Summary: Oligodendrocytes may play a different role in the development and progression of multiple sclerosis than previously thought.
Source: Karolinska Institute
An international team of researchers led by Karolinska Institutet in Sweden reports that cells in the central nervous system known as oligodendrocytes might have a different role in the development of multiple sclerosis (MS) than previously thought.
The findings, published in the journal Neuron, could open for new therapeutical approaches to MS.
MS is driven by immune cells attacking oligodendrocytes and the myelin they produce. Myelin is an insulating sheath around 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.
Open configuration of the genome
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.
“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 Gonçalo Castelo-Branco, professor at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet, who conducted the study with co-first authors Mandy Meijer, a Ph.D. student, and Eneritz Agirre, a researcher.
“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.”
About this multiple sclerosis research news
Author: Press Office
Source: Karolinska Institute
Contact: Press Office – Karolinska Institute
Image: The image is in the public domain
Original Research: Open access.
“Epigenomic priming of immune genes implicates oligodendroglia in multiple sclerosis susceptibility” by Branco Castelo et al. Neuron
Epigenomic priming of immune genes implicates oligodendroglia in multiple sclerosis susceptibility
- Chromatin priming of immune genes in OLG in homeostasis and disease
- BACH1, STAT1, and Polycomb involved in IFN-γ-mediated immune gene regulation in OPCs
- MS susceptibility SNPs overlap with open chromatin regions in OLG
- IFN-γ leads to altered chromatin and gene expression at SNP loci in mouse OPCs
Multiple sclerosis (MS) is characterized by a targeted attack on oligodendroglia (OLG) and myelin by immune cells, which are thought to be the main drivers of MS susceptibility. We 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.
We 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.
Thus, the susceptibility for MS may involve OLG, which therefore constitutes novel targets for immunological-based therapies for MS.