TET1-mediated DNA hydroxymethylation regulates adult remyelination in mice

Sarah Moyon (), Rebecca Frawley, Damien Marechal, Dennis Huang, Katy L. H. Marshall-Phelps, Linde Kegel, Sunniva M. K. Bøstrand, Boguslawa Sadowski, Yong-Hui Jiang, David A. Lyons, Wiebke Möbius and Patrizia Casaccia ()
Additional contact information
Sarah Moyon: Neuroscience Initiative Advanced Science Research Center
Rebecca Frawley: Neuroscience Initiative Advanced Science Research Center
Damien Marechal: Neuroscience Initiative Advanced Science Research Center
Dennis Huang: Neuroscience Initiative Advanced Science Research Center
Katy L. H. Marshall-Phelps: Centre for Discovery Brain Sciences
Linde Kegel: Centre for Discovery Brain Sciences
Sunniva M. K. Bøstrand: Centre for Discovery Brain Sciences
Boguslawa Sadowski: Department of Neurogenetics
Yong-Hui Jiang: Duke University School of Medicine
David A. Lyons: Centre for Discovery Brain Sciences
Wiebke Möbius: Department of Neurogenetics
Patrizia Casaccia: Neuroscience Initiative Advanced Science Research Center

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23735-3

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