Epigenomic priming of immune genes implicates oligodendroglia in multiple sclerosis susceptibility.

Neuron 2022 Jan 31

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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-γ) treatment. Some MS susceptibility single-nucleotide polymorphisms (SNPs) overlap with these regulatory regions in mouse and human OLG. Treatment of mouse OPCs with IFN-γ 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. Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

Mandy Meijer, Eneritz Agirre, Mukund Kabbe, Cassandra A van Tuijn, Abeer Heskol, Chao Zheng, Ana Mendanha Falcão, Marek Bartosovic, Leslie Kirby, Daniela Calini, Michael R Johnson, M Ryan Corces, Thomas J Montine, Xingqi Chen, Howard Y Chang, Dheeraj Malhotra, Gonçalo Castelo-Branco. Epigenomic priming of immune genes implicates oligodendroglia in multiple sclerosis susceptibility. Neuron. 2022 Jan 31;110(7):1193-1210.e13