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The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells

ABSTRACT: The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells

PROVIDER: PRJNA915070 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22446175.fastq.gz	Fastqsanger.gz
	SRR22446176.fastq.gz	Fastqsanger.gz
	SRR22446177.fastq.gz	Fastqsanger.gz
	SRR22446178.fastq.gz	Fastqsanger.gz
	SRR22889437_1.fastq.gz	Fastqsanger.gz

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The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells snRNA-Seq

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

The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells ChIP-seq

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The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells bulk RNA-seq of mouse OPCs

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The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells ChIP-seq

Project description:The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells ChIP-seq

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The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells snRNA-Seq

Project description:The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells snRNA-Seq

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The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells bulk RNA-seq of mouse OPCs

Project description:The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells bulk RNA-seq of mouse OPCs

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A trimeric Rab7 GEF controls NPC1-dependent lysosomal cholesterol export

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

Presenilin deficiency results in cellular cholesterol accumulation by impairment of protein glycosylation and NPC1 function.

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

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The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells.

Project description:The intracellular cholesterol transporter 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. Here, we use single-nucleus RNA-seq on the forebrain of Npc1-/- mice at P16 to identify cell types and pathways affected early in pathogenesis. Our analysis uncovers significant transcriptional changes in the oligodendrocyte lineage during developmental myelination, accompanied by diminished maturation of myelinating oligodendrocytes. We identify upregulation of genes associated with neurogenesis and synapse formation in Npc1-/- oligodendrocyte lineage cells, reflecting diminished gene silencing by H3K27me3. Npc1-/- oligodendrocyte progenitor cells reproduce impaired maturation in vitro, and this phenotype is rescued by treatment with GSK-J4, a small molecule inhibitor of H3K27 demethylases. Moreover, mobilizing stored cholesterol in Npc1-/- mice by a single administration of 2-hydroxypropyl-β-cyclodextrin at P7 rescues myelination, epigenetic marks, and oligodendrocyte gene expression. Our findings highlight an important role for NPC1 in oligodendrocyte lineage maturation and epigenetic regulation, and identify potential targets for therapeutic intervention.

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