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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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Autores principales: Bujalka, Helena, Koenning, Matthias, Jackson, Stacey, Perreau, Victoria M., Pope, Bernard, Hay, Curtis M., Mitew, Stanlislaw, Hill, Andrew F., Lu, Q. Richard, Wegner, Michael, Srinivasan, Rajini, Svaren, John, Willingham, Melanie, Barres, Ben A., Emery, Ben
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3742440/
https://www.ncbi.nlm.nih.gov/pubmed/23966833
http://dx.doi.org/10.1371/journal.pbio.1001625
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author Bujalka, Helena
Koenning, Matthias
Jackson, Stacey
Perreau, Victoria M.
Pope, Bernard
Hay, Curtis M.
Mitew, Stanlislaw
Hill, Andrew F.
Lu, Q. Richard
Wegner, Michael
Srinivasan, Rajini
Svaren, John
Willingham, Melanie
Barres, Ben A.
Emery, Ben
author_facet Bujalka, Helena
Koenning, Matthias
Jackson, Stacey
Perreau, Victoria M.
Pope, Bernard
Hay, Curtis M.
Mitew, Stanlislaw
Hill, Andrew F.
Lu, Q. Richard
Wegner, Michael
Srinivasan, Rajini
Svaren, John
Willingham, Melanie
Barres, Ben A.
Emery, Ben
author_sort Bujalka, Helena
collection PubMed
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.
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spelling pubmed-37424402013-08-21 MYRF Is a Membrane-Associated Transcription Factor That Autoproteolytically Cleaves to Directly Activate Myelin Genes Bujalka, Helena Koenning, Matthias Jackson, Stacey Perreau, Victoria M. Pope, Bernard Hay, Curtis M. Mitew, Stanlislaw Hill, Andrew F. Lu, Q. Richard Wegner, Michael Srinivasan, Rajini Svaren, John Willingham, Melanie Barres, Ben A. Emery, Ben PLoS Biol Research Article 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. Public Library of Science 2013-08-13 /pmc/articles/PMC3742440/ /pubmed/23966833 http://dx.doi.org/10.1371/journal.pbio.1001625 Text en © 2013 Bujalka et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Bujalka, Helena
Koenning, Matthias
Jackson, Stacey
Perreau, Victoria M.
Pope, Bernard
Hay, Curtis M.
Mitew, Stanlislaw
Hill, Andrew F.
Lu, Q. Richard
Wegner, Michael
Srinivasan, Rajini
Svaren, John
Willingham, Melanie
Barres, Ben A.
Emery, Ben
MYRF Is a Membrane-Associated Transcription Factor That Autoproteolytically Cleaves to Directly Activate Myelin Genes
title 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_short 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
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3742440/
https://www.ncbi.nlm.nih.gov/pubmed/23966833
http://dx.doi.org/10.1371/journal.pbio.1001625
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