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| Status |
Public on May 31, 2023 |
| Title |
The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells bulk RNA-seq of mouse OPCs |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
Oligodendrocyte progenitors were isolated from mouse brains using magnetic-activated cell sorting. RNA-seq was performed on cells from 3 WT and 3 Npc1-null mice.
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| Contributor(s) |
Kunkel TJ, Townsend A, Sullivan KA, Merlet J, Jacobson DA, Lieberman AP |
| Citation(s) |
37407594 |
| |
| Submission date |
Dec 19, 2022 |
| Last update date |
Sep 01, 2023 |
| Contact name |
Andrew Lieberman |
| Organization name |
University of Michigan
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| Department |
Pathology
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| Street address |
1150 W Medical Center Drive
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| City |
Ann Arbor |
| State/province |
MI |
| ZIP/Postal code |
48105 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (6)
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| This SubSeries is part of SuperSeries: |
| GSE221610 |
The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells |
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| Relations |
| BioProject |
PRJNA913916 |
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