Oligodendrocyte Gene Changes Evident Near MS Risk Mutations

Changes in the genome of oligodendrocytes were found in DNA regions associated with immune genes and risk mutations linked to multiple sclerosis (MS), a study shows.

The changes identified make it possible for these immune genes and MS-associated regions to have an altered expression — meaning being “on” or “off” when they normally wouldn’t be.

“Our findings suggest that the risk for multiple sclerosis might manifest by misfunction not only of immune cells, but also of oligodendrocytes and their precursor cells,” Gonçalo Castelo-Branco, PhD, a professor of medical biochemistry and biophysics at the Karolinska Institutet in Sweden and the study’s principal investigator, said in a university press release.

The study, “Epigenomic priming of immune genes implicates oligodendroglia in multiple sclerosis susceptibility,” was published in Neuron. 

MS is characterized by an autoimmune attack on oligodendrocytes, the cells responsible for forming the myelin sheath that surrounds and protects nerve cells.

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An international team led by researchers at the Karolinska Institutet now investigated how changes to oligodendrocyte DNA might underlie disease mechanisms in MS.

Chromatin accessibility indicates parts of DNA that are available for transcription factors to bind. When this happens, genes in the area can be turned on or off and their expression, or activity, level modulated.

Using a mouse model of MS, that researchers found areas of oligodendrocyte DNA with high levels of chromatin accessibility at the peak of disease progression. These regions were near genes related to the immune system.

In other words, because of increased chromatin accessibility, some immune system-related genes may be susceptible to expression changes.

These findings “indicate that [chromatin accessibility] changes in [MS-oligodendrocyte] populations are related to immune pathways,” the researchers wrote.

Similar results were observed when healthy mouse oligodendrocyte progenitor cells (OPCs), the precursors to mature oligodendrocytes, were treated with interferon-gamma (IFN-gamma) — a protein known to induce an inflammatory response.

Some DNA regions had equal amounts of chromatin accessibility in experimental and control groups, but a few genes had altered chromatin accessibility under inflammatory conditions, be it upon IFN-gamma exposure to cells in a culture (ex vivo) or in living mice of the MS model (in vivo).

According to the researchers, this suggests that some regions of DNA related to the immune system in oligodendrocytes are primed with high chromatin accessibility even before disease or inflammatory insult, making them even more susceptible to gene changes after disease onset.

“Our data indicate that OPCs already exhibit primed [chromatin accessibility] in a large subset of immune genes, prior to inflammatory insults both ex vivo and in vivo,” the researchers wrote.

While chromatin accessibility makes gene expression changes more likely, other factors appear to be involved in activating these genes after disease onset.

Further analysis revealed that activity at methylation sites in these areas — methylation is a process which allows genes to be either turned on or off under different circumstances — could also be involved.

The team also found that two specific transcription factors influenced gene expression in inflammatory conditions. Specifically, BACH1 lower the activation while STAT1 increased the activation of some immune genes after OPCs were exposed to IFN-gamma.

“Thus, our data indicate that [transcription factors such as] BACH1 and STAT1 participate in the regulation of IFN-[gamma]-induced immune gene expression in OPCs,” the researchers wrote.

They then analyzed healthy human brain tissue and found areas of higher chromatin accessibility near immune genes in oligodendrocytes, similar to that observed in mice.

Previously, mutations associated with MS susceptibility were identified near immune genes as well. Now, the researchers found that regions of chromatin accessibility in mouse and human oligodendrocytes overlap with these MS susceptibility sites.

Taken together, these data suggest that MS risk mutations can affect the expression of nearby immune genes, which could underly oligodendrocyte dysfunction in MS, the researchers stated.

“Our data suggest that these [mutations] might be involved in the modulation of regulatory regions in OLG [oligodendrocytes], leading to … altered function of OLG in the context of MS,” they wrote, adding that “susceptibility for MS might lead to disease onset, progression, or remission by the activation of abnormal immune and non-immune … programs not only in immune cells but also in OLG.”

“These findings indicate that these cells can also be targeted for therapeutical approaches for MS, to prevent misfunction that might be caused by these mutations,” Castelo-Branco said.

This work’s overall findings may also be applicable to other disease states, the researchers noted.

“The expression of immune genes in [oligodendrocytes] in the context of MS adds new roles to [their] functional portfolio … which might also occur in Alzheimer’s disease (AD) and in aging,” the team wrote.