The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells
Abstract 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,...
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| Format: | Article |
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Nature Portfolio
2023-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-39733-6 |
| _version_ | 1797784515697967104 |
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| author | Thaddeus J. Kunkel Alice Townsend Kyle A. Sullivan Jean Merlet Edward H. Schuchman Daniel A. Jacobson Andrew P. Lieberman |
| author_facet | Thaddeus J. Kunkel Alice Townsend Kyle A. Sullivan Jean Merlet Edward H. Schuchman Daniel A. Jacobson Andrew P. Lieberman |
| author_sort | Thaddeus J. Kunkel |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-13T00:41:01Z |
| format | Article |
| id | doaj.art-c8b6dbf7e23943d38d1303c4f334e573 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T00:41:01Z |
| publishDate | 2023-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-c8b6dbf7e23943d38d1303c4f334e5732023-07-09T11:19:21ZengNature PortfolioNature Communications2041-17232023-07-0114111710.1038/s41467-023-39733-6The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cellsThaddeus J. Kunkel0Alice Townsend1Kyle A. Sullivan2Jean Merlet3Edward H. Schuchman4Daniel A. Jacobson5Andrew P. Lieberman6Department of Pathology, University of Michigan Medical SchoolThe Bredesen Center for Interdisciplinary Research and Graduate Education, University of Tennessee KnoxvilleComputational and Predictive Biology, Oak Ridge National LaboratoryThe Bredesen Center for Interdisciplinary Research and Graduate Education, University of Tennessee KnoxvilleDepartment of Genetics and Genomic Sciences, The Icahn School of Medicine at Mount SinaiComputational and Predictive Biology, Oak Ridge National LaboratoryDepartment of Pathology, University of Michigan Medical SchoolAbstract 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.https://doi.org/10.1038/s41467-023-39733-6 |
| spellingShingle | Thaddeus J. Kunkel Alice Townsend Kyle A. Sullivan Jean Merlet Edward H. Schuchman Daniel A. Jacobson Andrew P. Lieberman The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells Nature Communications |
| title | The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells |
| title_full | The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells |
| title_fullStr | The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells |
| title_full_unstemmed | The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells |
| title_short | The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells |
| title_sort | cholesterol transporter npc1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells |
| url | https://doi.org/10.1038/s41467-023-39733-6 |
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