title: A system for genome-wide histone variant dynamics in ES cells reveals dynamic MacroH2A2 replacement at promoters.
abstract: Dynamic exchange of a subset of nucleosomes in vivo plays important roles in epigenetic inheritance of chromatin states, chromatin insulator function, chromosome folding, and the maintenance of the pluripotent state of embryonic stem cells. Here, we extend a pulse-chase strategy for carrying out genome-wide measurements of histone dynamics to several histone variants in murine embryonic stem cells and somatic tissues, recapitulating expected characteristics of the well characterized H3.3 histone variant. We extended this system to the less-studied MacroH2A2 variant, commonly described as a "repressive" histone variant whose accumulation in chromatin is thought to fix the epigenetic state of differentiated cells. Unexpectedly, we found that while large intergenic blocks of MacroH2A2 were stably associated with the genome, promoter-associated peaks of MacroH2A2 exhibited relatively rapid exchange dynamics in ES cells, particularly at highly-transcribed genes. Upon differentiation to embryonic fibroblasts, MacroH2A2 was gained primarily in additional long, stably associated blocks across gene-poor regions, while overall turnover at promoters was greatly dampened. Our results reveal unanticipated dynamic behavior of the MacroH2A2 variant in pluripotent cells, and provide a resource for future studies of tissue-specific histone dynamics in vivo.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Ozlem
authors.initials: O
authors.lastname: Yildirim
authors.affiliation: Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Jui-Hung
authors.initials: JH
authors.lastname: Hung
authors.affiliation: Department of Animal Biology, School of Veterinary Medicine and Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Cedeno
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America; Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Weng
authors.affiliation: Department of Animal Biology, School of Veterinary Medicine and Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lengner
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Rando
mesh_terms: D000818:Animals; D002843:Chromatin / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D057890:Epigenomics; D016678:Genome; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009707:Nucleosomes / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic
chemical_list: D002843:Chromatin; D006657:Histones; D009707:Nucleosomes; C120756:macroH2A histone
references.citation: Mol Cell Biol. 2007 Apr;27(7):2758-64
references.pmid: 17242180
references.citation: Cell Stem Cell. 2013 Feb 7;12(2):180-92
references.pmid: 23260488
references.citation: Genes Dev. 2010 Jan 1;24(1):21-32
references.pmid: 20008927
references.citation: Science. 2008 Mar 28;319(5871):1791-2
references.pmid: 18369138
references.citation: Cell. 2008 Nov 14;135(4):649-61
references.pmid: 18992931
references.citation: Cell. 2006 Apr 21;125(2):315-26
references.pmid: 16630819
references.citation: Mol Cell. 2007 Feb 9;25(3):345-55
references.pmid: 17289583
references.citation: Science. 2007 Mar 9;315(5817):1408-11
references.pmid: 17347439
references.citation: Cell. 2010 Oct 15;143(2):313-24
references.pmid: 20946988
references.citation: Nature. 2006 May 18;441(7091):349-53
references.pmid: 16625203
references.citation: Curr Biol. 2013 May 6;23(9):782-7
references.pmid: 23602475
references.citation: J Cell Biol. 2001 Jun 25;153(7):1341-53
references.pmid: 11425866
references.citation: Cell Rep. 2013 Apr 25;3(4):1005-11
references.pmid: 23545500
references.citation: Nat Genet. 1999 Aug;22(4):323-4
references.pmid: 10431231
references.citation: Hum Mol Genet. 2001 May 1;10(10):1101-13
references.pmid: 11331621
references.citation: Nat Genet. 2009 Aug;41(8):941-5
references.pmid: 19633671
references.citation: Genesis. 2006 Jan;44(1):23-8
references.pmid: 16400644
references.citation: Science. 2007 Mar 9;315(5817):1405-8
references.pmid: 17347438
references.citation: Cell. 2006 Aug 25;126(4):663-76
references.pmid: 16904174
references.citation: Nat Struct Mol Biol. 2013 May;20(5):547-54
references.pmid: 23604080
references.citation: Nature. 1998 Jun 11;393(6685):599-601
references.pmid: 9634239
references.citation: J Exp Med. 2010 Oct 25;207(11):2287-95
references.pmid: 20975044
references.citation: Mol Cell. 2007 Aug 3;27(3):393-405
references.pmid: 17679090
references.citation: EMBO J. 2011 May 06;30(12):2373-87
references.pmid: 21552206
references.citation: Genome Biol. 2010;11(10):218
references.pmid: 20959022
references.citation: Mol Cell. 2005 Jul 22;19(2):279-85
references.pmid: 16039596
references.citation: Epigenomics. 2012 Apr;4(2):221-7
references.pmid: 22449192
references.citation: Science. 2010 May 28;328(5982):1161-4
references.pmid: 20508129
references.citation: Proc Natl Acad Sci U S A. 2002 Dec 10;99 Suppl 4:16477-84
references.pmid: 12177448
references.citation: Cell Reprogram. 2010 Feb;12(1):43-53
references.pmid: 20132012
references.citation: Nat Genet. 2005 Oct;37(10):1090-7
references.pmid: 16155569
references.citation: Nat Commun. 2013;4:1565
references.pmid: 23463008
references.citation: Science. 2010 Apr 2;328(5974):94-8
references.pmid: 20360108
references.citation: Proc Natl Acad Sci U S A. 2012 Apr 3;109(14):5370-5
references.pmid: 22431625
references.citation: Cell. 2011 Dec 23;147(7):1498-510
references.pmid: 22196727
references.citation: Dev Cell. 2006 Jan;10(1):105-16
references.pmid: 16399082
references.citation: Cell. 2008 Jul 11;134(1):162-74
references.pmid: 18614019
references.citation: Cell. 2010 Mar 5;140(5):678-91
references.pmid: 20211137
references.citation: Mol Cell. 2002 Jun;9(6):1191-200
references.pmid: 12086617
references.citation: J Cell Sci. 2012 Dec 15;125(Pt 24):6094-104
references.pmid: 23077180
references.citation: Cell. 2002 Nov 1;111(3):281-4
references.pmid: 12419239
references.citation: Mol Cell Biol. 2012 Apr;32(8):1442-52
references.pmid: 22331466
references.citation: Nat Cell Biol. 2006 Mar;8(3):285-92
references.pmid: 16462733
references.citation: Mol Cell Biol. 2006 Jun;26(12):4410-20
references.pmid: 16738309
references.citation: Genome Biol. 2013;14(10):R121
references.pmid: 24176123