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

Thaddeus J. Kunkel; Alice Townsend; Kyle A. Sullivan; Jean Merlet; Edward H. Schuchman; Daniel A. Jacobson; Andrew P. Lieberman

doi:10.1038/s41467-023-39733-6

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

Thaddeus J. Kunkel, Alice Townsend, Kyle A. Sullivan, Jean Merlet, Edward H. Schuchman, Daniel A. Jacobson, Andrew P. Lieberman

Computational and Predictive Biology

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

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.

Original language	English
Article number	3964
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-39733-6
State	Published - Dec 2023

Funding

This manuscript has been authored by UT-Battelle, LLC under Contract No. DE-AC05-00OR22725 with the U.S. Department of Energy. The United States Government retains and the publisher, by accepting the article for publication, acknowledges that the United States Government retains a non-exclusive, paid-up, irrevocable, world-wide license to publish or reproduce the published form of this manuscript, or allow others to do so, for United States Government purposes. The Department of Energy will provide public access to these results of federally sponsored research in accordance with the DOE Public Access Plan ( http://energy.gov/downloads/doe-public-access-plan ). This work was funded by the National Institutes of Health (R01 NS122746 to A.P.L.; T32 GM113900 to T.J.K.; R01 DA051913, R01 DA051908 to D.A.J.) and the Firefly Fund (to A.P.L.). We thank Mark Schultz, Siva Kumar Natarajan, Matthew Pun, and Sriram Venneti for their insightful discussions. We also thank Halle Kunkel for allowing us to use her illustrations of oligodendrocytes (Fig. 4A). Library preparation and next-generation sequencing for RNA-seq experiments were carried out by the University of Michigan Advanced Genomics Core. This manuscript has been authored by UT-Battelle, LLC under Contract No. DE-AC05-00OR22725 with the U.S. Department of Energy. The United States Government retains and the publisher, by accepting the article for publication, acknowledges that the United States Government retains a non-exclusive, paid-up, irrevocable, world-wide license to publish or reproduce the published form of this manuscript, or allow others to do so, for United States Government purposes. The Department of Energy will provide public access to these results of federally sponsored research in accordance with the DOE Public Access Plan (http://energy.gov/downloads/doe-public-access-plan). This work was funded by the National Institutes of Health (R01 NS122746 to A.P.L.; T32 GM113900 to T.J.K.; R01 DA051913, R01 DA051908 to D.A.J.) and the Firefly Fund (to A.P.L.). We thank Mark Schultz, Siva Kumar Natarajan, Matthew Pun, and Sriram Venneti for their insightful discussions. We also thank Halle Kunkel for allowing us to use her illustrations of oligodendrocytes (Fig. ). Library preparation and next-generation sequencing for RNA-seq experiments were carried out by the University of Michigan Advanced Genomics Core.

Funders	Funder number
DOE Public Access Plan
United States Government
National Institutes of Health	DE-AC05-00OR22725, R01 NS122746, T32 GM113900, R01 DA051908, R01 DA051913
U.S. Department of Energy

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10.1038/s41467-023-39733-6

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title = "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, 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.",

author = "Kunkel, {Thaddeus J.} and Alice Townsend and Sullivan, {Kyle A.} and Jean Merlet and Schuchman, {Edward H.} and Jacobson, {Daniel A.} and Lieberman, {Andrew P.}",

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AU - Lieberman, Andrew P.

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N2 - 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.

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

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