Elsesser, Olga and Froeb, Franziska and Kuespert, Melanie and Tamm, Ernst R. and Fujii, Toshihiro and Fukunaga, Rikiro and Wegner, Michael (2019) Chromatin remodeler Ep400 ensures oligodendrocyte survival and is required for myelination in the vertebrate central nervous system. NUCLEIC ACIDS RESEARCH, 47 (12). pp. 6208-6224. ISSN 0305-1048, 1362-4962
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | GENE REGULATORY FACTOR; CNS MYELINATION; SPINAL-CORD; SOX10; EXCHANGE; IDENTIFICATION; TRANSCRIPTION; MAINTENANCE; DISRUPTION; ENHANCERS; |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Anatomie Biology, Preclinical Medicine > Institut für Anatomie > Lehrstuhl für Humananatomie und Embryologie Biology, Preclinical Medicine > Institut für Anatomie > Lehrstuhl für Humananatomie und Embryologie > Prof. Dr. Ernst Tamm |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 03 Apr 2020 06:04 |
| Last Modified: | 03 Apr 2020 06:04 |
| URI: | https://pred.uni-regensburg.de/id/eprint/26645 |
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