title: MYRF is a membrane-associated transcription factor that autoproteolytically cleaves to directly activate myelin genes.
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.
authors: Department of Anatomy and Neuroscience and the Centre for Neuroscience Research, University of Melbourne, Parkville, Australia.
authors: Helena
authors: H
authors: Bujalka
authors: Matthias
authors: M
authors: Koenning
authors: Stacey
authors: S
authors: Jackson
authors: Victoria M
authors: VM
authors: Perreau
authors: Bernard
authors: B
authors: Pope
authors: Curtis M
authors: CM
authors: Hay
authors: Stanlislaw
authors: S
authors: Mitew
authors: Andrew F
authors: AF
authors: Hill
authors: Q Richard
authors: QR
authors: Lu
authors: Michael
authors: M
authors: Wegner
authors: Rajini
authors: R
authors: Srinivasan
authors: John
authors: J
authors: Svaren
authors: Melanie
authors: M
authors: Willingham
authors: Ben A
authors: BA
authors: Barres
authors: Ben
authors: B
authors: Emery
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009186:Myelin Sheath / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D014157:Transcription Factors
references: Bioinformatics. 2011 Jun 15;27(12):1696-7
references: 21486936
references: Skelet Muscle. 2013 Apr 08;3(1):8
references: 23566431
references: Genes Dev. 2002 Jan 15;16(2):165-70
references: 11799060
references: Nucleic Acids Res. 2004 Jan 1;32(Database issue):D493-6
references: 14681465
references: Bioinformatics. 2009 Feb 15;25(4):555-6
references: 19129209
references: Cell. 2002 Apr 5;109(1):61-73
references: 11955447
references: Cell. 2002 Apr 5;109(1):75-86
references: 11955448
references: J Neurosci Res. 1992 Jan;31(1):193-204
references: 1613821
references: Comput Appl Biosci. 1994 Dec;10(6):685-6
references: 7704669
references: Cell. 2013 Jan 17;152(1-2):248-61
references: 23332759
references: Bioinformatics. 2004 Jan 1;20(1):136-7
references: 14693825
references: Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W244-8
references: 15980461
references: Nucleic Acids Res. 2003 Jan 1;31(1):82-6
references: 12519953
references: Bioinformatics. 2001 Sep;17(9):849-50
references: 11590105
references: Nucleic Acids Res. 2012 Jan;40(Database issue):D242-51
references: 22110040
references: Nat Methods. 2011 Nov 13;8(12):1056-8
references: 22081127
references: Nature. 1999 Apr 8;398(6727):518-22
references: 10206645
references: Trends Biochem Sci. 1999 Jan;24(1):34-6
references: 10087920
references: Bioinformatics. 2011 Jun 15;27(12):1653-9
references: 21543442
references: J Neurosci. 2008 Jan 2;28(1):264-78
references: 18171944
references: Bioinformatics. 2007 May 1;23(9):1159-60
references: 17332022
references: Nucleic Acids Res. 2009 Jan;37(Database issue):D205-10
references: 18984618
references: Nat Struct Mol Biol. 2010 Feb;17(2):210-5
references: 20118935
references: Bioinformatics. 2006 Feb 1;22(3):356-8
references: 16317077
references: Cancer Cell. 2008 Aug 12;14(2):123-34
references: 18691547
references: J Biol Chem. 2007 Feb 2;282(5):2821-31
references: 17158460
references: Development. 2001 Jul;128(14):2723-33
references: 11526078
references: Cytogenet Cell Genet. 2000;88(3-4):211-6
references: 10828591
references: Cell. 1997 May 2;89(3):331-40
references: 9150132
references: Int J Dev Biol. 2012;56(5):325-32
references: 22811266
references: J Neurosci. 2012 Sep 5;32(36):12528-42
references: 22956843
references: Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14041-6
references: 12384578
references: Glia. 2010 Jun;58(8):996-1006
references: 20229602
references: Genome Biol. 2008;9(9):R137
references: 18798982
references: Nat Biotechnol. 2010 May;28(5):495-501
references: 20436461
references: Nucleic Acids Res. 2011 Aug;39(15):e98
references: 21602262
references: Nucleic Acids Res. 2012 Jan;40(Database issue):D290-301
references: 22127870
references: J Neurosci. 2007 Dec 26;27(52):14375-82
references: 18160645
references: Mol Biol Cell. 1999 Nov;10(11):3787-99
references: 10564271
references: J Neurosci. 2005 Feb 9;25(6):1354-65
references: 15703389
references: Nat Struct Mol Biol. 2005 Jan;12(1):90-6
references: 15608653
references: Nucleic Acids Res. 2010 Jan;38(Database issue):D161-6
references: 19858104
references: Nature. 2004 Apr 1;428(6982):493-521
references: 15057822
references: Development. 2008 Apr;135(7):1271-81
references: 18287202
references: Proc Natl Acad Sci U S A. 2009 Sep 1;106(35):14926-31
references: 19706456
references: Nucleic Acids Res. 2004 May 25;32(9):2947-56
references: 15161958
references: Genes Dev. 2010 Feb 1;24(3):301-11
references: 20080941
references: J Neurosci. 2006 Oct 25;26(43):10967-83
references: 17065439
references: J Cell Biol. 2006 Mar 13;172(6):937-48
references: 16520383
references: Cell. 2009 Jul 10;138(1):172-85
references: 19596243
references: Genome Biol. 2007;8(2):R24
references: 17324271
references: Bioinformatics. 2010 Mar 15;26(6):841-2
references: 20110278
references: PLoS One. 2010 May 05;5(5):e10480
references: 20463920
references: Dev Cell. 2009 Jan;16(1):47-57
references: 19097946
references: Dev Biol. 2011 Dec 15;360(2):297-309
references: 21989027