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.


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


  • Chromatin
  • Interferon-gamma