DNA methylation changes in glial cells of the normal-appearing white matter in Multiple Sclerosis patients

Lara Kular, Ewoud Ewing, Maria Needhamsen, Majid Pahlevan Kakhki, Ruxandra Covacu, David Gomez-Cabrero, Lou Brundin, Maja Jagodic

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Multiple Sclerosis (MS), the leading cause of non-traumatic neurological disability in young adults, is a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS). Due to the poor accessibility to the target organ, CNS-confined processes underpinning the later progressive form of MS remain elusive thereby limiting treatment options. We aimed to examine DNA methylation, a stable epigenetic mark of genome activity, in glial cells to capture relevant molecular changes underlying MS neuropathology. We profiled DNA methylation in nuclei of non-neuronal cells, isolated from 38 post-mortem normal-appearing white matter (NAWM) specimens of MS patients (n = 8) in comparison to white matter of control individuals (n = 14), using Infinium MethylationEPIC BeadChip. We identified 1,226 significant (genome-wide adjusted P-value < 0.05) differentially methylated positions (DMPs) between MS patients and controls. Functional annotation of the altered DMP-genes uncovered alterations of processes related to cellular motility, cytoskeleton dynamics, metabolic processes, synaptic support, neuroinflammation and signaling, such as Wnt and TGF-β pathways. A fraction of the affected genes displayed transcriptional differences in the brain of MS patients, as reported by publically available transcriptomic data. Cell type-restricted annotation of DMP-genes attributed alterations of cytoskeleton rearrangement and extracellular matrix remodelling to all glial cell types, while some processes, including ion transport, Wnt/TGF-β signaling and immune processes were more specifically linked to oligodendrocytes, astrocytes and microglial cells, respectively. Our findings strongly suggest that NAWM glial cells are highly altered, even in the absence of lesional insult, collectively exhibiting a multicellular reaction in response to diffuse inflammation.
Original languageEnglish (US)
Pages (from-to)1-20
Number of pages20
JournalEpigenetics
DOIs
StatePublished - Jan 30 2022

Bibliographical note

KAUST Repository Item: Exported on 2022-02-01
Acknowledgements: We are grateful to A. van Vollenhoven for flow cytometry processing (Center for Molecular Medicine core facility). We acknowledge GenomeScan/ServiceXS (Leiden, The Netherlands) for processing Illumina EPIC arrays. We thank the Multiple Sclerosis and Parkinson’s Tissue Bank (Imperial College London) for provision of brain tissue samples. Computations were performed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX).

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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