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.
Highlights
Genome-wide association studies (GWASs) have allowed the identification of hundreds of single-nucleotide polymorphisms (SNPs) associated with susceptibility for multiple sclerosis (MS), many of which are located near genes expressed in the central and peripheral immune system (International Multiple Sclerosis Genetics Consortium, 2019)
Oligodendrocyte precursor cells (OPCs) in the adult central nervous system (CNS) are recruited to MS lesions and are thought to contribute to remyelination during disease remission (Franklin and Ffrench-Constant, 2017), this capacity is hindered upon disease progression (Ja€kel et al, 2019; Yeung et al, 2019)
We found that a cohort of immune genes increases chromatin accessibility (CA) in the context of EAE, whereas others already exhibit open chromatin in control (Ctr)-OLG, suggesting chromatin priming for these genes
Summary
Genome-wide association studies (GWASs) have allowed the identification of hundreds of single-nucleotide polymorphisms (SNPs) associated with susceptibility for multiple sclerosis (MS), many of which are located near genes expressed in the central and peripheral immune system (International Multiple Sclerosis Genetics Consortium, 2019). Oligodendrocyte precursor cells (OPCs) in the adult CNS are recruited to MS lesions and are thought to contribute to remyelination during disease remission (Franklin and Ffrench-Constant, 2017), this capacity is hindered upon disease progression (Ja€kel et al, 2019; Yeung et al, 2019). OPCs transition to an immune-like state in the context of MS and demyelination (Absinta et al, 2021; Falcao et al, 2019; Fernandez-Castaneda et al, 2020; Ja€kel et al, 2019; Kirby et al, 2019). Immune OPCs can present antigens to CD4 (Falcao et al, 2019) and CD8 T cells (Fernandez-Castaneda et al, 2020; Kirby et al, 2019).
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