Ciliogenesis defects after neurulation impact brain development and neuronal activity in larval zebrafish
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ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE244171 | GEO | 2024/04/16
REPOSITORIES: GEO
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Project description:Defects in cilia genes that is critical in cilia formation and function can cause complicated ciliopathy syndromes involving multiple organs and tissues; however, the underlying regulatory mechanisms of cilia gene networks in ciliopathy are largely unknown. Here, we define the genome-wide redistribution of chromatin accessibilities and extensive divergence of cilia genes expression programs happened in ciliopathy. Mechanistically, the distinct ciliopathy-activated accessible regions (CAAs) are characterized to positively regulate robust changes of flanking cilia genes, which are a key transcriptional feature of cilia required for the response to developmental signals. Moreover, the single transcriptional factors, ETS1, can be recruited to CAAs thus prominently reconstructing chromatin accessibility in ciliopathy. CAAs collapse driven by ETS1 suppression subsequently cause defective cilia formation and impaired developmental signal transduction, which eventually develops ciliopathy phenotypes of short fins and pericardium edema in larval fishes. Therefore, our results depicted a dynamic landscape of chromatin accessibility in ciliopathy, and uncover an insightful role of ETS1 in controlling global cilia genes transcriptional program by reprogramming widespread chromatin state.
2023-04-26 | GSE230552 | GEO
Project description:Defects in cilia genes that is critical in cilia formation and function can cause complicated ciliopathy syndromes involving multiple organs and tissues; however, the underlying regulatory mechanisms of cilia gene networks in ciliopathy are largely unknown. Here, we define the genome-wide redistribution of chromatin accessibilities and extensive divergence of cilia genes expression programs happened in ciliopathy. Mechanistically, the distinct ciliopathy-activated accessible regions (CAAs) are characterized to positively regulate robust changes of flanking cilia genes, which are a key transcriptional feature of cilia required for the response to developmental signals. Moreover, the single transcriptional factors, ETS1, can be recruited to CAAs thus prominently reconstructing chromatin accessibility in ciliopathy. CAAs collapse driven by ETS1 suppression subsequently cause defective cilia formation and impaired developmental signal transduction, which eventually develops ciliopathy phenotypes of short fins and pericardium edema in larval fishes. Therefore, our results depicted a dynamic landscape of chromatin accessibility in ciliopathy, and uncover an insightful role of ETS1 in controlling global cilia genes transcriptional program by reprogramming widespread chromatin state.
2022-07-28 | GSE209661 | GEO
Project description:Defects in cilia genes that is critical in cilia formation and function can cause complicated ciliopathy syndromes involving multiple organs and tissues; however, the underlying regulatory mechanisms of cilia gene networks in ciliopathy are largely unknown. Here, we define the genome-wide redistribution of chromatin accessibilities and extensive divergence of cilia genes expression programs happened in ciliopathy. Mechanistically, the distinct ciliopathy-activated accessible regions (CAAs) are characterized to positively regulate robust changes of flanking cilia genes, which are a key transcriptional feature of cilia required for the response to developmental signals. Moreover, the single transcriptional factors, ETS1, can be recruited to CAAs thus prominently reconstructing chromatin accessibility in ciliopathy. CAAs collapse driven by ETS1 suppression subsequently cause defective cilia formation and impaired developmental signal transduction, which eventually develops ciliopathy phenotypes of short fins and pericardium edema in larval fishes. Therefore, our results depicted a dynamic landscape of chromatin accessibility in ciliopathy, and uncover an insightful role of ETS1 in controlling global cilia genes transcriptional program by reprogramming widespread chromatin state.
2022-07-28 | GSE209660 | GEO
Project description:Defects in cilia genes that is critical in cilia formation and function can cause complicated ciliopathy syndromes involving multiple organs and tissues; however, the underlying regulatory mechanisms of cilia gene networks in ciliopathy are largely unknown. Here, we define the genome-wide redistribution of chromatin accessibilities and extensive divergence of cilia genes expression programs happened in ciliopathy. Mechanistically, the distinct ciliopathy-activated accessible regions (CAAs) are characterized to positively regulate robust changes of flanking cilia genes, which are a key transcriptional feature of cilia required for the response to developmental signals. Moreover, the single transcriptional factors, ETS1, can be recruited to CAAs thus prominently reconstructing chromatin accessibility in ciliopathy. CAAs collapse driven by ETS1 suppression subsequently cause defective cilia formation and impaired developmental signal transduction, which eventually develops ciliopathy phenotypes of short fins and pericardium edema in larval fishes. Therefore, our results depicted a dynamic landscape of chromatin accessibility in ciliopathy, and uncover an insightful role of ETS1 in controlling global cilia genes transcriptional program by reprogramming widespread chromatin state.
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Project description:Olfaction plays important roles in food and mate choice, and also in the avoidance of predators, making it a vital sensory modality for preservation and reproduction. In the vertebrates, olfactory receptors are thought to localise on multiple cilia elaborated on the dendritic knobs of olfactory sensory neurons (OSNs). Although olfactory cilia dysfunction can cause loss of the sense of smell, how their differentiation is programmed at the transcriptional level has remained largely unexplored. We discovered in zebrafish and mice that Foxj1, a fork head-domain containing transcription factor traditionally linked with motile cilia biogenesis, is expressed in OSNs and required for olfactory epithelium formation. In keeping with the immotile nature of the olfactory cilia, we observed that ciliary motility genes that are the targets of Foxj1 in motile ciliated cells, are repressed in the OSNs. Strikingly, we also found that besides ciliogenesis, Foxj1 controls the differentiation of the OSNs by regulating their cell type-specific gene expression, such as that of olfactory marker protein (omp) involved in odour-evoked signal transduction. In line with these requirements, response to bile acid, an odour detected by OMP-positive OSNs, was significantly diminished in the foxj1 mutant zebrafish. Taken together, our findings establish how the canonical Foxj1-mediated motile ciliogenic transcriptional program has been repurposed for the biogenesis of the immotile olfactory cilia and for the development of the OSNs themselves.
2023-12-04 | GSE232397 | GEO
Project description:Minichromosome maintenance (MCM) proteins facilitate replication by licensing origins and unwinding the DNA double strand. Interestingly, the number of MCM hexamers greatly exceeds the number of firing origins suggesting additional roles of MCMs. Here we show a hitherto unanticipated function of MCM2 in cilia formation in human cells and zebrafish that is uncoupled from replication. Zebrafish depleted of MCM2 develop ciliopathy-phenotypes including microcephaly and aberrant heart looping due to malformed cilia. In non-cycling human fibroblasts, loss of MCM2 promotes transcription of a subset of genes, which cause cilia shortening and centriole overduplication. Chromatin immunoprecipitation experiments show that MCM2 binds to transcription start sites of cilia inhibiting genes. We propose that such binding may block RNA polymerase II-mediated transcription. Depletion of a second MCM (MCM7), which functions in complex with MCM2 during its canonical functions, reveals an overlapping cilia-deficiency phenotype likely unconnected to replication, although MCM7 appears to regulate a distinct subset of genes and pathways. Our data suggests that MCM2 and 7 exert a role in ciliogenesis in post-mitotic tissues.
2018-10-20 | GSE120767 | GEO
Project description:Minichromosome maintenance (MCM) proteins facilitate replication by licensing origins and unwinding the DNA double strand. Interestingly, the number of MCM hexamers greatly exceeds the number of firing origins suggesting additional roles of MCMs. Here we show a hitherto unanticipated function of MCM2 in cilia formation in human cells and zebrafish that is uncoupled from replication. Zebrafish depleted of MCM2 develop ciliopathy-phenotypes including microcephaly and aberrant heart looping due to malformed cilia. In non-cycling human fibroblasts, loss of MCM2 promotes transcription of a subset of genes, which cause cilia shortening and centriole overduplication. Chromatin immunoprecipitation experiments show that MCM2 binds to transcription start sites of cilia inhibiting genes. We propose that such binding may block RNA polymerase II-mediated transcription. Depletion of a second MCM (MCM7), which functions in complex with MCM2 during its canonical functions, reveals an overlapping cilia-deficiency phenotype likely unconnected to replication, although MCM7 appears to regulate a distinct subset of genes and pathways. Our data suggests that MCM2 and 7 exert a role in ciliogenesis in post-mitotic tissues.
2018-10-20 | GSE120766 | GEO
Project description:Bardet-Biedl syndrome (BBS) is a ciliopathy characterized by retinal dystrophy, intellectual disability, polydactyly, obesity and renal anomalies. In photoreceptors (PR), light sensation occurs in outer segments (OSs), which are specialized primary cilia. BBS1, the major BBS gene, is part of a protein complex called “BBSome”, which is involved in intracellular protein transport. However, the precise function of BBS1/BBSome in controlling trafficking of ciliary proteins in PRs remains unclear. We generated a bbs1 knock out zebrafish mutant to investigate the role of Bbs1 and the BBSome in vivo. To detect global changes in the eye proteome and to verify the knock-out of Bbs1, we conducted a whole eyes proteomic investigation.
2022-02-10 | PXD030522 | Pride
Project description:Mutations in CEP290, a large multidomain coiled coil protein, are associated with multiple cilia-associated syndromes. Over 130 CEP290 mutations have been linked to a wide spectrum of human ciliopathies, raising the question of how mutations in a single gene cause different disease syndromes. In zebrafish the expressivity of cep290 deficiencies were linked to the type of genetic ablation: acute cep290 morpholino knockdown caused severe cilia-related phenotypes while defects in a Crispr/Cas9 genetic mutant were restricted to photoreceptor defects. Here we show that milder phenotypes in genetic mutants were associated with upregulation of genes encoding the cilia-associated small GTPases arl3, arl13b, and unc119b. Upregulation of UNC119b was also observed in urine-derived renal epithelial cells from human JBTS CEP290 patients. Ectopic expression of arl3, arl13b and unc119b in cep290 morphant zebrafish embryos rescued Kupffer's vesicle cilia and partially rescued photoreceptor outer segment defects. The results suggest that genetic compensation by upregulation of genes involved in a common subcellular process, lipidated protein trafficking to cilia, may be a conserved mechanism contributing to genotype-phenotype variations observed in CEP290 deficiencies.
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Project description:Mutations in TUB-like protein 1 (TULP1) are associated with severe early-onset retinal degeneration in humans. However, the pathogenesis remains largely unknown. There are two homologous genes of TULP1 in zebrafish, namely tulp1a and tulp1b. Here, we generated the single knockout (tulp1a-/- and tulp1b-/-) and double knockout (tulp1-dKO) models in zebrafish. Knockout of tulp1a results in the mislocalization of UV cone opsins and the degeneration of UV cones specifically, while knockout of tulp1b results in mislocalization of rod opsins and rod-cone degeneration. In the tulp1-dKO zebrafish, mislocalization of opsins was present in all types of photoreceptors, and severe degeneration was observed at a very early age, mimicking the clinical manifestations of TULP1 patients. Photoreceptor cilium length was significantly reduced in the tulp1-dKO retinas. RNA-seq analysis showed that the expression of tektin2 (tekt2), a ciliary and flagellar microtubule structural component, was downregulated in the tulp1-dKO zebrafish. Dual-luciferase reporter assay suggested that Tulp1a and Tulp1b transcriptionally activate the promoter of tekt2. Additionally, ferroptosis might be activated in the tulp1-dKO zebrafish, as suggested by the up-regulation of genes related to the ferroptosis pathway, the shrinkage of mitochondria, reduction or disappearance of mitochondria cristae, and the iron and lipid droplet deposition in the retina of tulp1-dKO zebrafish. In conclusion, our study establishes an appropriate zebrafish model for TULP1-associated retinal degeneration and proposes that loss of TULP1 causes defects in cilia structure and opsin trafficking through the downregulation of tekt2, which further increases the death of photoreceptors via ferroptosis. These findings offer insight into the pathogenesis and clinical treatment of early-onset retinal degeneration.
2022-11-23 | GSE214642 | GEO