Oligodendroglia as Active Mediators of Genetic Risk in Multiple Sclerosis
Multiple sclerosis (MS) is a complex neuroinflammatory disorder characterized by immune-mediated demyelination and neurodegeneration within the central nervous system. Genome-wide association studies (GWAS) have identified hundreds of MS-associated risk variants, the vast majority of which reside in non-coding regions of the genome. Historically, these variants have been interpreted primarily through the lens of immune cell dysfunction. However, the study by Carlström et al. challenges this paradigm by positioning oligodendroglial lineage cells as active functional effectors of MS risk variants, thereby expanding the cellular framework through which genetic susceptibility to MS should be understood.
Integrating Chromatin Accessibility With Genetic Risk
To address the long-standing “variant-to-function” problem in MS genetics, the authors integrated GWAS data with single-cell chromatin accessibility profiling across oligodendrocyte precursor cells (OPCs) and mature oligodendrocytes (MOLs). By intersecting MS-associated single nucleotide polymorphisms (SNPs) with ATAC-seq datasets from both homeostatic and inflammatory conditions, they identified 76 risk variants located within accessible chromatin regions of the oligodendroglial lineage. This finding is notable because chromatin accessibility is a prerequisite for regulatory activity, strongly suggesting that these variants have the potential to influence gene expression directly within oligodendroglia rather than exclusively in immune cells.
High-Throughput Functional Dissection of Non-Coding Variants
The study applied a powerful combination of massively parallel reporter assays (MPRA) and CRISPR-based epigenetic perturbation to functionally interrogate these candidate regulatory elements. MPRA enabled allele-specific assessment of cis-regulatory activity for more than a thousand variant-containing candidate enhancers, while CRISPR interference and activation (CRISPRi/a) coupled with single-cell RNA sequencing allowed the authors to map downstream transcriptional consequences in human induced pluripotent stem cell–derived OPCs. This dual approach provided both nucleotide-level resolution and cellular context, overcoming limitations of purely computational or correlative strategies.
Genetic Control of Oligodendrocyte Differentiation
One of the most compelling examples of oligodendroglial regulation emerged from the rs2248137:CYP24A1 locus. Functional experiments demonstrated that this non-coding variant regulates OPC differentiation through long-range chromatin interactions with the BCAS1 gene, a critical regulator of early oligodendrocyte maturation. Epigenetic repression of the rs2248137 locus reduced BCAS1 expression and impaired subsequent myelin basic protein expression, whereas locus activation had the opposite effect. These findings provide a mechanistic link between an MS-associated variant, vitamin D–related genomic regions, and defective remyelination capacity in oligodendroglia.
Regulation of OPC Proliferation via Long-Range Chromatin Interactions
The authors further identified rs483180:PHGDH as a regulatory locus controlling OPC proliferation. Through combined MPRA, CRISPRi/a, and Micro-C chromatin conformation analyses, they demonstrated that this locus engages in long-range interactions with S100A family genes located tens of megabases away. Perturbation of the rs483180 locus altered expression of both PHGDH and S100A6, leading to measurable changes in OPC cell-cycle progression. This discovery highlights how MS risk variants can exert trans-regulatory effects across large genomic distances, influencing fundamental aspects of oligodendroglial biology.
Oligodendroglia as Modulators of Neuroinflammation
Beyond cell-intrinsic effects, the study provides strong evidence that oligodendroglia can actively shape immune responses in MS. Activation of the rs1415069:DIPK1A locus increased secretion of the chemokine CCL2 from OPCs, thereby enhancing recruitment of peripheral blood mononuclear cells in vitro. This finding suggests a direct mechanism by which MS risk variants may promote immune cell infiltration into the central nervous system via oligodendroglial signaling, challenging the notion that such processes are driven solely by astrocytes or immune cells themselves.
Implications for MS Pathogenesis and Therapeutic Targeting
Collectively, this work reframes oligodendroglia as dynamic contributors to MS susceptibility, disease initiation, and progression. By demonstrating that non-coding MS risk variants regulate oligodendroglial proliferation, differentiation, and immune communication, the study underscores the importance of cell-type–specific functional genomics in complex disease research. These insights not only deepen our understanding of MS pathophysiology but also suggest that targeting epigenetic regulation within oligodendroglia may represent a complementary therapeutic strategy alongside immune-modulating approaches.
Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.
References:
Carlström, K. E., Agirre, E., Sun, T., Dumral, Ö., Kabbe, M., Mahmud, N., ... & Castelo-Branco, G. (2025). Oligodendroglia as functional effectors of Multiple Sclerosis risk variants. bioRxiv, 2025-11.
