Epigenomic priming of immune genes implicates oligodendroglia in multiple sclerosis susceptibility

被引：48

作者：

Meijer, Mandy ^{[1
]}

Agirre, Eneritz ^{[1
]}

Kabbe, Mukund ^{[1
]}

van Tuijn, Cassandra A. ^{[1
]}

Heskol, Abeer ^{[1
,2
]}

Zheng, Chao ^{[1
]}

Falcao, Ana Mendanha ^{[1
,3
,4
]}

Bartosovic, Marek ^{[1
]}

Kirby, Leslie ^{[1
]}

Calini, Daniela ^{[5
]}

Johnson, Michael R. ^{[6
]}

Corces, M. Ryan ^{[7
,8
,9
,10
]}

Montine, Thomas J. ^{[10
]}

Chen, Xingqi ^{[8
,9
,11
]}

Chang, Howard Y. ^{[8
,9
]}

Malhotra, Dheeraj ^{[5
]}

Castelo-Branco, Goncalo ^{[1
,12
]}

机构：

[1] Karolinska Inst, Dept Med Biochem & Biophys, Lab Mol Neurobiol, S-17177 Stockholm, Sweden

[2] Inst Gulbenkian Ciencias, P-2780156 Oeiras, Portugal

[3] Univ Minho, Sch Med, Life & Hlth Sci Res Inst ICVS, Braga, Portugal

[4] PT Govt Associate Lab, ICVS 3Bs Associate Lab, P-4710057 Braga, Portugal

[5] Roche Pharma Res & Early Dev, CH-4070 Basel, Switzerland

[6] Imperial Coll London, Fac Med, Dept Brain Sci, London SW7 2AZ, England

[7] Gladstone Inst Neurol Dis, San Francisco, CA 94158 USA

[8] Stanford Univ, Ctr Personal Dynam Regulomes, Stanford, CA 94305 USA

[9] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA

[10] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA

[11] Uppsala Univ, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden

[12] Karolinska Inst, Ming Wai Lau Ctr Reparat Med, Stockholm Node, S-17177 Stockholm, Sweden

来源：

NEURON | 2022年 / 110卷 / 07期

基金：

欧洲研究理事会; 瑞典研究理事会; 英国医学研究理事会;

关键词：

DIFFERENTIAL EXPRESSION ANALYSIS; TRANSCRIPTION FACTORS; INTERFERON-GAMMA; CHROMATIN ARCHITECTURE; CELL; MOUSE; VISUALIZATION; MECHANISMS; ENRICHMENT; RESPONSES;

D O I：

10.1016/j.neuron.2021.12.034

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Multiple sclerosis (MS) is characterized by a targeted attack on oligodendroglia (OLG) and myelin by immune cells, which are thought to be the main drivers of MS susceptibility. We found that immune genes exhibit a primed chromatin state in single mouse and human OLG in a non-disease context, compatible with transitions to immune-competent states in MS. We identified BACH1 and STAT1 as transcription factors involved in immune gene regulation in oligodendrocyte precursor cells (OPCs). A subset of immune genes presents bivalency of H3K4me3/H3K27me3 in OPCs, with Polycomb inhibition leading to their increased activation upon interferon gamma (IFN-g) treatment. Some MS susceptibility single-nucleotide polymorphisms (SNPs) overlap with these regulatory regions in mouse and human OLG. Treatment of mouse OPCs with IFN-g leads to chromatin architecture remodeling at these loci and altered expression of interacting genes. Thus, the susceptibility for MS may involve OLG, which therefore constitutes novel targets for immunological based therapies for MS.

引用

页码：1193 / +

页数：32

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