Cited by 272Neurogenesis and neuroplasticity mechanismsGenomics and Chromatin DynamicsMultiple Sclerosis Research Studies

MYRF is a membrane-associated transcription factor that autoproteolytically cleaves to directly activate myelin genes

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Bujalka, Helena, Koenning, Matthias, Jackson, Stacey, Perreau, Victoria M., Pope, Bernard, Hay, Curtis M., Mitew, Stanlislaw, Hill, Andrew F. +7 more·2013·PLoS Biology

Abstract

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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Crossref · 10.1371/journal.pbio.1001625

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  • The proximal 300 bp human MAG promoter fragment contains evolutionarily conserved binding sites for MRF and RNF10.

    “Finally, we also selected the proximal 300 bp fragment for further characterization as it contains evolutionary conserved binding sites for myelin gene regulatory factor (MRF) and Ring Finger Protein 10 (RNF10), critical activators of myelination in oligodendrocytes or Schwann cells, respectively (Hoshikawa et al., 2008; Emery et al., 2009; Bujalka et al., 2013).”

    From Recombinant Human Myelin-Associated Glycoprotein Promoter Drives Selective AAV-Mediated Transgene Expression in Oligodendrocytes (2016) · cites this paper as Bujalka et al., 2013

    The Results section, “MYRF Binds DNA Via a Defined Consensus Sequence” (page not provided), identifies a MYRF-binding motif near Mag and reports that mutating it abolished MYRF-dependent reporter activity. The cited passages do not establish that this site lies within the proximal 300 bp of the human MAG promoter, that it is evolutionarily conserved, or that the fragment contains an RNF10-binding site. (LLM, conf=0.88)

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  • This transition was accompanied by reduced activity of myelin-associated gene networks and diminished regulon activity of key transcriptional regulators, including MYRF and NKX6-2, which serve as central regulators of myelin gene expression programs.

    “This transition was accompanied by reduced activity of myelin-associated gene networks and diminished regulon activity of key transcriptional regulators, including MYRF and NKX6-2, which serve as central regulators of myelin gene expression programs (53-55) (Fig. 5J).”

    From Molecular and cellular processes disrupted in the early postnatal Down syndrome prefrontal cortex (2026) · cites this paper as [53]

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  • There is an early upregulation of a gamma-secretase component (NCSTN), the transcription factor MYRF, and a structural component of myelin (PLLP).

    “Additionally, there is an early upregulation of a gamma-secretase component (NCSTN), the transcription factor MYRF, which regulates myelination76, and a structural component of myelin itself (PLLP) (Fig. 7e, left, and Fig. 7g).”

    From Integrated multimodal cell atlas of Alzheimer’s disease (2024) · cites this paper as [76]

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Authors
Bujalka, H., Koenning, M., Jackson, S., Perreau, V. M., Pope, B., Hay, C. M., Mitew, S., Hill, A. F., Lu, Q. R., Wegner, M., Srinivasan, R., Svaren, J., Willingham, M., Barres, B. A., & Emery, B.
Affiliations
  • The University of Melbourne (AU)
  • Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
  • University of Wisconsin–Madison (US)
  • Stanford University (US)
Corresponding author
Emery, Ben
Venue
PLoS Biology
Published
2013-08-13
Volume
11
Issue
8
Pages
e1001625
ISSN
  • 1544-9173 (ISSN-L)
  • 1545-7885
OpenAlex
W2085442517
Cited by
271
References
60
Citations by year
2026: 18 · 2025: 20 · 2024: 24 · 2023: 23 · 2022: 24 · 2021: 26 · 2020: 19 · 2019: 26 · 2018: 23 · 2017: 22 · 2016: 11 · 2015: 17 · 2014: 7 · 2013: 7 · 2012: 4
FWCI
5.19
Type
journal article
Language
en
Open access
Locations
  • PLoS Biology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by)
  • Victoria University Research Repository (Victoria University) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
  • OPUS FAU (Kooperativer Bibliotheksverbund Berlin-Brandenburg (KOBV), on behalf of the Universitätsbibliothek Erlangen-Nürnberg) (submittedVersion, other-oa)
Funders
  • Myelin Repair Foundation
  • Multiple Sclerosis Australia
  • Trish Multiple Sclerosis Research Foundation
  • National Institutes of Health (NIH-R01)
  • Medical Research Council
  • National Health and Medical Research Council (1009095)
  • National Eye Institute (R01EY010257, R01 EY10257)
  • National Institute of Neurological Disorders and Stroke (R01NS075243, R01NS078092)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD003352)
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
Keywords
MYRF, autoproteolytic cleavage, oligodendrocyte differentiation, CNS myelination, enhancer binding, nuclear localization
MeSH terms
Animals, Cell Line, Cells, Cultured, Gene Expression Regulation, Humans, Membrane Proteins, Myelin Sheath, Oligodendroglia, Transcription Factors, Mutagenesis, Site-Directed, Chromatin Immunoprecipitation, Mice

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