美国哈佛医学院布莱根妇女医院Francisco J. Quintana团队近期取得重要工作进展，他们研究提出，与疾病相关的星形胶质细胞表观遗传记忆促进了中枢神经系统的病理变化。相关研究成果2024年3月20日在线发表于《自然》杂志上。

据介绍，疾病相关的星形胶质细胞亚群有助于神经系统疾病的病理学，包括多发性硬化症和实验性自身免疫性脑脊髓炎（EAE），这是一种多发性硬化症的实验模型。然而，对这些星形胶质细胞亚群的稳定性及其整合过去刺激事件的能力知之甚少。

研究人员报道了一种表观遗传学控制的记忆星形细胞亚群的鉴定，该亚群在再激发时表现出加剧的促炎反应。具体而言，通过单细胞RNA测序、转座酶可及染色质测定与测序、染色质免疫沉淀与测序、核酸检测以及基于细胞特异性体内CRISPR–Cas9的遗传扰动研究相结合，研究人员确定星形胶质细胞记忆由代谢酶ATP柠檬酸裂解酶（ACLY）控制，该酶产生acetyl-CoA（乙酰辅酶A），组蛋白乙酰转移酶p300使用acetyl-CoA来控制染色质可及性。急性和慢性EAE模型中ACLY⁺p300⁺记忆星形胶质细胞的数量增加，其基因失活改善了EAE。研究人员还在体外检测了人类星形胶质细胞的促炎记忆表型；单细胞RNA测序和免疫组织化学研究检测到慢性多发性硬化病变中ACLY⁺p300⁺星形胶质细胞数量增加。

总之，这些研究定义了一种表观遗传学控制的记忆星形胶质细胞亚群，它促进EAE和潜在的多发性硬化症的中枢神经系统病理学。这些发现可能为多发性硬化症和其它神经系统疾病的新治疗方法提供指导。

附： 英文原文

Title: Disease-associated astrocyte epigenetic memory promotes CNS pathology

Author: Lee, Hong-Gyun, Rone, Joseph M., Li, Zhaorong, Akl, Camilo Faust, Shin, Seung Won, Lee, Joon-Hyuk, Flausino, Lucas E., Pernin, Florian, Chao, Chun-Cheih, Kleemann, Kilian L., Srun, Lena, Illouz, Tomer, Giovannoni, Federico, Charabati, Marc, Sanmarco, Liliana M., Kenison, Jessica E., Piester, Gavin, Zandee, Stephanie E. J., Antel, Jack P., Rothhammer, Veit, Wheeler, Michael A., Prat, Alexandre, Clark, Iain C., Quintana, Francisco J.

Issue&Volume: 2024-03-20

Abstract: Disease-associated astrocyte subsets contribute to the pathology of neurologic diseases, including multiple sclerosis and experimental autoimmune encephalomyelitis1,2,3,4,5,6,7,8 (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.

DOI: 10.1038/s41586-024-07187-5

Source: https://www.nature.com/articles/s41586-024-07187-5