A primed immune transcriptional program is activated in oligodendroglia in multiple sclerosis

Abstract

Multiple sclerosis (MS) is a disease characterized by a targeted immune attack on myelin in the central nervous system (CNS). We have previously shown that oligodendrocytes (OLs), myelin producing cells in the CNS, and their precursors (OPCs), ac-quire disease-specific transcriptional states in MS 1,2. To under-stand how these alternative transcriptional programs are acti-vated in disease, we performed single-cell assay for transposase accessible chromatin using sequencing (scATAC-seq) on the OL lineage in the experimental autoimmune encephalomyeli-tis (EAE) mouse model of MS. We identified regulatory regions with increased accessibility in oligodendroglia (OLG) in EAE, some of which in the proximity of immune genes. A similar re-modeling of chromatin accessibility was observed upon treat-ment of postnatal OPCs with interferon-gamma (IFNγ), but not with dexamethasone. These changes in accessibility were not exclusive to distal enhancers, but also occurred at promoter re-gions, suggesting a role for promoters in mediating cell-state transitions. Notably, we found that a subset of immune genes al-ready exhibited chromatin accessibility in OPCs ex vivo and in vivo, suggesting a primed chromatin state in OLG compatible with rapid transitions to an immune-competent state. Several primed genes presented bivalency of H3K4me3 and H3K27me3 at promoters in OPCs, with loss of H3K27me3 upon IFNγ treatment. Inhibition of JMJD3/Kdm6b, mediating removal of H3K27me3, led to the inability to activate these genes upon IFNγ treatment. Importantly, OLGs from the adult human brain showed chromatin accessibility at immune gene loci, par-ticularly at MHC-I pathway genes. A subset of single-nucleotide polymorphisms (SNPs) associated with MS susceptibility over-lapped with these primed regulatory regions in OLG from both mouse and human CNS. Our data suggest that susceptibility for MS may involve activation of immune gene programs in OLG. These programs are under tight control at the chromatin level in OLG and may therefore constitute novel targets for immunological-based therapies for MS.

Cerebrospinal fluid of progressive multiple sclerosis patients reduces differentiation and immune functions of oligodendrocyte progenitor cells

“…These findings were re‐established by Kirby et al, who showed that OPCs are capable of presenting antigen (Kirby et al, 2019). Another study suggested that oligodendroglia are already primed at the chromatin level and can rapidly activate an immune program in the context of disease (Meijer et al, 2020). Upon injury, OPCs secrete IL1β and CCL2, which enhance their mobilization and thus contribute to the post‐injury inflammatory milieu (Duncan et al, 2020; Moyon et al, 2015; Ramesh et al, 2012).…”

“…For many years, oligodendrocytes were known only for their myelinating properties, and were considered as a passive target of the immune system in MS. However, accumulating evidences suggest that OPCs may have immunological properties as well: they survey their microenvironment (Bergles & Richardson, 2016; Hughes et al, 2013), express cytokine receptors (Arnett et al, 2001; Chew et al, 2005; Wang et al, 2017), migrate to injury site and respond to inflammatory cues (Akay et al, 2021; Dombrowski et al, 2017; Kang et al, 2013; Kirby & Castelo‐Branco, 2020; Meijer et al, 2020; Wang et al, 2017). These data suggest that OPCs may act as active players in the inflammatory pathogenesis of MS.…”

Oligodendrocyte progenitor cells differentiation induction with MAPK/ERK inhibitor fails to support repair processes in the chronically demyelinated CNS

“…It was shown that OPC can secrete cytokines and chemokines such as CCL2 and TNFa in response to injury (Moyon et al, 2015; Zveik, Fainstein, et al, 2022), they can present antigen via major histocompatibility complex (MHC)‐I and ‐II (Falcão et al, 2018; Kirby et al, 2019; Zveik, Fainstein, et al, 2022), affect T cell activation and proliferation (Falcão et al, 2018; Nishri et al, 2020; Zveik, Fainstein, et al, 2022), and internalize myelin debris through phagocytosis (Falcão et al, 2018). Furthermore, it has been suggested that oligodendroglia are pre‐programmed at the chromatin level and can rapidly activate an immune response in the context of disease (Meijer et al, 2020). These functions have reciprocal interactions with the regenerative functions and have been shown to affect OPCs differentiation (Dombrowski et al, 2017; Jiang et al, 2014; Kotter et al, 2001; McMurran et al, 2016; Zveik, Fainstein, et al, 2022).…”

Malaria-derived hemozoin alters chromatin remodelling and skews dendritic cell responses to subsequent bacterial infections

“…Furthermore, the differentiation also see changes in histone modifications and differentiation of monocytes to moDC involves loss of H3K4me3 at the promoter of the monocyte marker CD14 gene and a gain at the DC-SIGN gene (49). Similarly, the accessibility of gene promoter is pre-set during differentiation (50), which includes immune genes genomically primed at an earlier step in oligodendrolia development (51). We investigated the accessibility during Many immune genes require SWI/SNF complexes for transcriptional activation.…”