated as an oncogene in medulloblastoma, which is the most common malignant brain tumor in children. It is highly expressed in most medulloblastomas and amplified in a subset of them. The role of OTX2 in medulloblastoma and its downstream targets are unclear. Therefore, we generated D425 medulloblastoma cells in which we can silence endogenous OTX2 by inducible shRNA. Silencing of OTX2 strongly inhibited cell proliferation and resulted in a neuronal-like differentiation. Expression profiling of time courses after silencing showed a progressive change in gene expression for many cellular processes. Down regulated genes were highly enriched for cell cycle and visual perception genes, while up regulated genes were enriched for genes involved in development and differentiation. This shift in expression profiles is reminiscent to changes described to occur during normal cerebellum development. OTX2 is expressed in proliferating granular progenitor cells, but the expression diminishes when these cells exit the cell cycle and start differentiating. ChIP-on-chip analyses of OTX2 in D425 cells showed that cell cycle and perception genes were direct OTX2 targets, while regulation of most differentiation genes appears to be indirect. These analyses provide the first insight in the molecular network of OTX2, demonstrating that OTX2 is essential in medulloblastoma and directly drives proliferation by regulating the expression of cell cycle genes. Since many of these genes also correlate in expression with OTX2 in primary tumors, they might be potential targets for therapy in medulloblastoma patients. Keywords: OTX2, medulloblastoma, mRNA profiling *** This Series represents the gene expression component of the study. Three independent time course experiments of OTX2 silencing, and 1 control experiment in D425 medulloblastoma cells.
2012-07-03 | E-GEOD-22875 | biostudies-arrayexpress