Epigenomic priming of immune genes implicates oligodendroglia in multiple sclerosis susceptibility

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

doi:10.1016/j.neuron.2021.12.034

Epigenomic priming of immune genes implicates oligodendroglia in multiple sclerosis susceptibility

Neuron. 2022 Apr 6;110(7):1193-1210.e13. doi: 10.1016/j.neuron.2021.12.034. Epub 2022 Jan 31.

Authors

Mandy Meijer¹, Eneritz Agirre¹, Mukund Kabbe¹, Cassandra A van Tuijn¹, Abeer Heskol², Chao Zheng¹, Ana Mendanha Falcão³, Marek Bartosovic¹, Leslie Kirby¹, Daniela Calini⁴, Michael R Johnson⁵, M Ryan Corces⁶, Thomas J Montine⁷, Xingqi Chen⁸, Howard Y Chang⁹, Dheeraj Malhotra⁴, Gonçalo Castelo-Branco¹⁰

Affiliations

¹ Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.
² Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden; Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal.
³ Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3B's Associate Laboratory, PT Government Associate Laboratory, 4710-057 Braga/Guimarães, Portugal.
⁴ Roche Pharma Research and Early Development, 4070 Basel, Switzerland.
⁵ Faculty of Medicine, Department of Brain Sciences, Imperial College of London, SW7 2AZ London, UK.
⁶ Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Center for Personal Dynamic Regulomes and Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
⁷ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
⁸ Center for Personal Dynamic Regulomes and Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA; Department of Immunology, Genetics, and Pathology, Uppsala University, 751 85 Uppsala, Sweden.
⁹ Center for Personal Dynamic Regulomes and Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305-5101, USA.
¹⁰ Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden; Ming Wai Lau Centre for Reparative Medicine, Stockholm node, Karolinska Institutet, 171 77 Stockholm, Sweden. Electronic address: goncalo.castelo-branco@ki.se.

Abstract

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.

Keywords: Polycomb; chromatin; genome-wide association studies; histone modifications; major histocompatibility complex; multiple sclerosis; myelin; neuroimmunology; oligodendrocyte; single-nucleotide polymorphisms.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation / physiology
Chromatin / metabolism
Epigenomics
Interferon-gamma / genetics
Mice
Multiple Sclerosis* / genetics
Multiple Sclerosis* / metabolism
Myelin Sheath / metabolism
Oligodendroglia / metabolism

Substances

Chromatin
Interferon-gamma

Abstract

Publication types

MeSH terms

Substances

Grants and funding