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Cited by 501Multiple Sclerosis Research StudiesNeuroinflammation and Neurodegeneration MechanismsSingle-cell and spatial transcriptomics

MAFG-driven astrocytes promote CNS inflammation

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Wheeler, Michael A., Clark, Iain C., Tjon, Emily C., Li, Zhaorong, Zandee, Stephanie E. J., Couturier, Charles P., Watson, Brianna R., Scalisi, Giulia +14 more·2020·Nature
DOI 10.1038/s41586-020-1999-0PMC PMC8049843
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Abstract

Multiple sclerosis is a chronic inflammatory disease of the CNS 1. Astrocytes contribute to the pathogenesis of multiple sclerosis 2, but little is known about the heterogeneity of astrocytes and its regulation. Here we report the analysis of astrocytes in multiple sclerosis and its preclinical model experimental autoimmune encephalomyelitis (EAE) by single-cell RNA sequencing in combination with cell-specific Ribotag RNA profiling, assay for transposase-accessible chromatin with sequencing (ATAC-seq), chromatin immunoprecipitation with sequencing (ChIP-seq), genome-wide analysis of DNA methylation and in vivo CRISPR-Cas9-based genetic perturbations. We identified astrocytes in EAE and multiple sclerosis that were characterized by decreased expression of NRF2 and increased expression of MAFG, which cooperates with MAT2α to promote DNA methylation and represses antioxidant and anti-inflammatory transcriptional programs. Granulocyte-macrophage colony-stimulating factor (GM-CSF) signalling in astrocytes drives the expression of MAFG and MAT2α and pro-inflammatory transcriptional modules, contributing to CNS pathology in EAE and, potentially, multiple sclerosis. Our results identify candidate therapeutic targets in multiple sclerosis.

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  • ScRNAseq and snRNAseq are becoming established as valuable tools to gain insight into basal and reactive-astrocyte heterogeneity.

    “ScRNAseq and snRNAseq are becoming established as valuable tools to gain insight into basal94 and reactive-astrocyte heterogeneity (Fig. 1e)40,78,95.”

    From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [40]

    The ‘scRNA-seq analysis of astrocytes in EAE’ section reports that scRNA-seq identified several astrocyte subpopulations during CNS inflammation, supporting its value for studying reactive-astrocyte heterogeneity. The cited paper does not establish the corresponding point for snRNA-seq. The sentence cites a different source for basal heterogeneity. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Single-cell and single-nucleus RNAseq studies in mouse models and human brains of chronic neurodegenerative diseases have unraveled numerous stage-dependent transcriptomic states in HD, AD, and MS that do not clearly comply with A1-A2 profiles.

    “For example, single-cell and single-nucleus RNAseq (scRNAseq and snRNAseq, respectively) studies in mouse models and human brains of chronic neurodegenerative diseases have unraveled numerous stage-dependent transcriptomic states in HD74, AD75,78, and MS40 that do not clearly comply with A1–A2 profiles.”

    From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [40]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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  • Classical knockout-, knockdown-, or CRISPR-based approaches to inactivate gene expression are available to gain insight into the impact on disease of a given pathway within previously identified astrocyte subsets.

    “Classical knockout-, knockdown-, or CRISPR-based approaches to inactivate gene expression are available to gain insight into the impact on disease of a given pathway within previously identified astrocyte subsets40.”

    From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [40]

    The paper identifies astrocyte subpopulations by scRNA-seq (scRNA-seq analysis of astrocytes in EAE) and uses Nfe2l2 knockdown, astrocyte-directed CRISPR–Cas9 inactivation, and an astrocyte-specific Csf2rb knockout to examine effects on EAE (NRF2 in astrocytes suppresses EAE; MAFG drives pathogenic astrocytes; GM-CSF boosts pathogenic astrocytes; pages unavailable). These perturbations targeted astrocytes generally, not specifically the previously identified subpopulations, so the subset-specific part of the claim is not established. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • The outcome of activating a signaling pathway may depend on the upstream stimuli or priming caused by previous exposure to other stimuli, perhaps through epigenetic control.

    “To complicate things further, the outcome of activating a signaling pathway may depend on the upstream stimuli82 or priming caused by previous exposure to other stimuli97, perhaps through epigenetic control40.”

    From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [40]

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Authors
Wheeler, M. A., Clark, I. C., Tjon, E. C., Li, Z., Zandee, S. E. J., Couturier, C. P., Watson, B. R., Scalisi, G., Alkwai, S., Rothhammer, V., Rotem, A., Heyman, J. A., Thaploo, S., Sanmarco, L. M., Ragoussis, J., Weitz, D. A., Petrecca, K., Moffitt, J. R., Becher, B., Antel, J. P., Prat, A., & Quintana, F. J.
Affiliations
  • Brigham and Women's Hospital (US)
  • Montreal Neurological Institute and Hospital (CA)
  • Boston Children's Hospital (US)
  • Harvard University (US)
  • McGill University and Génome Québec Innovation Centre (CA)
  • University of Zurich (CH)
  • Centre Hospitalier de l’Université de Montréal (CA)
  • Broad Institute (US)
Corresponding author
Quintana, Francisco J.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2020-02-12
Volume
578
Issue
7796
Pages
593-599
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-020-1999-0
PMC
PMC8049843
OpenAlex
W3006566345
Cited by
501
References
28
Citations by year
2026: 51 · 2025: 84 · 2024: 82 · 2023: 90 · 2022: 76 · 2021: 78 · 2020: 38 · 2012: 1
FWCI
47.18
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
Funders
  • National Cancer Institute (T32CA207021, P30CA006516)
  • National Institute of Allergy and Infectious Diseases (R01AI093903, R56AI093903, R01AI126880)
  • National Institute of Neurological Disorders and Stroke (F32NS101790, R01NS102807, R21NS087867)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
Keywords
multiple sclerosis, astrocytes, MAFG, Nrf2, DNA methylation, experimental autoimmune encephalomyelitis, neuroinflammation, astrocyte heterogeneity, therapeutic target
MeSH terms
Animals, Antioxidants, Astrocytes, Central Nervous System, Encephalomyelitis, Autoimmune, Experimental, Female, Humans, Inflammation, Male, Methionine Adenosyltransferase, Multiple Sclerosis, Repressor Proteins, Transcription, Genetic, Signal Transduction, Granulocyte-Macrophage Colony-Stimulating Factor, Sequence Analysis, RNA, DNA Methylation, MafG Transcription Factor, NF-E2-Related Factor 2, Mice

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