TET1-mediated DNA hydroxy-methylation regulates adult remyelination

Abstract

Adult myelination is essential for brain function and response to injury, but the molecular mechanisms remain elusive. Here we identify DNA hydroxy-methylation, an epigenetic mark catalyzed by Ten-Eleven translocation (TET) enzymes, as necessary for adult myelin repair. While DNA hydroxy-methylation and high levels of TET1 are detected in young adult mice during myelin regeneration after demyelination, this process is defective in old mice. Constitutive or inducible lineage-specific ablation of Tet1 (but not of Tet2) recapitulate the age-related decline of DNA hydroxy-methylation and inefficient remyelination. Genome-wide hydroxy-methylation and transcriptomic analysis identify numerous TET1 targets, including several members of the solute carrier (Slc) gene family. Lower transcripts for Slc genes, including Slc12a2, are observed in Tet1 mutants and old mice and are associated with swelling at the neuroglial interface, a phenotype detected also in zebrafish slc12a2b mutants. We conclude that TET1-mediated DNA hydroxy-methylation is necessary for adult remyelination after injury.