DNA methylation landscape of cerebrospinal fluid cells in multiple sclerosis: an epigenome-wide association study
Year: 2026
Type: article
Study design: Observational Study
Abstract: Background Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system in which DNA methylation may link genetic and environmental risk factors. Methods We profiled genome-wide DNA methylation in cerebrospinal fluid (CSF) cells from people with MS (pwMS) and matched controls. Differentially methylated positions (DMPs) and regions (DMRs) were integrated with transcriptomic data, T-cell chromatin annotations, and pathway analyses. Protocadherin gamma (PCDHγ) expression was assessed in primary CD4+ T-cell subsets and confirmed by flow cytometry. Findings We identified 2710 DMPs and 4330 DMRs associating with genes that were enriched in immune signalling, adhesion and migration processes, and were accompanied by corresponding RNA changes. MS-associated methylation changes enriched in the cohesin chromatin-regulation pathway localised to T-cell regulatory regions, and this pathway included multiple protocadherin ( PCDH ) genes, which displayed consistent methylation and expression changes in CSF cells of pwMS compared to controls. PCDHγ cluster gene expression was detected in CD4 + T-cell subsets, and flow cytometry confirmed PCDHγ protein expression in peripheral blood T cells. Moreover, co-expression analysis suggests a role of PCDH genes in aryl hydrocarbon receptor (AHR) signalling. Protein-level validation showed fewer PCDHγ-positive CD4+ T cells in pwMS and activation-induced PCDHγ upregulation after T-cell stimulation. Interpretation DNA methylation changes in CSF resident cells reflect dysregulated T cell activation and migration in pwMS and suggest involvement of protocadherin molecules in MS pathogenesis. Funding European Research Council, Swedish Research Council, Swedish Brain Foundation, Swedish MS Foundation, Knut and Alice Wallenberg Foundation, European Union and others.
Source: EBioMedicine
Authors: Yanan Han, Galina Yurevna Zheleznyakova, Heng Liang, Chiara Sorini, Majid Pahlevan Kakhki, Nicolas Ruffin, Nils Hallén, Chandana Rao Prakash, Viveca Beckers, Elena Ivanova, Mohsen Khademi, Tomas Olsson, Mikael C.I. Karlsson, Fredrik Piehl, Gavin Kelsey, Lara Kular, Maria Needhamsen, Maja Jagodic
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,780
Funders: European Commission, Svenska Sällskapet för Medicinsk Forskning, Karolinska Institutet, Knut och Alice Wallenbergs Stiftelse, Stockholms Läns Landsting, Vetenskapsrådet, Neuroförbundet, Science for Life Laboratory, Directorate for Biological Sciences, HORIZON EUROPE Framework Programme, Medical Research Council, Biotechnology and Biological Sciences Research Council, Uppsala Multidisciplinary Center for Advanced Computational Science, H2020 European Research Council
Awards: Multiple manifestations of genetic and non-genetic factors in Multiple Sclerosis disentangled with a multi-omics approach to accelerate personalised medicine, G2896939462, Epigenetic responses to dietary change across organismal lifespan, G4632909464, A Systems Approach to Understanding Methylation Programming in Oocytes and its Consequences in Development, G6523014278, Targeting the epigenome: towards a better understanding of disease pathogenesis and novel therapeutic strategies in Multiple Sclerosis, G7598680444, NAISS
OpenAlex ID: W7204481074