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 RothhammerMichael A. Wheeler, Alexandre Prat, Iain C. Clark, Francisco J. Quintana

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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.

Original languageEnglish
Pages (from-to)865-872
Number of pages8
JournalNature
Volume627
Issue number8005
DOIs
StatePublished - 28 Mar 2024
Externally publishedYes

Bibliographical note

Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature Limited 2024.

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