이홍균 (Harvard Medical School, Brigham and Women's Hospital) | 한빛사논문 > 한빛사

한빛사논문

조회2,450

Harvard Medical School, Brigham and Women's Hospital

CV File 237 kb

Nature, 20 March 2024 | https://doi.org/10.1038/s41586-024-07187-5 Disease-associated astrocyte epigenetic memory promotes CNS pathology

Hong-Gyun Lee ¹, Joseph M. Rone ¹, Zhaorong Li ^1,2, Camilo Faust Akl ¹, Seung Won Shin ³, Joon-Hyuk Lee ¹, Lucas E. Flausino ¹, Florian Pernin ⁴, Chun-Cheih Chao ¹, Kilian L. Kleemann ⁵, Lena Srun ¹, Tomer Illouz ¹, Federico Giovannoni ¹, Marc Charabati¹, Liliana M. Sanmarco ¹, Jessica E. Kenison ¹, Gavin Piester ^1,6, Stephanie E. J. Zandee ⁷, Jack P. Antel ⁴, Veit Rothhammer ^1,8, Michael A. Wheeler ^1,2, Alexandre Prat ⁷, Iain C. Clark ³ & Francisco J. Quintana ^1,2,9 ,*

¹Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.
²Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³Department of Bioengineering, College of Engineering, California Institute for Quantitative Biosciences, QB3, University of California Berkeley, Berkeley, CA, USA.
⁴Neuroimmunology Unit, Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
⁵School of Computing, University of Portsmouth, Portsmouth, UK.
⁶Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
⁷Neuroimmunology Research Lab, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montreal, Quebec, Canada.
⁸Department of Neurology, University Hospital, Friedrich-Alexander University Erlangen Nuremberg, Erlangen, Germany.
⁹Gene Lay Institute of Immunology and Inflammation, Boston, MA, USA.

^*Corresponding author: correspondence to Francisco J. Quintana

Abstract

Disease-associated astrocyte subsets contribute to the pathology of neurologic diseases, including multiple sclerosis and experimental autoimmune encephalomyelitis (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.

논문정보

형식Research article
게재일2024년 03월 (BRIC 등록일 2024-03-22)
연구진국외 연구진
분야 의약학 > 신경의학

댓글 작성 로그인

CV 열람하기

연락처 보기