From methylation to myelination: epigenomic and transcriptomic profiling of chronic inactive demyelinated multiple sclerosis lesions

• DOI: 10.1007/s00401-023-02596-8
• Publication Date: 2023-06-07T17:01:46Z
• Authors: Assia Tiane; Melissa Schepers; Rick A. Reijnders; Lieve van Veggel; Sarah Chenine; Ben Rombaut; Emma Dempster; Catherine Verfaillie; Kobi Wasner; Anne Grünewald; Jos Prickaerts; Ehsan Pishva; Niels Hellings; Daniel van den Hove; Tim Vanmierlo
• Keywords: Epigenomics

In the progressive phase of multiple sclerosis (MS), hampered differentiation capacity oligodendrocyte precursor cells (OPCs) eventually results in remyelination failure. We have previously shown that DNA methylation Id2/Id4 is highly involved OPC and remyelination. this study, we took an unbiased approach by determining genome-wide patterns within chronically demyelinated MS lesions investigated how certain epigenetic signatures relate to capacity. compared transcriptional profiles between matched normal-appearing white matter (NAWM), making use post-mortem brain tissue (n = 9/group). differences inversely correlated with mRNA expression their corresponding genes were validated for cell-type specificity laser-captured OPCs using pyrosequencing. The CRISPR-dCas9-DNMT3a/TET1 system was used epigenetically edit human-iPSC-derived oligodendrocytes assess effect on cellular differentiation. Our data show hypermethylation CpGs cluster gene ontologies related myelination axon ensheathment. Cell type-specific validation indicates a region-dependent MBP, encoding myelin basic protein, obtained from NAWM-derived OPCs. By altering state specific promotor region editing, can be bidirectionally manipulated vitro. indicate acquire inhibitory phenotype, which translates into crucial myelination-related genes. Altering status MBP restore possibly boost (re)myelination.