MAFG驱动的星形胶质细胞促进中枢神经系统炎症
2020-02-14   阅读:523   来源:自然

MAFG驱动的星形胶质细胞促进中枢神经系统炎症,这一成果由美国哈佛医学院Francisco J. Quintana课题组近日取得。相关论文2020年2月12日在线发表于国际学术期刊《自然》。

通过单细胞RNA测序结合细胞特异性Ribotag RNA谱分析、转座酶可及染色质测序分析(ATAC–seq)、染色质免疫沉淀测序(ChIP-seq)、DNA甲基化的全基因组分析以及基于CRISPR-Cas9的体内遗传干扰技术,研究人员报道了多发性硬化中的星形胶质细胞及其临床前模型实验性自身免疫性脑脊髓炎(EAE)的分析结果。他们在EAE和多发性硬化症中鉴定出星形胶质细胞,其特征在于NRF2的表达减少和MAFG的表达增加,而MAFG与MAT2α协同作用以促进DNA甲基化并抑制抗氧化剂和抗炎转录程序。星形胶质细胞中的粒细胞-巨噬细胞集落刺激因子(GM-CSF)信号驱动MAFG和MAT2α的表达以及促炎性转录模块,导致EAE中枢神经系统病理,并可能导致多发性硬化。因此,这些结果确定了多发性硬化症的候选治疗靶标。
 
据悉,多发性硬化症是中枢神经系统的慢性炎性疾病。星形胶质细胞可引起多发性硬化症发病,但对星形胶质细胞的异质性及其调控知之甚少。
 
附:英文原文

Title: MAFG-driven astrocytes promote CNS inflammation

Author: 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, Francisco J. Quintana

Issue&Volume: 2020-02-12

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.

DOI: 10.1038/s41586-020-1999-0

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