TET1-mediated DNA hydroxy-methylation regulates adult remyelination

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 were detected in young adult mice during myelin regeneration after demyelination, this process was defective in old mice. Constitutive or inducible lineage-specific ablation of Tet1 (but not of Tet2) recapitulated the age-related decline of DNA hydroxy-methylation and inefficient remyelination. Genome-wide hydroxy-methylation and transcriptomic analysis identified solute carrier gene families as TET1 targets. Lower transcripts for these genes in Tet1 mutants and old mice were 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 myelination after injury, by modulating the levels of the solute carrier SLC12A2 at the axo-myelin interface. mRNA profiles of oligodendroglial-enriched samples from P60 control (Olig1+/+;Tet1fl/fl) and Tet1 mutants (Olig1cre/+;Tet1fl/fl), from either unlesioned spinal cord or 4-day-post-lysolecithin-injection lesions. Samples generated by RNA-sequencing, in triplicate, using Illumina HiSeq 4000.