Epigenomic priming of immune genes implicates oligodendroglia in multiple sclerosis susceptibility
Open accessAbstract
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.
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The high accessibility but modest or low RNA expression of Pax6, Sox2 and Myt1l may indicate lineage priming of these genes in embryonic brain development.
“which may indicate lineage priming10,27 of these genes in embryonic brain development.”
From Spatial epigenome–transcriptome co-profiling of mammalian tissues (2023) · cites this paper as [27]
The elevated chromatin accessibility at earlier stages for genes such as Dcx and Tubb3 suggests lineage priming of these genes in expression.
“suggesting lineage priming of these genes in expression10,27.”
From Spatial epigenome–transcriptome co-profiling of mammalian tissues (2023) · cites this paper as [27]
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Factor, D. C., Barbeau, A. M., Allan, K. C., Hu, L. R., Madhavan, M., Hoang, A. T., Hazel, K. E. A., Hall, P. A., Nisraiyya, S., Najm, F. J., et al. (2020) · Cell · doi:10.1016/j.cell.2020.03.002 · Cited by 46 · see citing works
Majumder, P., Scharer, C. D., Choi, N. M., & Boss, J. M. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1303205 · Cited by 27 · see citing works
An accessible database for mouse and human whole transcriptome qPCR primers
Zeisel, A., Yitzhaky, A., Moshe, N. B. B., & Domany, E. (2013) · Bioinformatics · doi:10.1093/bioinformatics/btt145 · Cited by 27 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Morgan Martin, Falcon Seth, and Gentleman Robert (2021). GSEABase: Gene set enrichment data structures and methods. Bioconductor R package version 1.56.0.. 10.18129/B9.bioc.GSEABase. · DOI
Cited by
Sorted by citations
Spatial epigenome–transcriptome co-profiling of mammalian tissues
Zhang, D., Deng, Y., Kukanja, P., Agirre, E., Bartosovic, M., Dong, M., Ma, C., Ma, S., Su, G., Bao, S., et al. (2023) · Nature · doi:10.1038/s41586-023-05795-1 · Cited by 483 · see citing works
Self-citationMultimodal chromatin profiling using nanobody-based single-cell CUT&Tag
Bartosovic, M., & Castelo-Branco, G. (2023) · Nature Biotechnology · doi:10.1038/s41587-022-01535-4 · Cited by 146 · see citing works
Self-citationMyelin insulation as a risk factor for axonal degeneration in autoimmune demyelinating disease
Schäffner, E., Bosch-Queralt, M., Edgar, J. M., Lehning, M., Strauß, J., Fleischer, N., Kungl, T., Wieghofer, P., Berghoff, S. A., Reinert, T., et al. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01366-9 · Cited by 101 · see citing works
- Authors
- Meijer, M., Agirre, E., Kabbe, M., van Tuijn, C. A., Heskol, A., Zheng, C., Mendanha Falcão, A., Bartosovic, M., Kirby, L., Calini, D., Johnson, M. R., Corces, M. R., Montine, T. J., Chen, X., Chang, H. Y., Malhotra, D., & Castelo-Branco, G.
- Affiliations
- Karolinska Institutet (SE)
- F. Hoffmann-La Roche AG (CH)
- Imperial College London (GB)
- Gladstone Institutes (US)
- Stanford Medicine (US)
- Uppsala University (SE)
- Howard Hughes Medical Institute (US)
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2022-04
- Volume
- 110
- Issue
- 7
- Pages
- 1193-1210.e13
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC9810341
- OpenAlex
- W4210632297
- Cited by
- 98
- References
- 85
- Citations by year
- 2026: 18 · 2025: 26 · 2024: 27 · 2023: 17 · 2022: 10
- FWCI
- 13.55
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neuron (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by)
- Uppsala University Publications (Uppsala University) (submittedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- Funders
- China Scholarship Council (201906170058)
- Hjärnfonden (FO2017-0075, FO2018-0162)
- National Institutes of Health (RM1-HG007735, VR-2017-02074)
- European Commission
- European Committee for Treatment and Research in Multiple Sclerosis
- National Institute on Aging (P50 NS062684, K99AG059918, U01AG072573)
- Vetenskapsrådet (2019-01360, 2018-05973)
- European Research Council (681893)
- Svenska Sallskapet for Medicinsk Forskning (JUB2019)
- Science for Life Laboratory
- Cancerfonden (CAN2016/555)
- F. Hoffmann-La Roche
- Karolinska Institutet
- Knut and Alice Wallenberg Foundation (2019-0107, 2019-0089)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- multiple sclerosis, oligodendroglia, oligodendrocyte precursor cells, immune gene regulation, chromatin state, BACH1, STAT1, interferon-gamma, chromatin remodeling, myelin
- MeSH terms
- Animals, Cell Differentiation, Chromatin, Interferon-gamma, Multiple Sclerosis, Myelin Sheath, Oligodendroglia, Mice, Epigenomics
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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