TET1-mediated DNA hydroxymethylation regulates adult remyelination in mice

Nat Commun. 2021 Jun 7;12(1):3359. doi: 10.1038/s41467-021-23735-3.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Cells, Cultured
  • DNA Methylation*
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Gene Expression Profiling / methods*
  • Mice, Knockout
  • Mice, Transgenic
  • Mutation
  • Myelin Sheath / genetics*
  • Myelin Sheath / metabolism
  • Oligodendroglia / cytology
  • Oligodendroglia / metabolism
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • RNA-Seq / methods
  • Remyelination / genetics*
  • Solute Carrier Family 12, Member 2 / genetics
  • Solute Carrier Family 12, Member 2 / metabolism
  • Zebrafish / genetics


  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • Solute Carrier Family 12, Member 2
  • TET1 protein, mouse