Lack of de novo phosphatidylinositol synthesis leads to endoplasmic reticulum stress and hepatic steatosis in cdipt-deficient zebrafish
Ontology highlight
ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE17711 | GEO | 2011/05/09
SECONDARY ACCESSION(S): PRJNA118453
REPOSITORIES: GEO
Similar Datasets
Project description:cdipt is an essential gene in the synthesis of phosphatidylinositol (PtdIns) in the zebrafish, Danio rerio. The zebrafish mutant cdipt^hi559Tg (ZL782) carries a retroviral insertion which inactivates cdipt. Homozygous mutants exhibit hepatocellular endoplasmic reticulum (ER) stress and non-alcoholic fatty liver disease (NAFLD) pathologies at 5 days post fertilization (dpf). This study reveals a novel link between PtdIns, ER stress, and steatosis. We compared whole animal gene expression profiles of hi559 mutant larvae with phenotypically wild type larvae from a heterozygote incross in triplicate.
2011-05-09 | E-GEOD-17711 | biostudies-arrayexpress
Project description:ING2 (inhibitor of growth family member 2) is a component of a chromatin-regulatory complex that represses gene expression and is implicated in cellular processes that promote tumor suppression. However, few direct genomic targets of ING2 have been identified and the mechanism(s) by which ING2 selectively regulates genes remains unknown. Here we provide evidence that direct association of ING2 with the nuclear phosphoinositide phosphatidylinositol-5-phosphate (PtdIns(5)P) regulates a subset of ING2 targets in response to DNA damage. At these target genes, the binding event between ING2 and PtdIns(5)P is required for ING2 promoter occupancy and ING2-associated gene repression. Moreover, depletion of PtdIns(5)P attenuates ING2-mediated regulation of these targets in the presence of DNA damage. Taken together, these findings support a model in which PtdIns(5)P functions as a sub-nuclear trafficking factor that stabilizes ING2 at discrete genomic sites.
2013-12-31 | GSE47645 | GEO
Project description:ING2 (inhibitor of growth family member 2) is a component of a chromatin-regulatory complex that represses gene expression and is implicated in cellular processes that promote tumor suppression. However, few direct genomic targets of ING2 have been identified and the mechanism(s) by which ING2 selectively regulates genes remains unknown. Here we provide evidence that direct association of ING2 with the nuclear phosphoinositide phosphatidylinositol-5-phosphate (PtdIns(5)P) regulates a subset of ING2 targets in response to DNA damage. At these target genes, the binding event between ING2 and PtdIns(5)P is required for ING2 promoter occupancy and ING2-associated gene repression. Moreover, depletion of PtdIns(5)P attenuates ING2-mediated regulation of these targets in the presence of DNA damage. Taken together, these findings support a model in which PtdIns(5)P functions as a sub-nuclear trafficking factor that stabilizes ING2 at discrete genomic sites.
2013-12-31 | GSE47688 | GEO
Project description:ING2 (inhibitor of growth family member 2) is a component of a chromatin-regulatory complex that represses gene expression and is implicated in cellular processes that promote tumor suppression. However, few direct genomic targets of ING2 have been identified and the mechanism(s) by which ING2 selectively regulates genes remains unknown. Here we provide evidence that direct association of ING2 with the nuclear phosphoinositide phosphatidylinositol-5-phosphate (PtdIns(5)P) regulates a subset of ING2 targets in response to DNA damage. At these target genes, the binding event between ING2 and PtdIns(5)P is required for ING2 promoter occupancy and ING2-associated gene repression. Moreover, depletion of PtdIns(5)P attenuates ING2-mediated regulation of these targets in the presence of DNA damage. Taken together, these findings support a model in which PtdIns(5)P functions as a sub-nuclear trafficking factor that stabilizes ING2 at discrete genomic sites. Genome-wide expression profiling of HT1080 cells stably transduced with ING2 or a ING2 lipid binding mutant in the presence of vehicle (DMSO) or etoposide. Each condition is tested in triplicate
2013-12-31 | E-GEOD-47645 | biostudies-arrayexpress
Project description:ING2 (inhibitor of growth family member 2) is a component of a chromatin-regulatory complex that represses gene expression and is implicated in cellular processes that promote tumor suppression. However, few direct genomic targets of ING2 have been identified and the mechanism(s) by which ING2 selectively regulates genes remains unknown. Here we provide evidence that direct association of ING2 with the nuclear phosphoinositide phosphatidylinositol-5-phosphate (PtdIns(5)P) regulates a subset of ING2 targets in response to DNA damage. At these target genes, the binding event between ING2 and PtdIns(5)P is required for ING2 promoter occupancy and ING2-associated gene repression. Moreover, depletion of PtdIns(5)P attenuates ING2-mediated regulation of these targets in the presence of DNA damage. Taken together, these findings support a model in which PtdIns(5)P functions as a sub-nuclear trafficking factor that stabilizes ING2 at discrete genomic sites. FLAG-ING2 ChIP-chip of stably-transduced HT1080 cells in the presence of vehicle (DMSO) or etoposide. Each condition is tested in duplicate.
2013-12-31 | E-GEOD-47688 | biostudies-arrayexpress
Project description:Polyphosphoinositides (PPIn) play essential functions as lipid signalling molecules and many of their functions have been elucidated in the cytoplasm. However, PPIns are also intranuclear where they contribute to chromatin remodelling, transcription and mRNA splicing. The PPIn, phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) has been mapped to the nucleus and nucleoli but its role remains unclear in this subcellular compartment. To gain further insights into the nuclear functions of PtdIns(3,4,5)P3, we applied a previously developed quantitative mass spectrometry-based approach to identify the targets of PtdIns(3,4,5)P3 from isolated nuclei. We identified 179 potential PtdIns(3,4,5)P3-interacting proteins and gene ontology analysis for the biological functions of this dataset revealed an enrichment in RNA processing/splicing, cytokinesis, protein folding and DNA repair. Interestingly, about half of these interactors were common to nucleolar protein datasets, some of which had dual functions in rRNA transcription and DNA repair, including Poly(ADP-Ribose) Polymerase 1 (PARP1),. PARP1 was found to interact directly with PPIns and to co-localise with PtdIns(3,4,5)P3 in the nucleolus. Focusing on another factor involved in RNA processing, heterogeneous nuclear ribonucleoprotein U (hnRNPU/SAF-A) was also identified and validated as a direct PPIn-interacting protein. Deletion of the polybasic motif in its DNA binding domain prevented PPIn interaction. In conclusion, the PtdIns(3,4,5)P3 interactome reported here identified several nucleolar proteins and splicing factors and further pointed to roles for this lipid in these processes.
2021-06-28 | PXD020870 | Pride
Project description:Hepatic steatosis is the initial stage of nonalcoholic fatty liver disease (NAFLD) and may predispose to more severe hepatic disease, including hepatocellular carcinoma. Endoplasmic reticulum (ER) stress has been recently implicated as a novel mechanism that may lead to NAFLD, although the genetic factors invoking ER stress are largely unknown. During a screen for liver defects from a zebrafish insertional mutant library, we isolated the mutant cdipthi559Tg/+ (hi559). CDIPT is known to play an indispensable role in phosphatidylinositol (PtdIns) synthesis. Here we show that cdipt is expressed in the developing liver, and its disruption in hi559 mutants abrogates de novo PtdIns synthesis, resulting in hepatomegaly at 5 days postfertilization. The hi559 hepatocytes display features of NAFLD, including macrovesicular steatosis, ballooning, and necroapoptosis. Gene set enrichment of microarray profiling revealed significant enrichment of endoplasmic reticulum stress response (ERSR) genes in hi559 mutants. ER stress markers, including atf6, hspa5, calr, and xbp1, are selectively up-regulated in the mutant liver. The hi559 expression profile showed significant overlap with that of mammalian hepatic ER stress and NAFLD. Ultrastructurally, the hi559 hepatocytes display marked disruption of ER architecture with hallmarks of chronic unresolved ER stress. Induction of ER stress by tunicamycin in wild-type larvae results in a fatty liver similar to hi559, suggesting that ER stress could be a fundamental mechanism contributing to hepatic steatosis.cdipt-deficient zebrafish exhibit hepatic ER stress and NAFLD pathologies, implicating a novel link between PtdIns, ER stress, and steatosis. The tractability of hi559 mutant provides a valuable tool to dissect ERSR components, their contribution to molecular pathogenesis, and evaluation of novel therapeutics of NAFLD.
| S-EPMC3140628 | biostudies-literature
Project description:Condition specific zebrafish metabolic models generated using the COBRA MetaboTools framework. The Wang et al., (2021) zebrafish genome-scale metabolic model (GEM) was constrained with experimental data from 5 days post fertilized (dpf) zebrafish to generate a 'base-model'.
In turn this 5 dpf zebrafish base-model was constrained with experimental (transcriptomics and metabolomics) data from 5 dpf zebrafish exposed to the environmental pollutant perfluorooctane sulfonate (PFOS), at three levels - Low (0.06 uM), Medium (0.6 uM), and High (2 uM) PFOS.
The MetaboTools framework was used to construct three condition-sepcific models: Low, Medium, and High PFOS.
Key simulation predictions of effects on the carnitine shuttle and lipid metabolism were confirmed in wild-caught fish and dolphins (stranded animals) sampled from the northern Gulf of Mexico - published in Nolen et al., (2024) https://doi.org/10.1016/j.cbpc.2023.109817
2024-03-04 | MODEL2403010004 | BioModels
Project description:The causative agent of Legionnaires’ disease, Legionella pneumophila, governs interactions with host cells by secreting ca. 330 different “effector” proteins. The facultative intracellular bacteria replicate in macrophages and amoeba within a unique compartment, the Legionella-containing vacuole (LCV). Hallmarks of LCV formation are the phosphoinositide (PI) lipid conversion from PtdIns(3)P to PtdIns(4)P, fusion with endoplasmic reticulum (ER)-derived vesicles and a tight association with the ER. Proteomics of purified LCVs revealed the presence of membrane contact sites (MCS) proteins implicated in lipid exchange. Using dually fluorescence-labeled Dictyostelium discoideum amoeba, we reveal that the VAMP-associated protein (Vap), the PtdIns(4)P 4-phosphatase Sac1, and the large fusion GTPase Sey1/atlastin-3 localize to the ER, but not to the LCV membrane, and these ER-resident proteins promote intracellular replication of L. pneumophila and LCV remodeling. Moreover, oxysterol binding proteins (OSBPs) exclusively localize to the ER (OsbH) or the LCV membrane (OsbK), respectively, and promote (OsbH) or restrict (OsbK) intracellular replication of L. pneumophila and LCV expansion. Furthermore, the PtdIns(4)P-subverting L. pneumophila effectors LepB and SidC also promote LCV remodeling. Taken together, the Legionella-driven PtdIns(4)P gradient at LCV-ER MCSs promotes Vap-, OSBP- and Sac1-dependent pathogen vacuole remodeling.
2023-02-21 | PXD034490 | Pride
Project description:Cholesterol and phosphoinositides (PI) are two critically important lipids that are found in cellular membranes and dysregulated in many disorders. Therefore, uncovering molecular pathways connecting these essential lipids may offer new therapeutic insights. We report that loss of function of lysosomal Niemann-Pick Type C1 (NPC1) cholesterol transporter, which leads to neurodegenerative NPC disease, initiates a signaling cascade that alters the cholesterol/phosphatidylinositol 4-phosphate (PtdIns4P) countertransport cycle between Golgi-endoplasmic reticulum (ER), as well as lysosome-ER membrane contact sites (MCS). Central to these disruptions is increased recruitment of phosphatidylinositol 4-kinases-PI4KIIα and PI4KIIIβ-which boosts PtdIns4P metabolism at Golgi and lysosomal membranes. Aberrantly increased PtdIns4P levels elevate constitutive anterograde secretion from the Golgi complex, and mTORC1 recruitment to lysosomes. NPC1 disease mutations phenocopy the transporter loss of function and can be rescued by inhibition or knockdown of either key phosphoinositide enzymes or their recruiting partners. In summary, we show that the lysosomal NPC1 cholesterol transporter tunes the molecular content of Golgi and lysosome MCS to regulate intracellular trafficking and growth signaling in health and disease.
2021-09-15 | MTBLS2612 | MetaboLights