TET1-mediated DNA hydroxymethylation regulates adult remyelination in mice

2021 | journal article

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​TET1-mediated DNA hydroxymethylation regulates adult remyelination in mice​
Moyon, S.; Frawley, R.; Marechal, D.; Huang, D.; Marshall-Phelps, K. L. H.; Kegel, L. & Bøstrand, S. M. K. et al.​ (2021) 
Nature Communications12(1) art. 3359​.​ DOI: https://doi.org/10.1038/s41467-021-23735-3 

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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.; Casaccia, Patrizia
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.
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.
Issue Date
2021
Journal
Nature Communications 
eISSN
2041-1723
Language
English

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