Epigenomic priming of immune genes implicates oligodendroglia in multiple sclerosis susceptibility


MS is driven by immune cells attacking oligodendrocytes and the myelin they produce, which is an insulating layer ensheathing nerve cells. These attacks disrupt information flow in the brain and spinal cord and causes nerve damage that triggers symptoms associated with MS such as tremors and loss of gait.

Understanding which mechanisms influence the risk of MS is central to finding effective therapies. Previous genetic studies have found regions in the human genome that contain mutations (single nucleotide polymorphisms) associated with increased risk of MS. Many of these regions are localized near genes that are active in immune cells.

In this study, the researchers show in mice and human brain samples that oligodendrocytes and their progenitors have an open configuration of the genome near immune genes and at MS-risk associated regions. This suggests that the MS risk mutations may have a role in the activation of nearby genes in oligodendrocytes and their progenitors, meaning they could play a more important part than previously thought in the development of MS.

The researchers found that immune genes exhibit a primed chromatin state in single mouse and human OLG in a non-disease context, compatible with transitions to immune-competent states in MS. They identified BACH1 and STAT1 as transcription factors involved in immune gene regulation in oligodendrocyte precursor cells (OPCs).

A subset of immune genes presents bivalency of H3K4me3/H3K27me3 in OPCs, with Polycomb inhibition leading to their increased activation upon interferon gamma (IFN-γ) treatment. Some MS susceptibility single-nucleotide polymorphisms (SNPs) overlap with these regulatory regions in mouse and human OLG. Treatment of mouse OPCs with IFN-γ leads to chromatin architecture remodeling at these loci and altered expression of interacting genes.

“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,” says one of the co-first authors. “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.”

https://www.cell.com/neuron/fulltext/S0896-6273(21)01089-8

http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fepigenomic-priming-of&filter=22

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