Unveiling the functional outcome of single nucleotide polymorphisms and variants in oligodendroglia in multiple sclerosis

Project Information

SingleMS

Grant agreement ID: 101096064

DOI

10.3030/101096064

EC signature date 23 November 2023

Start date 1 January 2024

End date 31 December 2028

Funded under

• European Research Council (ERC)

Total cost

€ 3 182 846,00

EU contribution

€ 3 182 846,00

Coordinated by

KAROLINSKA INSTITUTET
Sweden

Periodic Reporting for period 1 - SingleMS (Unveiling the functional outcome of single nucleotide polymorphisms and variants in oligodendroglia in multiple sclerosis)

Reporting period: 2024-01-01 to 2026-06-30

Summary of the context and overall objectives of the project

Multiple sclerosis (MS) is a disease that often begins in young adults and can lead to long term disability. Today’s treatments work well in the early, relapsing stage of MS, but they are much less effective once patients enter the progressive stage. One important reason is that the brain’s ability to repair damaged nerve insulation, called myelin, decreases over time. This repair normally depends on special brain cells called oligodendrocytes and their precursors. For many years, MS research has focused mainly on the immune system, which attacks myelin. However, recent discoveries from our group show that oligodendrocytes themselves can adopt “immune like” behaviors. We also found that many genetic risk factors for MS may act directly in these cells. This suggests that oligodendrocytes play a far more active and important role in MS than previously thought. The SingleMS project aims to understand exactly how MS risk genetic variants affect oligodendrocytes. We will map the DNA regulation and gene activity of these risk regions in great detail, using advanced methods such as genome editing, single cell analysis, and spatial omics. We will study both human oligodendrocytes and specialized mouse models that mimic human MS. By revealing how these genetic variants influence oligodendrocyte function, such as their ability to maintain myelin, support nerve cells, and respond to inflammation, we hope to uncover new biological mechanisms that contribute to MS onset, progression, and the body’s ability to repair damage.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The SingleMS project aims to understand whether a type of brain cell called oligodendrocyte plays an active role in Multiple Sclerosis (MS), and how genetic risk factors for MS affect these cells.
Oligodendrocytes are the cells that make myelin—the protective insulation around nerve fibers that is damaged in MS.

What the project has achieved so far:

- Mapping human brain cells at high resolution: we have created a detailed map of the epigenetic landscape (chemical marks on DNA that regulate gene activity) of human oligodendroglia from different parts of the brain and spinal cord. This revealed regulatory switches (like a SOX10 enhancer) and developmental programs (HOX genes) that vary across regions (Kabbe et al., Nature Neuroscience 2026).

- Understanding disease‑related cell states: Using a mouse model of MS, we showed that oligodendroglia enter special “immune‑responsive” states early in disease that can persist long after inflammation, suggesting that these cells develop a type of memory of the disease environment (Zheng & Hervé et al., Nature Neuroscience 2025)

- High‑resolution spatial mapping: we developed a new new spatial multi‑omic method to map, at very high resolution, where myelination changes and immune cell activity occur during demyelination in tissue (Zhang & Kirby et al., Nature 2025).

- Role of MS‑risk genetic variants that act in oligodendroglia: we found a subset of MS‑associated genetic variants located in regions of DNA that are accessible in oligodendroglia. Using CRISPR in human stem‑cell–derived oligodendrocytes, we tested these variants one by one and discovered how they influence the function of human oligodendroglia, namely in cell growth, maturation, and immune interactions. We are continuing these studies performing also CRISPR-editing technologies as prime editing.

- Developing humanized mouse models: we are building mouse models with human immune system in which engineered human oligodendrocytes can be transplanted, allowing direct testing of how specific human genetic variants affect oligodendrocyte behavior.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

In the publication “Spatial dynamics of brain development and neuroinflammation”, we developed a novel spatial multiomics technology, combining protein, RNA and epigenomic information, that allowed us to discover for instance distal activation of microglia upon lesions in the central nervous system. This could suggest that lesions in MS might be able to “propagate” between different regions of the brain, beyond the original lesion site.

The publication “Distinct transcriptomic and epigenomic responses of mature oligodendrocytes during disease progression in a mouse model of multiple sclerosis” unveiled that different populations of oligodendrocytes react differently to the neuroinflammation in a mouse model of MS. This highlights that indeed are much more active players in the disease evolution that previously thought.

The publication “Single-nucleus epigenomic profiling of the adult human central nervous system unveils epigenetic memory of developmental programs” provides the first single cell mapping of 2 histone modifications in the same cell in different regions of the adult human central nervous system, which will be an unique resource both for the scientific community.