Age-dependent decline of TET1-mediated DNA hydroxy-methylation impairs myelin regeneration after injury

Adult myelination is recognized as essential for brain function and response to injury and yet, its molecular understanding is mostly inferred from developmental studies. In this study, we identify DNA hydroxy-methylation, an epigenetic mark catalyzed by Ten-Eleven translocation (TET) enzymes, as necessary for adult, but not for developmental, myelin formation. While hydroxy-methylation and high levels of TET1 were detected in young adult mice during myelin regeneration after lysolecithin-induced demyelination, this process was defective in older mice. Lineage specific ablation of the enzyme Tet1 (but not of Tet2) recapitulated the age-related decline of TET1 and inefficient remyelination, without impacting developmental myelination. Genome-wide DNA hydroxy-methylation profiling of adult progenitors and mature oligodendrocytes, identified solute carriers regulating neuronal-glial communication as gene targets, whose expression was dramatically decreased in mutants and in older mice. We conclude that TET1-mediated hydroxy-methylation is critical for adult myelination in response to injury. Overall design: Transcriptomic profiles and DNA hydroxymethylation whole-genome profiles of FAC-sorted P60 Pdgfra-EGFP and P60 Plp-EGFP purified cell samples from mouse brains were generated by RNA-Sequencing and Reduced Representation Hydroxymethylation Profiling (RRHP), respectively (in triplicates).