MYRF Is a Membrane-Associated Transcription Factor That Autoproteolytically Cleaves to Directly Activate Myelin Genes

The myelinationof axons is a crucial step during vertebrate central nervous system (CNS) development, allowing for rapid and energy efficient saltatory conductionof nerve impulses. Accordingly, the differentiation of oligodendrocytes, the myelinatingcells of the CNS, and their expression of myelingenes are under tight transcriptional control. We previously identified a putative transcription factor, Myelin Regulatory Factor(Myrf), as being vital for CNS myelination. Myrf is required for the generation of CNS myelinationduring development and also for its maintenance in the adult. It has been controversial, however, whether Myrf directly regulates transcription, with reports of a transmembrane domainand lack of nuclear localization. Here we show that Myrf is a membrane-associated transcription factor that undergoes an activating proteolytic cleavage to separate its transmembrane domain-containing C-terminal region from a nuclear-targeted N-terminal region. Unexpectedly, this cleavage event occurs via a protein domainrelated to the autoproteolytic intramolecular chaperone domain of the bacteriophage tail spike proteins, the first time this domain has been found to play a role in eukaryotic proteins. Using ChIP-Seq we show that the N-terminal cleavage product directly binds the enhancer regions of oligodendrocyte-specific and myelingenes. This binding occurs via a defined DNA-binding consensus sequence and strongly promotes the expression of target genes. These findings identify Myrf as a novel example of a membrane-associated transcription factor and provide a direct molecular mechanism for its regulation of oligodendrocytedifferentiation and CNS myelination.