title: Cooperative stabilization of the SIR complex provides robust epigenetic memory in a model of SIR silencing in Saccharomyces cerevisiae.
abstract: How alternative chromatin-based regulatory states can be made stable and heritable in order to provide robust epigenetic memory is poorly understood. Here, we develop a stochastic model of the silencing system in Saccharomyces cerevisiae that incorporates cooperative binding of the repressive SIR complex and antisilencing histone modifications, in addition to positive feedback in Sir2 recruitment. The model was able to reproduce key features of SIR regulation of an HM locus, including heritable bistability, dependence on the silencer elements, and sensitivity to SIR dosage. We found that antisilencing methylation of H3K79 by Dot1 was not needed to generate these features, but acted to reduce spreading of SIR binding, consistent with its proposed role in containment of silencing. In contrast, cooperative inter-nucleosome interactions mediated by the SIR complex were critical for concentrating SIR binding around the silencers in the absence of barriers, and for providing bistability in SIR binding. SIR-SIR interactions magnify the cooperativity in the Sir2-histone deacetylation positive feedback reaction and complete a double-negative feedback circuit involving antisilencing modifications. Thus, our modeling underscores the potential importance of cooperative interactions between nucleosome-bound complexes both in the SIR system and in other chromatin-based complexes in epigenetic regulation.
authors.affiliation: a Centre for Models of Life; Niels Bohr Institute; University of Copenhagen; Copenhagen , Denmark.
authors.forename: Kim
authors.initials: K
authors.lastname: Sneppen
authors.forename: Ian B
authors.initials: IB
authors.lastname: Dodd
mesh_terms: D003198:Computer Simulation; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D008745:Methylation; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism; D009707:Nucleosomes / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D037941:Silencer Elements, Transcriptional; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000378:metabolism*; D056565:Sirtuin 2 / Q000378:metabolism
chemical_list: D006657:Histones; D009687:Nuclear Proteins; D009707:Nucleosomes; D029701:Saccharomyces cerevisiae Proteins; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; C416235:Dot1 protein, S cerevisiae; D011495:Histone-Lysine N-Methyltransferase; C087778:SIR2 protein, S cerevisiae; D056565:Sirtuin 2
keywords: budding yeast; epigenetic inheritance; heterochromatin; mathematical modeling; nucleosome modifications; positive feedback
references.citation: Structure. 2003 Jun;11(6):637-49
references.pmid: 12791253
references.citation: Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1820-5
references.pmid: 12574507
references.citation: J Biol Chem. 2005 Apr 1;280(13):12065-8
references.pmid: 15664979
references.citation: Mol Cell Biol. 2005 Jun;25(11):4514-28
references.pmid: 15899856
references.citation: Curr Opin Cell Biol. 2009 Jun;21(3):359-66
references.pmid: 19477626
references.citation: Genes Dev. 1993 Jul;7(7A):1133-45
references.pmid: 8319906
references.citation: Mol Cell. 2006 Jul 21;23(2):219-29
references.pmid: 16857588
references.citation: J Biol Chem. 2005 Mar 25;280(12):11987-94
references.pmid: 15659401
references.citation: Nature. 2011 Aug 4;476(7358):105-8
references.pmid: 21785438
references.citation: Nucleic Acids Res. 2014 Feb;42(4):2235-44
references.pmid: 24288373
references.citation: PLoS Biol. 2011 Jun;9(6):e1001075
references.pmid: 21666805
references.citation: Genes Dev. 2001 Dec 1;15(23):3169-82
references.pmid: 11731480
references.citation: EMBO J. 2005 Jun 15;24(12):2138-49
references.pmid: 15920479
references.citation: Nat Rev Genet. 2011 Aug;12(8):565-75
references.pmid: 21765458
references.citation: Mol Cell. 2009 Sep 24;35(6):769-81
references.pmid: 19782027
references.citation: Nucleic Acids Res. 2012 Jan;40(Database issue):D700-5
references.pmid: 22110037
references.citation: EMBO J. 1999 Dec 1;18(23):6630-41
references.pmid: 10581237
references.citation: PLoS Biol. 2005 Oct;3(10):e328
references.pmid: 16122352
references.citation: Chaos. 2001 Mar;11(1):170-179
references.pmid: 12779451
references.citation: Science. 2011 Nov 18;334(6058):977-82
references.pmid: 22096199
references.citation: Nature. 2003 Oct 16;425(6959):737-41
references.pmid: 14562106
references.citation: Curr Opin Cell Biol. 2002 Dec;14(6):756-62
references.pmid: 12473351
references.citation: Genes Dev. 2007 Aug 15;21(16):2018-29
references.pmid: 17675446
references.citation: Nat Genet. 2009 Jul;41(7):800-6
references.pmid: 19543267
references.citation: Genes Dev. 1999 Mar 15;13(6):698-708
references.pmid: 10090726
references.citation: Nat Rev Mol Cell Biol. 2014 May;15(5):340-56
references.pmid: 24755934
references.citation: Mol Cell. 2007 Dec 28;28(6):1015-28
references.pmid: 18158899
references.citation: Genes Dev. 1991 Apr;5(4):605-15
references.pmid: 2010086
references.citation: Proc Natl Acad Sci U S A. 2011 Jan 25;108(4):1209-16
references.pmid: 21262833
references.citation: Genome Res. 2014 Feb;24(2):267-80
references.pmid: 24310002
references.citation: Nucleic Acids Res. 1998 Feb 15;26(4):942-7
references.pmid: 9461451
references.citation: Genes Dev. 2012 Nov 1;26(21):2443-55
references.pmid: 23124068
references.citation: Mol Cell Biol. 1998 Sep;18(9):5392-403
references.pmid: 9710623
references.citation: Genes Dev. 2014 Feb 1;28(3):245-58
references.pmid: 24493645
references.citation: Mol Cell. 2007 Dec 28;28(6):1002-14
references.pmid: 18158898
references.citation: Nat Struct Mol Biol. 2008 Apr;15(4):381-8
references.pmid: 18345014
references.citation: Biochem Cell Biol. 2005 Aug;83(4):438-48
references.pmid: 16094447
references.citation: Mol Cell. 2013 Jul 11;51(1):80-91
references.pmid: 23849629
references.citation: Mol Cell. 2011 Apr 8;42(1):118-26
references.pmid: 21474073
references.citation: Cell. 1989 Nov 17;59(4):637-47
references.pmid: 2684414
references.citation: Genetics. 1998 Oct;150(2):613-32
references.pmid: 9755194
references.citation: Nature. 2007 Oct 18;449(7164):928-32
references.pmid: 17898715
references.citation: Mol Cell Biol. 1996 Aug;16(8):4349-56
references.pmid: 8754835
references.citation: Curr Opin Cell Biol. 2002 Apr;14(2):140-8
references.pmid: 11891111
references.citation: Proc Natl Acad Sci U S A. 2013 May 21;110(21):8495-500
references.pmid: 23650358
references.citation: Phys Biol. 2007 Nov;4(4):246-55
references.pmid: 17991991
references.citation: Cold Spring Harb Perspect Biol. 2013 Jul;5(7). pii: a017491. doi: 10.1101/cshperspect.a017491
references.pmid: 23818500
references.citation: PLoS Biol. 2013 Jul;11(7):e1001601
references.pmid: 23843746
references.citation: Cell. 2007 May 18;129(4):813-22
references.pmid: 17512413
references.citation: PLoS Comput Biol. 2013;9(7):e1003121
references.pmid: 23874171
references.citation: Genes Dev. 1996 Jul 15;10(14):1796-811
references.pmid: 8698239
references.citation: Mol Cell. 2011 Jan 7;41(1):67-81
references.pmid: 21211724
references.citation: J Mol Biol. 2011 Dec 9;414(4):624-37
references.pmid: 22037584
references.citation: Nature. 1996 Sep 5;383(6595):92-6
references.pmid: 8779721
references.citation: Annu Rev Biochem. 2003;72:481-516
references.pmid: 12676793
references.citation: Genes Dev. 2011 Sep 1;25(17):1835-46
references.pmid: 21896656
references.citation: Mol Cell Biol. 1993 Jul;13(7):3919-28
references.pmid: 8321199
references.citation: Curr Opin Cell Biol. 2010 Jun;22(3):284-90
references.pmid: 20299197
references.citation: EMBO J. 2013 Feb 6;32(3):437-49
references.pmid: 23299941
references.citation: EMBO J. 2011 Jul 6;30(13):2610-21
references.pmid: 21666601
references.citation: Bioessays. 2012 Oct;34(10):901-13
references.pmid: 22911103
references.citation: Mol Cell. 2009 Feb 13;33(3):323-34
references.pmid: 19217406
references.citation: Mol Cell. 2011 Apr 8;42(1):127-36
references.pmid: 21474074
references.citation: Cell. 2013 Mar 28;153(1):38-55
references.pmid: 23540689
references.citation: Cell. 2011 Aug 19;146(4):510-8
references.pmid: 21854979
references.citation: Mol Cell Biol. 2002 Jun;22(12):4167-80
references.pmid: 12024030
references.citation: Mol Biol Cell. 2002 Jul;13(7):2207-22
references.pmid: 12134062
references.citation: Genes Dev. 2007 Sep 15;21(18):2271-6
references.pmid: 17875664