Cell type specificity of intralocus interactions reveals oligodendrocyte intrinsic mechanisms for multiple sclerosis [ChIP-Seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE142084 | GEO | 2020/12/06
REPOSITORIES: GEO
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Project description:Multiple sclerosis (MS) is an autoimmune disease characterized by attack on oligodendrocytes within the central nervous system (CNS). Despite widespread use of immunomodulatory therapies, patients face progressive disability due to failure of myelin regeneration and loss of neurons, suggesting additional cellular pathologies. Here, we describe a general approach for identifying specific cell types in which a disease allele exerts a pathogenic effect. Applying this approach to MS risk loci, we pinpoint likely pathogenic cell types for 70%. In addition to T cell loci, we unexpectedly identified myeloid and CNS-specific risk loci, including two sites that dysregulate transcriptional pause release in oligodendrocytes. Functional studies demonstrated inhibition of transcriptional elongation is a dominant pathway blocking oligodendrocyte maturation. Furthermore, pause release factors are frequently dysregulated in MS brain tissue and are associated with white matter microstructure. These data implicate cell-intrinsic aberrations outside of the immune system and suggest new avenues for therapeutic development.
2020-12-06 | GSE142085 | GEO
Project description:T helper (Th)17 cells are considered to contribute to inflammatory mechanisms in diseases such as multiple sclerosis (MS). However, the discussion persists regarding their true role in patients. Here, we visualized central nervous system (CNS) inflammatory processes in models of MS live in vivo and in MS brains and discovered that CNS-infiltrating Th17 cells form prolonged stable contact with oligodendrocytes. Strikingly, compared to Th2 cells, direct contact with Th17 worsened experimental demyelination, caused damage to human oligodendrocyte processes and increased cell death. Importantly, we found that in comparison to Th2 cells, both human and murine Th17 cells express higher levels of the integrin CD29, which is linked to glutamate release pathways. Of note, contact of human Th17 cells with oligodendrocytes triggered release of glutamate. As we found that Th17-polarized cells release glutamate in contact with oligodendrocytic cells, we then assessed the impact of glutamate itself on human oligodendrocytes in primary culture. We found that 12-24h application of glutamate - but not pro-inflammatory cytokines TNFα or IFN-γ - strongly decreased the area and complexity of human oligodendrocyte processes in vitro without affecting oligodendrocyte survival. To further investigate the impact of glutamate on human oligodendrocytes we used single cell RNA sequencing (scRNAseq) of the human oligodendrocytes in primary culture, unstimulated (vehicle) and stimulated with glutamate. Following exposure to glutamate we observed induced cell stress and changes in biosynthesis of cholesterol and lipids in mature human oligodendrocytes. Finally, exposure to glutamate decreased myelination whereas blockade of CD29 preserved oligodendrocyte processes from Th17-mediated injury. Our data provide first evidence for direct and deleterious attack of Th17 cells on the myelin compartment and show the potential for new therapeutic opportunities in MS.
2021-07-25 | GSE180670 | GEO
Project description:Central nervous system (CNS) resident cells such as microglia, oligodendrocytes and astrocytes are gaining increasing attention in respect to their contribution to CNS pathologies including Multiple Sclerosis (MS). Several studies have demonstrated the involvement of pro- inflammatory glial subsets in the pathogenesis and propagation of inflammatory events in MS and its animal models. However, it has only recently become clear that the underlying heterogeneity of astrocytes and microglia can not only drive inflammation, but also lead to its resolution through direct and indirect mechanisms. Failure of these tissue-protective mechanisms may potentiate disease and increase the risk of conversion to progressive stages of MS, for which currently available therapies are limited. Using proteomic analyses of cerebrospinal fluid specimens from MS patients in combination with experimental studies, we here identify Heparin-binding EGF-like growth factor (HB-EGF) as a central mediator of tissue-protective and anti-inflammatory effects important for the recovery from acute inflammatory lesions in CNS autoimmunity. Hypoxic conditions drive the rapid upregulation of HB-EGF by astrocytes during early CNS inflammation, while pro-inflammatory conditions suppress trophic HB-EGF signaling through epigenetic modifications. Finally, we demonstrate both anti-inflammatory and tissue-protective effects of HB-EGF in a broad variety of cell types in vitro and use intranasal administration of HB-EGF in acute and post-acute stages of neuroinflammation to attenuate disease in a preclinical mouse model of MS. Altogether, we identify astrocyte-derived HB-EGF and its epigenetic regulation as a novel modulator of autoimmune CNS inflammation and potential therapeutic target in MS.
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Project description:Central nervous system (CNS) resident cells such as microglia, oligodendrocytes and astrocytes are gaining increasing attention in respect to their contribution to CNS pathologies including Multiple Sclerosis (MS). Several studies have demonstrated the involvement of pro- inflammatory glial subsets in the pathogenesis and propagation of inflammatory events in MS and its animal models. However, it has only recently become clear that the underlying heterogeneity of astrocytes and microglia can not only drive inflammation, but also lead to its resolution through direct and indirect mechanisms. Failure of these tissue-protective mechanisms may potentiate disease and increase the risk of conversion to progressive stages of MS, for which currently available therapies are limited. Using proteomic analyses of cerebrospinal fluid specimens from MS patients in combination with experimental studies, we here identify Heparin-binding EGF-like growth factor (HB-EGF) as a central mediator of tissue-protective and anti-inflammatory effects important for the recovery from acute inflammatory lesions in CNS autoimmunity. Hypoxic conditions drive the rapid upregulation of HB-EGF by astrocytes during early CNS inflammation, while pro-inflammatory conditions suppress trophic HB-EGF signaling through epigenetic modifications. Finally, we demonstrate both anti-inflammatory and tissue-protective effects of HB-EGF in a broad variety of cell types in vitro and use intranasal administration of HB-EGF in acute and post-acute stages of neuroinflammation to attenuate disease in a preclinical mouse model of MS. Altogether, we identify astrocyte-derived HB-EGF and its epigenetic regulation as a novel modulator of autoimmune CNS inflammation and potential therapeutic target in MS.
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Project description:While the role of the immune system in multiple sclerosis (MS) is widely acknowledged, our comprehension of the transcriptional foundations of this prevalent neurological disorder remains largely incomplete. Here, we conducted high-depth RNA sequencing on monocytes from a cohort of patients with MS to explore rare RNA species associated with the disease. In a subset of the patients, a markedly altered transcriptome was observed, coinciding with a decreased expression of the epigenetic silencer HP1α/CBX5. These patients also exhibited diminished expression of multiple genes encoding subunits of the Integrator complex. Alongside, there were clear indications of decreased Integrator activity, including impaired U snRNA and enhancer-RNA maturation/degradation and dysregulated RNA polymerase II (RNAPII) pause-release. Inactivation of Cbx5 in the mouse recapitulated the defects in Integrator activity and resulted in hypersensitivity to Experimental Autoimmune Encephalomyelitis (EAE). While these data implied an unexpected function for HP1α in regulating RNAPII pause-release, they also showed that the dysregulation of numerous genes in MS patients could be attributed to either the biased distribution of transcription toward the 5' end of genes or the heightened elongation and stability of enhancer RNAs. An impaired Integrator activity, which has been hinted at by mutations within Integrator subunits previously linked to an increased risk of MS, provides a well-defined mechanistic understanding of the transcriptional anomalies associated with the disease, while introducing new criteria to categorize MS patients.
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Project description:While the role of the immune system in multiple sclerosis (MS) is widely acknowledged, our comprehension of the transcriptional foundations of this prevalent neurological disorder remains largely incomplete. Here, we conducted high-depth RNA sequencing on monocytes from a cohort of patients with MS to explore rare RNA species associated with the disease. In a subset of the patients, a markedly altered transcriptome was observed, coinciding with a decreased expression of the epigenetic silencer HP1α/CBX5. These patients also exhibited diminished expression of multiple genes encoding subunits of the Integrator complex. Alongside, there were clear indications of decreased Integrator activity, including impaired U snRNA and enhancer-RNA maturation/degradation and dysregulated RNA polymerase II (RNAPII) pause-release. Inactivation of Cbx5 in the mouse recapitulated the defects in Integrator activity and resulted in hypersensitivity to Experimental Autoimmune Encephalomyelitis (EAE). While these data implied an unexpected function for HP1α in regulating RNAPII pause-release, they also showed that the dysregulation of numerous genes in MS patients could be attributed to either the biased distribution of transcription toward the 5' end of genes or the heightened elongation and stability of enhancer RNAs. An impaired Integrator activity, which has been hinted at by mutations within Integrator subunits previously linked to an increased risk of MS, provides a well-defined mechanistic understanding of the transcriptional anomalies associated with the disease, while introducing new criteria to categorize MS patients.
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Project description:Multiple Sclerosis (MS) is a neuroinflammatory disease characterized by demyelinated lesions in the CNS. Remyelination in MS is variable between individuals and tends to become less efficient with aging. Microglia and astrocytes are known to have critical roles in MS pathogenesis, but to what extent their activity is altered by remyelination failure remains unclear. To determine the effects of demyelination on neuroinflammation, we use two mouse models that genetically ablate myelinating oligodendrocytes. We use the Plp1-CreERT mouse line crossed with the Myrf fl/fl mouse line to induce genetic demyelination throughout the CNS following adult tamoxifen administration. Subsequent remyelination is mediated by the proliferation and differentiation of oligodendrocyte precursor cells (OPCs) to newly formed oligodendrocytes. To assess the consequences of remyelination failure, we deleted Myrf from both mature oligodendrocytes and OPCs using Myrf fl/fl; Sox10-CreERT mice, which both induces demyelination and impairs subsequent remyelination. To characterize the glial cells in these demyelinated mice, we performed single-nucleus RNA-sequencing (snRNAseq) of optic nerves at peak demyelination, generating an atlas of non-neuronal cells including oligodendrocyte lineage cells, astrocytes, microglia, endothelial cells, pericytes, arachnoid barrier cells, vascular and leptomeningeal cells.
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Project description:Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system (CNS), resulting in neurological disability that worsens over time. While progress has been made in defining the immune system’s role in MS pathophysiology, the contribution of intrinsic CNS-cell dysfunction remains unclear. Here, we generated a collection of iPSC lines from people with MS spanning diverse clinical subtypes and differentiated them into glia-enriched cultures. Using single-cell transcriptomic profiling and orthogonal analyses, we observed several distinguishing characteristics of MS cultures pointing to glia-intrinsic disease mechanisms. We found that primary progressive MS-derived cultures contained fewer oligodendrocytes. Moreover, MS-derived oligodendrocyte lineage cells and astrocytes showed increased expression of immune and inflammatory genes, matching those of glia from MS postmortem brains. Thus, iPSC-derived MS models provide a unique platform for dissecting glial contributions to disease phenotypes independent of the peripheral immune system and identify potential glia-specific targets for therapeutic intervention.
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2020-02-12 | GSE129608 | GEO