Ten-eleven translocation (TET) proteins, the dioxygenase for DNA hydroxymethylation, are important players in nervous system development and diseases. However, their role in myelination and remyelination after injury remains elusive. Here, we identify a genome-wide and locus-specific DNA hydroxymethylation landscape shift during differentiation of oligodendrocyte-progenitor cells (OPC). Ablation of Tet1 results in stage-dependent defects in oligodendrocyte (OL) development and myelination in the mouse brain. The mice lacking Tet1 in the oligodendrocyte lineage develop behavioral deficiency. We also show that TET1 is required for remyelination in adulthood. Transcriptomic, genomic occupancy, and 5-hydroxymethylcytosine (5hmC) profiling reveal a critical TET1-regulated epigenetic program for oligodendrocyte differentiation that includes genes associated with myelination, cell division, and calcium transport. Tet1-deficient OPCs exhibit reduced calcium activity, increasing calcium activity rescues the differentiation defects in vitro. Deletion of a TET1-5hmC target gene, Itpr2, impairs the onset of OPC differentiation. Together, our results suggest that stage-specific TET1-mediated epigenetic programming and intracellular signaling are important for proper myelination and remyelination in mice.

DNA methylation is critical for oligodendrocyte development. The role of the converse process, DNA demethylation regulated by Ten-Eleven-Translocation (TET) dioxygenases, in oligodendrocyte homeostasis, myelination and remyelination however remains elusive. Here, we identify a genomewide and locus-specific DNA hydroxymethylation landscape shift during oligodendrocyte progenitor cell (OPC) differentiation. Tet1 ablation results in defects in oligodendrocyte development and myelination in the developing brain, while impairing remyelination after demyelination in adult brains.Transcriptomic and DNA hydroxymethylation analyses reveal a TET1-regulated epigenetic program for oligodendrocyte differentiation and identify a set of target genes associated with Ca 2+ homeostasis. Tet1-deficient OPCs exhibited reduced [Ca 2+ ] oscillations, while activation of calcium channels partially restores the differentiation defect of Tet1-deficient OPCs. Moreover, dysregulated oligodendrocyte homeostasis caused by Tet1-deficiency impairs action potential propagation and synaptic transmission. Thus, our results suggest that stage-specific TET1-mediated epigenetic programming of oligodendrocyte homeostasis is required for proper myelination and repair as well as neuronal physiology in cell-autonomous and non-cell-autonomous mechanisms, respectively.

Myelin is lipid‐rich structure that is necessary to avoid leakage of electric signals and to ensure saltatory impulse conduction along axons. Oligodendrocytes in central nervous system (CNS) and Schwann cells in peripheral nervous system (PNS) are responsible for myelin formation. Axonal demyelination after injury or diseases greatly impairs normal nervous system function. Therefore, understanding how the myelination process is programmed, coordinated, and maintained is crucial for developing therapeutic strategies for remyelination in the nervous system. Epigenetic mechanisms have been recognized as a fundamental contributor in this process. In recent years, histone modification, DNA modification, ATP‐dependent chromatin remodeling, and non‐coding RNA modulation are very active area of investigation. We will present a conceptual framework that integrates crucial epigenetic mechanisms with the regulation of oligodendrocyte and Schwann cell lineage progression during development and myelin degeneration in pathological conditions. It is anticipated that a refined understanding of the molecular basis of myelination will aid in the development of treatment strategies for debilitating disorders that involve demyelination, such as multiple sclerosis in the CNS and neuropathies in the PNS.