BEAM-MS - Brain-resident cell Epigenetics Altered by the Metabolome to target Multiple Sclerosis

Multiple Sclerosis (MS) is a major neurological disorder, characterized by the loss of myelin around nerve axons in the central nervous system due to autoimmune attacks.

Oligodendrocyte precursor cells (OPCs) differentiate into myelin-producing oligodendrocytes (OLGs) and MS progression is associated with neurodegeneration due to their incapacity to sufficiently remyelinate after myelin loss. Why remyelination fails is elusive but the inflammation and oxidative stress may contribute to OLG exhaustion.

As OLGs differentiate to myelinate, metabolites and regulatory enzymes are simultaneously required for anabolic processes but also in the nucleus to orchestrate epigenetic remodeling via post-translational modifications (PTMs) at histones.

How relocation of metabolites and enzymes between subcellular compartments is regulated and contribute to OLG exhaustion is poorly understood.

In BEAM-MS I will address this by applying leading edge-technologies including nanoCut&Tag and Prime editing for epigenetic profiling and genomic engineering to address 1) the role of lactate in epigenetic remodeling 2) single-cell CRISPR screens targeting metabolic enzymes and 3) study temporal dynamics from metabolic enzymes upon ontogenetically induced nuclear translocation.

This will be carried out in human induced pluripotent stem cells (iPSC)-derived OLGs and animal models mimicking MS. BEAM-MS strive to generate invaluable knowledge contributing to advancement of MS diagnosis and therapies.