TET1-mediated DNA hydroxymethylation regulates adult remyelination in mice

authors

• Moyon Sarah
• Frawley Rebecca
• Marechal Damien
• Huang Dennis
• Marshall-Phelps Katy L H
• Kegel Linde
• Bøstrand Sunniva M K
• Sadowski Boguslawa
• Jiang Yong-Hui
• Lyons David A
• Möbius Wiebke
• Casaccia Patrizia

keywords

• DNA methylation
• Molecular neuroscience
• Myelin biology and repair
• Oligodendrocyte

abstract

The mechanisms regulating myelin repair in the adult central nervous system (CNS) are unclear. Here, we identify DNA hydroxymethylation, catalyzed by the Ten-Eleven-Translocation (TET) enzyme TET1, as necessary for myelin repair in young adults and defective in old mice. Constitutive and inducible oligodendrocyte lineage-specific ablation of Tet1 (but not of Tet2 ), recapitulate this age-related decline in repair of demyelinated lesions. DNA hydroxymethylation and transcriptomic analyses identify TET1-target in adult oligodendrocytes, as genes regulating neuro-glial communication, including the solute carrier ( Slc ) gene family. Among them, we show that the expression levels of the Na + /K + /Cl − transporter, SLC12A2, are higher in Tet1 overexpressing cells and lower in old or Tet1 knockout. Both aged mice and Tet1 mutants also present inefficient myelin repair and axo-myelinic swellings. Zebrafish mutants for slc12a2b also display swellings of CNS myelinated axons. Our findings suggest that TET1 is required for adult myelin repair and regulation of the axon-myelin interface.

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