Distinct transcriptomic and epigenomic responses of mature oligodendrocytes during disease progression in a mouse model of multiple sclerosis

“Distinct transcriptomic and epigenomic responses of mature oligodendrocytes during disease progression in a mouse model of multiple sclerosis.”

Chao Zheng, et al. – Karolinska Institute.

While expression of MHC genes is low in astrocytes under control conditions, the chromatin for these genes is modestly to highly open, suggesting a moderate readiness to induce signaling. Chromatin for these genes remains highly open late in EAE, even after their expression is reduced, indicating a more robust priming for inflammatory signaling.

Background: Oligodendrocytes (OLs) take on immune-like phenotypes in MS, expressing major histocompatibility complex (MHC) proteins capable of presenting antigens to T cells. Identifying when this phenotypic switch occurs is essential for understanding the phase(s) of the disease in which immune-like OLs participate, as well as determining whether these OLs remain in an immune-like state once a relapse concludes.

This Study: Zhang and colleagues used ATAC-Seq and RNA-Seq in mice following induction with experimental autoimmune encephalitis (EAE) to determine which regions of the genome in mature OLs (MOLs) are open for transcription and being actively transcribed, respectively, during the early (day 8-9), peak (day 14-15), and late (day 37-40) phases of EAE.

Changes to gene accessibility and transcription began during the early phase of EAE, and while most MOLs returned to a homeostatic phenotype during the late phase, a minority retained phenotypes similar to those found during the disease peak.
Prior work from this group identified several MOL clusters. MOL2 appears to be the predominant driver of immune-like responses due to the most intense expression of immune genes, with the most intense expression at the disease peak; nonetheless, accessibility and expression of these genes began to appear during the early phase.
In contrast, MOL5/6 cells appear to have greater regenerative potential, showing greater accessibility of an enhancer that positively regulates expression of Hoxb genes, which are involved in OL patterning and thus potentially repair and remyelination.
Chromatin accessibility appears to be more dynamic in MOL2 than MOL5/6. Loci in MOL2 showed greatest accessibility at early, peak, or late disease stages, or in naïve controls, whereas dynamic MOL5/6 loci only reached their maxima during peak and late stages.

Open Question: Do MOLs that remain in an immune-like state contribute to worsening symptoms in subsequent relapses?

Bottom Line: Immune-like transitions for MOLs occur early in the disease process, with some persisting in this state after relapses conclude. Therapeutics should limit the immune responses of MOL2 cells and maximize the regenerative potential of MOL5/6 cells.