The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells snRNA-Seq
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PROVIDER: PRJNA915078 | ENA |
REPOSITORIES: ENA
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Project description:Cholesterol is required for oligodendrocyte maturation and CNS myelination. Here, we demonstrate an essential role for the intracellular cholesterol transporter NPC1 in these processes. NPC1 functions in late endosomes and lysosomes to efflux unesterified cholesterol, and its deficiency causes Niemann-Pick disease Type C, an autosomal recessive lysosomal disorder characterized by progressive neurodegeneration and early death. To identify cell types and pathways affected early in pathogenesis, we performed single nuclear RNA-seq on the forebrain of Npc1-/- mice at P16. This analysis uncovered striking transcriptional changes in the oligodendrocyte lineage during the period of developmental myelination, accompanied by diminished maturation of myelinating oligodendrocytes. Unexpectedly, we identified a significant upregulation of genes associated with neurogenesis and synapse formation in Npc1-/- oligodendrocyte lineage cells, reflecting diminished gene silencing by H3K27me3 and H3K9me3.
2023-05-31 | GSE221609 | GEO
Project description:Cholesterol is required for oligodendrocyte maturation and CNS myelination. Here, we demonstrate an essential role for the intracellular cholesterol transporter NPC1 in these processes. NPC1 functions in late endosomes and lysosomes to efflux unesterified cholesterol, and its deficiency causes Niemann-Pick disease Type C, an autosomal recessive lysosomal disorder characterized by progressive neurodegeneration and early death. To identify cell types and pathways affected early in pathogenesis, we performed single nuclear RNA-seq on the forebrain of Npc1-/- mice at P16. This analysis uncovered striking transcriptional changes in the oligodendrocyte lineage during the period of developmental myelination, accompanied by diminished maturation of myelinating oligodendrocytes. Unexpectedly, we identified a significant upregulation of genes associated with neurogenesis and synapse formation in Npc1-/- oligodendrocyte lineage cells, reflecting diminished gene silencing by H3K27me3 and H3K9me3. Npc1-/- oligodendrocyte progenitor cells reproduced impaired maturation in vitro and this phenotype was rescued by treatment with GSK-J4, a small molecule inhibitor of H3K27 demethylases. This study sought to determine the genes being directly impacted by the epigenetic dysfunction at H3K27.
2023-05-31 | GSE219007 | GEO
Project description:Cholesterol is required for oligodendrocyte maturation and CNS myelination. Here, we demonstrate an essential role for the intracellular cholesterol transporter NPC1 in these processes. NPC1 functions in late endosomes and lysosomes to efflux unesterified cholesterol, and its deficiency causes Niemann-Pick disease Type C, an autosomal recessive lysosomal disorder characterized by progressive neurodegeneration and early death. To identify cell types and pathways affected early in pathogenesis, we performed single nuclear RNA-seq on the forebrain of Npc1-/- mice at P16. This analysis uncovered striking transcriptional changes in the oligodendrocyte lineage during the period of developmental myelination, accompanied by diminished maturation of myelinating oligodendrocytes. Unexpectedly, we identified a significant upregulation of genes associated with neurogenesis and synapse formation in Npc1-/- oligodendrocyte lineage cells, reflecting diminished gene silencing by H3K27me3 and H3K9me3. Npc1-/- oligodendrocyte progenitor cells reproduced impaired maturation in vitro and this phenotype was rescued by treatment with GSK-J4, a small molecule inhibitor of H3K27 demethylases. This study sought to determine the genes being directly impacted by the epigenetic dysfunction at H3K27.
2023-05-31 | GSE221336 | GEO
Project description:The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells
| PRJNA915070 | ENA
Project description:The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells ChIP-seq
| PRJNA906579 | ENA
Project description:Cholesterol import in mammalian cells is mediated by the LDL receptor pathway. Here, we perform a genome-wide CRISPR screen using an endogenous cholesterol reporter and identify >100 genes involved in LDL-cholesterol import. We characterise C18orf8 as a core subunit of the mammalian Mon1-Ccz1 guanidine exchange factor (GEF) for Rab7, required for complex stability and function. C18orf8-deficient cells lack Rab7 activation and show severe defects in late endosome morphology and endosomal LDL trafficking, resulting in cellular cholesterol deficiency. Unexpectedly, free cholesterol accumulates within swollen lysosomes, suggesting a critical defect in lysosomal cholesterol export. We find that active Rab7 interacts with the NPC1 cholesterol transporter and licenses lysosomal cholesterol export. This process is abolished in C18orf8-, Ccz1- and Mon1A/B-deficient cells and restored by a constitutively active Rab7. The trimeric Mon1-Ccz1-C18orf8 (MCC) GEF therefore plays a central role in cellular cholesterol homeostasis coordinating Rab7 activation, endosomal LDL trafficking and NPC1-dependent lysosomal cholesterol export.
2020-10-29 | PXD021444 | Pride
Project description:The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells bulk RNA-seq of mouse OPCs
| PRJNA913916 | ENA
Project description:Presenilin (PS) proteins represent the catalytic subunits of γ-secretase, and play a critical role in the generation of the Amyloid β (Aβ) peptide and the pathogenesis of Alzheimer’s disease (AD). Indeed, mutations in presenilin 1 (PS1) or PS2 are a major cause of early onset familial Alzheimer’s disease (FAD). However, PS proteins also exert multiple functions beyond Aβ generation. In this study, we examine the individual roles of PS1 and PS2 in cellular cholesterol metabolism. Deletion of PS1 or PS2 in mouse models led to cholesterol accumulation in cerebral neurons. Cholesterol accumulation was also observed in lysosomes of embryonic fibroblasts from PS1-KO and PS2-KO mice, and associated with decreased expression of the Niemann-Pick type C1 (NPC1) protein involved in intracellular cholesterol transport at late endosome/lysosome. Mass spectrometry and complementary biochemical methods also revealed abnormal N-glycosylation of NPC1 and several other membrane proteins in PS1-KO and PS2-KO cells. Interestingly, pharmacological inhibition of N-glycosylation resulted in intracellular cholesterol accumulation prominently in lysosomes as well as decrease of NPC1 expression in wild-type MEFs, thereby resembling the changes in PS1-KO and PS2-KO MEFs. In turn, treatment of PS1-KO and PS2-KO MEFs with a chaperone inducer, Arimoclomol, attenuated decrease of NPC1 and rescued the lysosomal cholesterol accumulation. Additionally, the intracellular cholesterol accumulation in PS1-KO and PS2-KO MEFs was prevented by NPC1 overexpression. Collectively, these data indicate that PS/γ-secretase dysfunction results in an impairment of protein N-glycosylation, which eventually causes NPC1 decrease and intracellular cholesterol accumulation. 3'RNASeq of mouse embryonic fibroblasts with PS1- or PS2-deficiency compared with controls. Biological replicates
2024-05-26 | GSE223572 | GEO
Project description:Background: Niemann-Pick type C is a rare autosomal recessive lysosomal storage disorder presenting aggravating neurologic symptoms due degeneration of specific types of CNS neurons. At present, it is not well understood how neurons react to NPC1 deficiency and why some neuronal cell types are more vulnerable than others. Purpose: We took aimed to uncover how a specific type of CNS neuron that can be highly purified reacts to NPC1 deficiency based on changes in gene expression. Methods: Retinal ganglion cells were purified from individual one-week old Balb/c mice homozygous for a mutant NPC1 allele (NPC1m1N) and wildtype littermates (n = 4 mice each genotype) using immunopanning. Total RNA was isolated from acutely isolated neurons and subjected to RNAseq using 4 biological replicates for each genotype. Results: Our analysis revealed a strong downregulation of transcripts known to be decreased in mutant mice including Npc1 and Calb1 thus validating our approach. We observed a strong upregulation of genes for cellular cholesterol accretion and the downregulation of those for cholesterol release. Other changes including downregulation genes involved in the immune response and synaptic components. Conclusions: The observed changes suggest that neurons already at one week of age sense a cholesterol deficit because lipids accumulate in the endosomal-lysosomal system and cannot be redistributed intracellularly. Gene expression analysis by RNAseq in retinal ganglion cells acutely purified from eight-days-old NPC1-deficient mice and wildtype littermates
2016-07-27 | E-GEOD-75775 | biostudies-arrayexpress
Project description:Background: Niemann-Pick type C is a rare autosomal recessive lysosomal storage disorder presenting aggravating neurologic symptoms due degeneration of specific types of CNS neurons. At present, it is not well understood how neurons react to NPC1 deficiency and why some neuronal cell types are more vulnerable than others. Purpose: We took aimed to uncover how a specific type of CNS neuron that can be highly purified reacts to NPC1 deficiency based on changes in gene expression. Methods: Retinal ganglion cells were purified from individual one-week old Balb/c mice homozygous for a mutant NPC1 allele (NPC1m1N) and wildtype littermates (n = 4 mice each genotype) using immunopanning. Total RNA was isolated from acutely isolated neurons and subjected to RNAseq using 4 biological replicates for each genotype. Results: Our analysis revealed a strong downregulation of transcripts known to be decreased in mutant mice including Npc1 and Calb1 thus validating our approach. We observed a strong upregulation of genes for cellular cholesterol accretion and the downregulation of those for cholesterol release. Other changes including downregulation genes involved in the immune response and synaptic components. Conclusions: The observed changes suggest that neurons already at one week of age sense a cholesterol deficit because lipids accumulate in the endosomal-lysosomal system and cannot be redistributed intracellularly.
2016-07-27 | GSE75775 | GEO