title: The Histone Variant MacroH2A1.2 Is Necessary for the Activation of Muscle Enhancers and Recruitment of the Transcription Factor Pbx1.
abstract: Histone variants complement and integrate histone post-translational modifications in regulating transcription. The histone variant macroH2A1 (mH2A1) is almost three times the size of its canonical H2A counterpart, due to the presence of an ∼25 kDa evolutionarily conserved non-histone macro domain. Strikingly, mH2A1 can mediate both gene repression and activation. However, the molecular determinants conferring these alternative functions remain elusive. Here, we report that mH2A1.2 is required for the activation of the myogenic gene regulatory network and muscle cell differentiation. H3K27 acetylation at prospective enhancers is exquisitely sensitive to mH2A1.2, indicating a role of mH2A1.2 in imparting enhancer activation. Both H3K27 acetylation and recruitment of the transcription factor Pbx1 at prospective enhancers are regulated by mH2A1.2. Overall, our findings indicate a role of mH2A1.2 in marking regulatory regions for activation.
authors.affiliation: Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD 20892, USA.
authors.forename: Stefania
authors.initials: S
authors.lastname: Dell'Orso
authors.affiliation: Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD 20892, USA.
authors.forename: A Hongjun
authors.initials: AH
authors.lastname: Wang
authors.affiliation: Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, NIAMS, NIH, Bethesda, MD 20892, USA.
authors.forename: Han-Yu
authors.initials: HY
authors.lastname: Shih
authors.affiliation: Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD 20892, USA.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Saso
authors.affiliation: Epigenetics and Regenerative Medicine, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy.
authors.forename: Libera
authors.initials: L
authors.lastname: Berghella
authors.affiliation: Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD 20892, USA.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Gutierrez-Cruz
authors.affiliation: Butenandt Institute, LMU Biomedical Center, Department of Physiological Chemistry, Ludwig-Maximilians-University of Munich, 81377 Munich, Germany.
authors.forename: Andreas G
authors.initials: AG
authors.lastname: Ladurner
authors.affiliation: Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, NIAMS, NIH, Bethesda, MD 20892, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: O'Shea
authors.affiliation: Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD 20892, USA. Electronic address: sartorev@mail.nih.gov.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Sartorelli
authors.affiliation: Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD 20892, USA.
authors.forename: Hossein
authors.initials: H
authors.lastname: Zare
mesh_terms: D000107:Acetylation; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002843:Chromatin / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D044127:Epigenesis, Genetic; D053263:Gene Regulatory Networks; D016678:Genome; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D032342:Muscle Cells / Q000166:cytology / Q000378:metabolism; D024510:Muscle Development / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism*; D017570:MyoD Protein / Q000378:metabolism; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011485:Protein Binding / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D059467:Transcriptome / Q000235:genetics
chemical_list: D002843:Chromatin; D006657:Histones; D018398:Homeodomain Proteins; D017570:MyoD Protein; C481797:Pbx1 protein, mouse; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D014157:Transcription Factors; C120756:macroH2A histone
references.citation: Development. 2007 Sep;134(18):3371-82
references.pmid: 17699609
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1533-8
references.pmid: 18227505
references.citation: Genome Biol. 2008;9(9):R137
references.pmid: 18798982
references.citation: Nat Protoc. 2009;4(1):44-57
references.pmid: 19131956
references.citation: Nucleic Acids Res. 2009 Jan;37(1):1-13
references.pmid: 19033363
references.citation: Bioinformatics. 2009 May 1;25(9):1105-11
references.pmid: 19289445
references.citation: Nature. 2009 May 7;459(7243):108-12
references.pmid: 19295514
references.citation: Science. 1992 Sep 4;257(5075):1398-400
references.pmid: 1529340
references.citation: Nature. 1993 Mar 18;362(6417):219-23
references.pmid: 8384699
references.citation: Nature. 1993 Jul 29;364(6436):412-20
references.pmid: 8332212
references.citation: Genes Dev. 1997 Feb 15;11(4):436-50
references.pmid: 9042858
references.citation: Nature. 1998 Jun 11;393(6685):599-601
references.pmid: 9634239
references.citation: Nucleic Acids Res. 1999 Sep 15;27(18):3685-9
references.pmid: 10471737
references.citation: Mol Cell Biol. 2005 May;25(10):3997-4009
references.pmid: 15870273
references.citation: Development. 2005 Jun;132(12):2685-95
references.pmid: 15930108
references.citation: Nat Struct Mol Biol. 2005 Jul;12(7):624-5
references.pmid: 15965484
references.citation: Mol Cell Biol. 2005 Sep;25(17):7616-24
references.pmid: 16107708
references.citation: FASEB J. 2015 May;29(5):1676-87
references.pmid: 25526730
references.citation: Cell. 2015 Apr 23;161(3):555-68
references.pmid: 25892221
references.citation: Mol Cell. 2010 May 28;38(4):576-89
references.pmid: 20513432
references.citation: Nature. 2010 Dec 23;468(7327):1105-9
references.pmid: 21179167
references.citation: Nature. 2011 Feb 10;470(7333):279-83
references.pmid: 21160473
references.citation: Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21931-6
references.pmid: 21106759
references.citation: Cell Cycle. 2010 Jul 1;9(13):2568-74
references.pmid: 20543561
references.citation: EMBO J. 2011 Jun 15;30(12):2373-87
references.pmid: 21552206
references.citation: Nat Rev Genet. 2011 Aug;12(8):554-64
references.pmid: 21747402
references.citation: Genome Res. 2011 Aug;21(8):1273-83
references.pmid: 21632746
references.citation: Genes Dev. 2011 Nov 1;25(21):2227-41
references.pmid: 22056668
references.citation: PLoS Genet. 2011 Nov;7(11):e1002368
references.pmid: 22125492
references.citation: Nat Genet. 2012 Feb;44(2):148-56
references.pmid: 22231485
references.citation: Mol Cell. 2012 Jan 27;45(2):255-62
references.pmid: 22196887
references.citation: Genes Dev. 2012 Mar 1;26(5):433-8
references.pmid: 22391447
references.citation: Mol Cell Biol. 2012 Apr;32(8):1442-52
references.pmid: 22331466
references.citation: Nat Protoc. 2012 Sep;7(9):1728-40
references.pmid: 22936215
references.citation: Nat Biotechnol. 2013 Jan;31(1):46-53
references.pmid: 23222703
references.citation: Nat Commun. 2013;4:1565
references.pmid: 23463008
references.citation: Cell. 2013 Apr 11;153(2):307-19
references.pmid: 23582322
references.citation: Cell Rep. 2013 Apr 25;3(4):1005-11
references.pmid: 23545500
references.citation: Development. 2013 Jun;140(12):2513-24
references.pmid: 23715545
references.citation: Cell Rep. 2015 Mar 31;10(12):1937-46
references.pmid: 25801030
references.citation: Mol Cell Biol. 2001 Apr;21(7):2404-12
references.pmid: 11259589
references.citation: J Cell Biol. 2001 May 14;153(4):773-84
references.pmid: 11352938
references.citation: Genome Biol. 2009;10(3):R25
references.pmid: 19261174
references.citation: Bioinformatics. 2009 Aug 1;25(15):1952-8
references.pmid: 19505939
references.citation: Nat Genet. 2009 Aug;41(8):941-5
references.pmid: 19633671
references.citation: Nat Struct Mol Biol. 2009 Oct;16(10):1074-9
references.pmid: 19734898
references.citation: Genes Dev. 2010 Jan 1;24(1):21-32
references.pmid: 20008927
references.citation: Bioinformatics. 2010 Mar 15;26(6):841-2
references.pmid: 20110278
references.citation: Nature. 2015 Feb 19;518(7539):317-30
references.pmid: 25693563
references.citation: Nat Genet. 2003 Jul;34(3):267-73
references.pmid: 12808457
references.citation: Mol Cell. 2003 Jul;12(1):1-3
references.pmid: 12887886
references.citation: Cell. 2003 Dec 12;115(6):751-63
references.pmid: 14675539
references.citation: Mol Cell. 2004 May 21;14(4):465-77
references.pmid: 15149596
references.citation: Nature. 1977 Dec 22-29;270(5639):725-7
references.pmid: 563524
references.citation: Cell. 1987 Dec 24;51(6):987-1000
references.pmid: 3690668
references.citation: Cell. 1990 Apr 6;61(1):49-59
references.pmid: 2156629
references.citation: J Biol Chem. 2001 Jun 15;276(24):21776-84
references.pmid: 11262398
references.citation: Science. 2001 Aug 10;293(5532):1074-80
references.pmid: 11498575
references.citation: Mol Cell. 2002 Feb;9(2):279-89
references.pmid: 11864602
references.citation: Mol Cell. 1999 Dec;4(6):961-9
references.pmid: 10635321
references.citation: Mol Cell. 2013 Sep 12;51(5):606-17
references.pmid: 23993744
references.citation: Nat Methods. 2013 Dec;10(12):1213-8
references.pmid: 24097267
references.citation: Nat Rev Genet. 2014 Apr;15(4):259-71
references.pmid: 24614311
references.citation: Mol Cell Biol. 2014 Jul;34(13):2437-49
references.pmid: 24752897
references.citation: Nat Struct Mol Biol. 2014 Nov;21(11):981-9
references.pmid: 25306110
references.citation: Genes Dev. 2014 Dec 15;28(24):2679-92
references.pmid: 25512556
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
references.pmid: 16199517
references.citation: Mol Cell Biol. 2006 Feb;26(3):1156-64
references.pmid: 16428466
references.citation: J Biol Chem. 2006 Sep 1;281(35):25522-31
references.pmid: 16803903
references.citation: Cell. 2007 May 18;129(4):823-37
references.pmid: 17512414
references.citation: Genes Dev. 2007 Jun 15;21(12):1519-29
references.pmid: 17575053