Proteasomal activation ameliorates neuronal phenotypes linked to FBXO11-deficiency [fly]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1213860 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR32071212.fastq.gz | Fastqsanger.gz | |||
| SRR32071215.fastq.gz | Fastqsanger.gz | |||
| SRR32071216.fastq.gz | Fastqsanger.gz | |||
| SRR32071219.fastq.gz | Fastqsanger.gz |
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Project description:Haploinsufficiency of FBXO11, encoding a ubiquitin ligase complex subunit, is associated with a variable neurodevelopmental disorder. So far, the underlying nervous-system related pathomechanisms are poorly understood, and specific therapies are lacking. Using a combined approach, we established an FBXO11-deficient human stem cell-based neuronal model using CRISPR/CAS9 and a Drosophila model using tissue specific knockdown techniques. We performed transcriptomic analyses on iPSC-derived neurons and molecular phenotyping in both models. RNA-sequencing revealed disrupted transcriptional networks related to processes important for neuronal development, such as differentiation, migration and cell signaling. Consistently, we found that loss of FBXO11 leads to neuronal phenotypes such as impaired neuronal migration and abnormal proliferation/differentiation balance in human cultured neurons and impaired dendritic development and behavior in Drosophila. Interestingly, application of three different proteasome activating substances could alleviate FBXO11-deficiency-associated phenotypes in both human neurons and flies. One of these substances is the long-approved drug Verapamil, opening the possibility of drug repurposing in the future. Our study shows the importance of FBXO11 for neurodevelopment and highlights the reversibility of related phenotypes, opening an avenue for potential development of therapeutic approaches through drug repurposing.
2025-03-25 | GSE287637 | GEO
Project description:Proteasomal activation ameliorates neuronal phenotypes linked to FBXO11-deficiency [human]
| PRJNA1213861 | ENA
Project description:Haploinsufficiency of FBXO11, encoding a ubiquitin ligase complex subunit, is associated with a variable neurodevelopmental disorder. So far, the underlying nervous-system related pathomechanisms are poorly understood, and specific therapies are lacking. Using a combined approach, we established an FBXO11-deficient human stem cell-based neuronal model using CRISPR/CAS9 and a Drosophila model using tissue specific knockdown techniques. We performed transcriptomic analyses on iPSC-derived neurons and molecular phenotyping in both models. RNA-sequencing revealed disrupted transcriptional networks related to processes important for neuronal development, such as differentiation, migration and cell signaling. Consistently, we found that loss of FBXO11 leads to neuronal phenotypes such as impaired neuronal migration and abnormal proliferation/differentiation balance in human cultured neurons and impaired dendritic development and behavior in Drosophila. Interestingly, application of three different proteasome activating substances could alleviate FBXO11-deficiency-associated phenotypes in both human neurons and flies. One of these substances is the long-approved drug Verapamil, opening the possibility of drug repurposing in the future. Our study shows the importance of FBXO11 for neurodevelopment and highlights the reversibility of related phenotypes, opening an avenue for potential development of therapeutic approaches through drug repurposing.
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Project description:Transcriptional profiling of mouse 4T1 breast cancer cells stably tranduced with pLEX-MCS based lentivirus. Three groups were compared, Vector cells, SNAIL expressing cells; and SNAIL+FBXO11 expressing cells. SNAIL expression induced strong EMT phenotype while SNAIL/FBXO11 reversed cells back to epithelial cells.
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Project description:Transcriptional profiling of mouse HMLEN breast cancer cells (HMLE cells transformed with -Neu oncogene) stably tranduced with pLEX-MCS based lentivirus. Three groups were compared, Vector cells, SNAIL expressing cells; and SNAIL+FBXO11 expressing cells. SNAIL expression induced strong EMT phenotype while SNAIL/FBXO11 reversed cells back to epithelial cells.
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Project description:Mutations in Ubiquilins, UBQLN2, and UBQLN4 cause familial ALS. The role of UBQLNs in proteasomal degradation is well established but their role in autophagy-lysosomal clearance is poorly defined. Here, we performed Ubqn-GFP pull down from fly samples to find Ubqn binding partners.
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Project description:This experiment is assocaited with a publication defining a tumor supressor role of FBXO11 in the transformation of MDS. We observe decreased expression of FBXO11 is associated with transformation to secondary AML.
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Project description:BCL6 is a key oncogene in lymphoma pathogenesis. The expression of BCL6 in lymphoid cells can be deregulated by several mechanisms, including chromosomal translocations, somatic mutations in the promoter regulatory regions or reduced proteasome-mediated degradation. FBXO11 was recently identified as a major ubiquitin ligase involved in the degradation of BCL6 and is frequently inactivated in diffuse large B-cell lymphoma (DLBCL). In this work, we found that FBXO11 is frequently mutated in Burkitt lymphoma (BL) but rarely mutated in other BCL6-positive lymphomas, such as follicular lymphoma (FL). All mutations tested impaired FBXO11 mediated BCL6 degradation and FBXO11 knock-out completely stabilized BCL6 levels in human BL cell lines. Conditional deletion of one copy or both copies of FBXO11 in c-Myc-driven B cell lymphoma in mice accelerated lymphomagenesis, genetically confirming that FBXO11 is a haplo-insufficient oncosuppressor in lymphoma. In both FBOX11 WT and deficient BL mouse and human cell lines, blockade of BCL6 via a specific degrader or BCL6 inhibitors, impaired lymphoma growth in vitro and in vivo, an effect further enhanced by co-inhibition of c-Myc activity. Overall these findings not only establish FBXO11 as one of the most frequently mutated genes in BL, but also elucidate its biological functions in lymphomagenesis and thereby identify BCL6 as a specific therapeutic target in BL.
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Project description:The histone mark H3K27me3 and its reader/writer Polycomb repressive complex 2 (PRC2) mediate widespread transcriptional repression in stem and progenitor cells. Mechanisms that regulate this activity are critical for tissue development but poorly understood. Here we show that the E3 ubiquitin ligase FBXO11 relieves PRC2-mediated repression during erythroid maturation by targeting its newly identified substrate BAHD1, an H3K27me3 reader that recruits transcriptional co-repressors. Erythroblasts lacking FBXO11 are developmentally delayed, with reduced expression of maturation-associated genes, most of which harbor bivalent histone marks (activating H3K4me3 and repressive H3K27me3), bind BAHD1, and fail to recruit the erythroid transcription factor GATA1. The BAHD1 complex interacts physically with PRC2 and depletion of either component restores FBXO11-deficient erythroid gene expression. Previous studies showed that FBXO11 promotes B-cell development and inhibits lymphomagenesis by degrading the transcriptional repressor BCL6. We show that in aggressive B-cell lymphoma lines, depletion of FBXO11 causes the accumulation of both BCL6 and BAHD1, and that suppression of BAHD1 slows cell expansion. Our studies identify BAHD1 as a novel effector of PRC2-mediated repression and reveal how a single E3 ubiquitin ligase eliminates PRC2 repression at developmentally poised bivalent genes during erythropoiesis. The FBXO11-BAHD1 regulatory axis may function in other developmental pathways, including B-lymphopoiesis and lymphomagenesis.
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Project description:Drosophila melanogaster FBXO11, F-box protein 11, is expressed in 2 baseline experiment(s);
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