Disease-associated astrocyte epigenetic memory promotes CNS pathology

Hong-Gyun Lee, Joseph M. Rone, Zhaorong Li, Camilo Faust Akl, Seung Won Shin, Joon-Hyuk Lee, Lucas E. Flausino, Florian Pernin, Chun-Cheih Chao, Kilian L. Kleemann, Lena Srun, Tomer Illouz, Federico Giovannoni, Marc Charabati, Liliana M. Sanmarco, Jessica E. Kenison, Gavin Piester, Stephanie E. J. Zandee, Jack P. Antel, Veit Rothhammer, Michael A. Wheeler, Alexandre Prat, Iain C. Clark and Francisco J. Quintana ()
Additional contact information
Hong-Gyun Lee: Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School
Joseph M. Rone: Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School
Zhaorong Li: Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School
Camilo Faust Akl: Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School
Seung Won Shin: University of California Berkeley
Joon-Hyuk Lee: Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School
Lucas E. Flausino: Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School
Florian Pernin: McGill University
Chun-Cheih Chao: Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School
Kilian L. Kleemann: University of Portsmouth
Lena Srun: Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School
Tomer Illouz: Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School
Federico Giovannoni: Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School
Marc Charabati: Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School
Liliana M. Sanmarco: Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School
Jessica E. Kenison: Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School
Gavin Piester: Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School
Stephanie E. J. Zandee: Neuroimmunology Research Lab, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM)
Jack P. Antel: McGill University
Veit Rothhammer: Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School
Michael A. Wheeler: Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School
Alexandre Prat: Neuroimmunology Research Lab, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM)
Iain C. Clark: University of California Berkeley
Francisco J. Quintana: Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School

Nature, 2024, vol. 627, issue 8005, 865-872

Abstract: Abstract Disease-associated astrocyte subsets contribute to the pathology of neurologic diseases, including multiple sclerosis and experimental autoimmune encephalomyelitis1–8 (EAE), an experimental model for multiple sclerosis. However, little is known about the stability of these astrocyte subsets and their ability to integrate past stimulation events. Here we report the identification of an epigenetically controlled memory astrocyte subset that exhibits exacerbated pro-inflammatory responses upon rechallenge. Specifically, using a combination of single-cell RNA sequencing, assay for transposase-accessible chromatin with sequencing, chromatin immunoprecipitation with sequencing, focused interrogation of cells by nucleic acid detection and sequencing, and cell-specific in vivo CRISPR–Cas9-based genetic perturbation studies we established that astrocyte memory is controlled by the metabolic enzyme ATP-citrate lyase (ACLY), which produces acetyl coenzyme A (acetyl-CoA) that is used by histone acetyltransferase p300 to control chromatin accessibility. The number of ACLY+p300+ memory astrocytes is increased in acute and chronic EAE models, and their genetic inactivation ameliorated EAE. We also detected the pro-inflammatory memory phenotype in human astrocytes in vitro; single-cell RNA sequencing and immunohistochemistry studies detected increased numbers of ACLY+p300+ astrocytes in chronic multiple sclerosis lesions. In summary, these studies define an epigenetically controlled memory astrocyte subset that promotes CNS pathology in EAE and, potentially, multiple sclerosis. These findings may guide novel therapeutic approaches for multiple sclerosis and other neurologic diseases.

Date: 2024
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DOI: 10.1038/s41586-024-07187-5

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