MYRF is a membrane-associated transcription factor that autoproteolytically cleaves to directly activate myelin genes.
The myelination of axons is a crucial step during vertebrate central nervous system (CNS) development, allowing for rapid and energy efficient saltatory conduction of nerve impulses. Accordingly, the differentiation of oligodendrocytes, the myelinating cells of the CNS, and their expression of myeli...
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2013
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oai:doaj.org-article:946c16919be64298bd55ab4d3e4a051d2021-11-18T05:37:53ZMYRF is a membrane-associated transcription factor that autoproteolytically cleaves to directly activate myelin genes.1544-91731545-788510.1371/journal.pbio.1001625https://doaj.org/article/946c16919be64298bd55ab4d3e4a051d2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23966833/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885The myelination of axons is a crucial step during vertebrate central nervous system (CNS) development, allowing for rapid and energy efficient saltatory conduction of nerve impulses. Accordingly, the differentiation of oligodendrocytes, the myelinating cells of the CNS, and their expression of myelin genes 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 myelination during development and also for its maintenance in the adult. It has been controversial, however, whether Myrf directly regulates transcription, with reports of a transmembrane domain and 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 domain related 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 myelin genes. 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 oligodendrocyte differentiation and CNS myelination.Helena BujalkaMatthias KoenningStacey JacksonVictoria M PerreauBernard PopeCurtis M HayStanlislaw MitewAndrew F HillQ Richard LuMichael WegnerRajini SrinivasanJohn SvarenMelanie WillinghamBen A BarresBen EmeryPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 11, Iss 8, p e1001625 (2013) |
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DOAJ |
| collection |
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| language |
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| topic |
Biology (General) QH301-705.5 |
| spellingShingle |
Biology (General) QH301-705.5 Helena Bujalka Matthias Koenning Stacey Jackson Victoria M Perreau Bernard Pope Curtis M Hay Stanlislaw Mitew Andrew F Hill Q Richard Lu Michael Wegner Rajini Srinivasan John Svaren Melanie Willingham Ben A Barres Ben Emery MYRF is a membrane-associated transcription factor that autoproteolytically cleaves to directly activate myelin genes. |
| description |
The myelination of axons is a crucial step during vertebrate central nervous system (CNS) development, allowing for rapid and energy efficient saltatory conduction of nerve impulses. Accordingly, the differentiation of oligodendrocytes, the myelinating cells of the CNS, and their expression of myelin genes 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 myelination during development and also for its maintenance in the adult. It has been controversial, however, whether Myrf directly regulates transcription, with reports of a transmembrane domain and 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 domain related 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 myelin genes. 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 oligodendrocyte differentiation and CNS myelination. |
| format |
article |
| author |
Helena Bujalka Matthias Koenning Stacey Jackson Victoria M Perreau Bernard Pope Curtis M Hay Stanlislaw Mitew Andrew F Hill Q Richard Lu Michael Wegner Rajini Srinivasan John Svaren Melanie Willingham Ben A Barres Ben Emery |
| author_facet |
Helena Bujalka Matthias Koenning Stacey Jackson Victoria M Perreau Bernard Pope Curtis M Hay Stanlislaw Mitew Andrew F Hill Q Richard Lu Michael Wegner Rajini Srinivasan John Svaren Melanie Willingham Ben A Barres Ben Emery |
| author_sort |
Helena Bujalka |
| title |
MYRF is a membrane-associated transcription factor that autoproteolytically cleaves to directly activate myelin genes. |
| title_short |
MYRF is a membrane-associated transcription factor that autoproteolytically cleaves to directly activate myelin genes. |
| title_full |
MYRF is a membrane-associated transcription factor that autoproteolytically cleaves to directly activate myelin genes. |
| title_fullStr |
MYRF is a membrane-associated transcription factor that autoproteolytically cleaves to directly activate myelin genes. |
| title_full_unstemmed |
MYRF is a membrane-associated transcription factor that autoproteolytically cleaves to directly activate myelin genes. |
| title_sort |
myrf is a membrane-associated transcription factor that autoproteolytically cleaves to directly activate myelin genes. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/946c16919be64298bd55ab4d3e4a051d |
| work_keys_str_mv |
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