MAFG-driven astrocytes promote CNS inflammation

Michael A. Wheeler, Iain C. Clark, Emily C. Tjon, Zhaorong Li, Stephanie E. J. Zandee, Charles P. Couturier, Brianna R. Watson, Giulia Scalisi, Sarah Alkwai, Veit Rothhammer, Assaf Rotem, John A. Heyman, Shravan Thaploo, Liliana M. Sanmarco, Jiannis Ragoussis, David A. Weitz, Kevin Petrecca, Jeffrey R. Moffitt, Burkhard Becher, Jack P. Antel, Alexandre Prat and Francisco J. Quintana ()
Additional contact information
Michael A. Wheeler: Harvard Medical School
Iain C. Clark: Harvard Medical School
Emily C. Tjon: Harvard Medical School
Zhaorong Li: Harvard Medical School
Stephanie E. J. Zandee: Centre de recherche du CHUM (CRCHUM)
Charles P. Couturier: McGill University
Brianna R. Watson: Boston Children’s Hospital
Giulia Scalisi: Harvard Medical School
Sarah Alkwai: Harvard Medical School
Veit Rothhammer: Harvard Medical School
Assaf Rotem: Harvard University
John A. Heyman: Harvard University
Shravan Thaploo: Harvard Medical School
Liliana M. Sanmarco: Harvard Medical School
Jiannis Ragoussis: McGill University
David A. Weitz: Harvard University
Kevin Petrecca: McGill University
Jeffrey R. Moffitt: Boston Children’s Hospital
Burkhard Becher: University of Zurich
Jack P. Antel: McGill University
Alexandre Prat: Centre de recherche du CHUM (CRCHUM)
Francisco J. Quintana: Harvard Medical School

Nature, 2020, vol. 578, issue 7796, 593-599

Abstract: Abstract Multiple sclerosis is a chronic inflammatory disease of the CNS1. Astrocytes contribute to the pathogenesis of multiple sclerosis2, 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.

Date: 2020
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DOI: 10.1038/s41586-020-1999-0

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