TET1-DNA Hydroxymethylation Mediated Oligodendrocyte Homeostasis is Required for CNS Myelination and Remyelination

Abstract Ten-eleven translocation (TET) proteins, encoding dioxygenase for DNA hydroxymethylation, are important players in nervous system development and diseases. However, their role in oligodendrocyte homeostasis, myelination and remyelination remains elusive. Here, we detected a genome-wide and locus-specific DNA hydroxymethylation landscape shift during oligodendrocyte-progenitor (OPC) differentiation. Ablation of Tet1, but not Tet3, results in stage-dependent defects in oligodendrocyte development and myelination in the brain. The mice lacking Tet1 in the oligodendrocyte lineage develop schizophrenia-like behaviors. We further show that TET1 is also required for proper remyelination after demyelination injury in the adult mice. Transcriptomic and DNA hydroxymethylation profiling revealed a critical TET1-regulated epigenetic program for oligodendrocyte differentiation and identified a set of TET1-5hmC target genes associated with myelination, cell division, and calcium transport. Tet1-deficient OPCs exhibited reduced calcium activity in response to stimulus in culture. Moreover, deletion of a TET1-5hmC target gene, Itpr2, an oligodendrocyte-enriched intracellular calcium-release channel, significantly impaired the onset of oligodendrocyte differentiation. Together, our results suggest that stage-specific TET1-mediated epigenetic programming and oligodendrocyte homeostasis is required for proper myelination and repair.