Chromatin remodeler Ep400 ensures oligodendrocyte survival and is required for myelination in the vertebrate central nervous system.

Chromatin remodeler Ep400 ensures oligodendrocyte survival and is required for myelination in the vertebrate central nervous system.

Publication date: May 13, 2019

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.

Elsesser, O., Fr”ob, F., K”uspert, M., Tamm, E.R., Fujii, T., Fukunaga, R., and Wegner, M. Chromatin remodeler Ep400 ensures oligodendrocyte survival and is required for myelination in the vertebrate central nervous system. 17988. 2019 Nucleic Acids Res.

Concepts Keywords
Apoptosis Apoptosis
ATP Oligodendrocyte progenitor cell
Central Nervous System Schwann cell
Chromatin Chromatin
Chromatin Remodelers Oligodendrocyte
Mice Myelin
Modulation Glial cells
Multiple Sclerosis Branches of biology
Myelin
Myelination
Nucleic
Oligodendrocyte
Oligodendrocytes
Phenotypically
Regulatory Regions
Transcription Factor
Transcriptional Regulator
Vertebrate
Wildtype

Semantics

Type Source Name
disease DOID multiple sclerosis
disease MESH multiple sclerosis
pathway BSID Apoptosis
disease MESH DNA damage
gene UNIPROT MYRF
gene UNIPROT SOX10
gene UNIPROT KAT5
gene UNIPROT ATP8A2
drug DRUGBANK ATP
gene UNIPROT EP400

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