RRC ID 55782
Author Elsesser O, Fröb F, Küspert M, Tamm ER, Fujii T, Fukunaga R, Wegner M.
Title Chromatin remodeler Ep400 ensures oligodendrocyte survival and is required for myelination in the vertebrate central nervous system.
Journal Nucleic Acids Res
Abstract Differentiating oligodendrocytes generate myelin to ensure rapid saltatory conduction in the vertebrate central nervous system. Although oligodendroglial differentiation and myelination are accompanied by dramatic chromatin reorganizations, previously studied chromatin remodelers had only limited direct effects on the process. To study the functional significance of chromatin changes for myelination and identify relevant remodelers, we deleted Ep400, the central ATP-hydrolyzing subunit of the TIP60/EP400 complex, at defined times of mouse oligodendrocyte development. Whereas Ep400-deficient oligodendrocyte precursors develop normally, terminal differentiation and myelination are dramatically impaired. Mechanistically, Ep400 interacts with transcription factor Sox10, binds to regulatory regions of the Myrf gene and is required to induce this central transcriptional regulator of the myelination program. In addition to reduced and aberrant myelin formation, oligodendrocytes exhibit increased DNA damage and apoptosis so that numbers never reach wildtype levels during the short lifespan of Ep400-deficient mice. Ep400 deletion in already mature oligodendrocytes remains phenotypically inapparent arguing that Ep400 is dispensable for myelin maintenance. Given its essential function in myelin formation, modulation of Ep400 activity may be beneficial in conditions such as multiple sclerosis where this process is compromised.
Volume 47(12)
Pages 6208-6224
Published 2019-7-9
DOI 10.1093/nar/gkz376
PII 5488534
PMID 31081019
PMC PMC6614847
MeSH Animals Brain / cytology Brain / embryology Brain / growth & development Brain / metabolism Cell Differentiation Cell Survival Cells, Cultured DNA Helicases / genetics DNA Helicases / metabolism DNA Helicases / physiology* DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism DNA-Binding Proteins / physiology* Gene Regulatory Networks HEK293 Cells Humans Mice, Transgenic Myelin Sheath / physiology* Myelin Sheath / ultrastructure Oligodendroglia / cytology* Oligodendroglia / metabolism Rats Rats, Wistar Spinal Cord / cytology* Spinal Cord / embryology Spinal Cord / growth & development Spinal Cord / metabolism
IF 11.147
Times Cited 4
Mice RBRC03987