title: Characterization of an antagonistic switch between histone H3 lysine 27 methylation and acetylation in the transcriptional regulation of Polycomb group target genes.
abstract: Polycomb group (PcG) proteins are transcriptional repressors, which regulate proliferation and cell fate decisions during development, and their deregulated expression is a frequent event in human tumours. The Polycomb repressive complex 2 (PRC2) catalyzes trimethylation (me3) of histone H3 lysine 27 (K27), and it is believed that this activity mediates transcriptional repression. Despite the recent progress in understanding PcG function, the molecular mechanisms by which the PcG proteins repress transcription, as well as the mechanisms that lead to the activation of PcG target genes are poorly understood. To gain insight into these mechanisms, we have determined the global changes in histone modifications in embryonic stem (ES) cells lacking the PcG protein Suz12 that is essential for PRC2 activity. We show that loss of PRC2 activity results in a global increase in H3K27 acetylation. The methylation to acetylation switch correlates with the transcriptional activation of PcG target genes, both during ES cell differentiation and in MLL-AF9-transduced hematopoietic stem cells. Moreover, we provide evidence that the acetylation of H3K27 is catalyzed by the acetyltransferases p300 and CBP. Based on these data, we propose that the PcG proteins in part repress transcription by preventing the binding of acetyltransferases to PcG target genes.
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
authors.forename: Diego
authors.initials: D
authors.lastname: Pasini
authors.forename: Martina
authors.initials: M
authors.lastname: Malatesta
authors.forename: Hye Ryung
authors.initials: HR
authors.lastname: Jung
authors.forename: Julian
authors.initials: J
authors.lastname: Walfridsson
authors.forename: Anton
authors.initials: A
authors.lastname: Willer
authors.forename: Linda
authors.initials: L
authors.lastname: Olsson
authors.forename: Julie
authors.initials: J
authors.lastname: Skotte
authors.forename: Anton
authors.initials: A
authors.lastname: Wutz
authors.forename: Bo
authors.initials: B
authors.lastname: Porse
authors.forename: Ole Nørregaard
authors.initials: ON
authors.lastname: Jensen
authors.forename: Kristian
authors.initials: K
authors.lastname: Helin
mesh_terms: D000107:Acetylation; D000818:Animals; D053595:Embryonic Stem Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D051548:Histone Acetyltransferases / Q000378:metabolism; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D051379:Mice; D063151:Polycomb Repressive Complex 2; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D006657:Histones; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; C494163:Suz12 protein, mouse; D063151:Polycomb Repressive Complex 2; D051548:Histone Acetyltransferases; D008239:Lysine
references.citation: Mol Cancer Ther. 2007 Sep;6(9):2391-8
references.pmid: 17876038
references.citation: Nat Protoc. 2006;1(4):2082-7
references.pmid: 17487198
references.citation: Cell. 2009 Dec 24;139(7):1290-302
references.pmid: 20064375
references.citation: Science. 2002 Nov 1;298(5595):1039-43
references.pmid: 12351676
references.citation: Development. 2009 Sep;136(18):3131-41
references.pmid: 19700617
references.citation: Cell. 2002 Oct 18;111(2):197-208
references.pmid: 12408864
references.citation: Cell. 2002 Oct 18;111(2):185-96
references.pmid: 12408863
references.citation: EMBO J. 2000 Sep 1;19(17):4655-64
references.pmid: 10970858
references.citation: Proc Natl Acad Sci U S A. 2001 May 22;98(11):6348-53
references.pmid: 11371647
references.citation: Genes Dev. 2008 May 15;22(10):1345-55
references.pmid: 18483221
references.citation: Cell. 2007 Nov 16;131(4):633-6
references.pmid: 18022353
references.citation: Nature. 1999 Jan 14;397(6715):164-8
references.pmid: 9923679
references.citation: EMBO J. 2003 Oct 1;22(19):5186-96
references.pmid: 14517256
references.citation: Nat Immunol. 2003 Feb;4(2):124-31
references.pmid: 12496962
references.citation: EMBO J. 2007 Mar 21;26(6):1637-48
references.pmid: 17332741
references.citation: Cell. 2004 Oct 15;119(2):157-67
references.pmid: 15479634
references.citation: Cell. 1998 May 1;93(3):361-72
references.pmid: 9590171
references.citation: Genes Dev. 2004 May 1;18(9):965-74
references.pmid: 15132992
references.citation: Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11606-11
references.pmid: 14500907
references.citation: Development. 2007 Jan;134(2):223-32
references.pmid: 17185323
references.citation: Cell. 2009 Dec 24;139(7):1303-14
references.pmid: 20064376
references.citation: EMBO J. 2006 Jul 12;25(13):3110-22
references.pmid: 16763550
references.citation: Cancer Cell. 2003 Sep;4(3):197-207
references.pmid: 14522254
references.citation: Cancer Cell. 2007 Jun;11(6):513-25
references.pmid: 17560333
references.citation: Cell. 2006 Apr 21;125(2):301-13
references.pmid: 16630818
references.citation: Genes Dev. 2006 May 1;20(9):1123-36
references.pmid: 16618801
references.citation: Eur J Haematol. 2008 Dec;81(6):475-80
references.pmid: 18778367
references.citation: Nature. 2007 Aug 2;448(7153):553-60
references.pmid: 17603471
references.citation: Genes Dev. 2002 Nov 15;16(22):2893-905
references.pmid: 12435631
references.citation: Curr Biol. 2005 May 24;15(10):942-7
references.pmid: 15916951
references.citation: Cancer Cell. 2006 Oct;10(4):257-68
references.pmid: 17045204
references.citation: Nature. 2002 Oct 10;419(6907):624-9
references.pmid: 12374981
references.citation: Mol Cell. 2008 Jun 20;30(6):755-66
references.pmid: 18514006
references.citation: Blood. 2002 Jan 1;99(1):121-9
references.pmid: 11756161
references.citation: Nat Cell Biol. 2004 Jan;6(1):67-72
references.pmid: 14647293
references.citation: Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2468-73
references.pmid: 12589020
references.citation: Nat Rev Genet. 2007 Jan;8(1):9-22
references.pmid: 17173055
references.citation: Mol Cell. 2005 Dec 22;20(6):845-54
references.pmid: 16359901
references.citation: Trends Genet. 1998 May;14(5):178-83
references.pmid: 9613201
references.citation: J Biol Chem. 2003 May 23;278(21):19134-40
references.pmid: 12624111
references.citation: Cell Biol Int. 1998;22(6):397-400
references.pmid: 10328847
references.citation: Blood. 2004 Mar 1;103(5):1823-8
references.pmid: 14615372
references.citation: Cell. 2007 Feb 23;128(4):735-45
references.pmid: 17320510
references.citation: Mol Cell Biol. 2004 Jan;24(2):741-56
references.pmid: 14701746
references.citation: Cell. 1996 Jun 14;85(6):853-61
references.pmid: 8681380
references.citation: J Cell Biochem. 2005 Jun 1;95(3):429-36
references.pmid: 15786493
references.citation: Mech Dev. 2000 Jul;95(1-2):133-45
references.pmid: 10906457
references.citation: Trends Endocrinol Metab. 2002 Mar;13(2):55-60
references.pmid: 11854019
references.citation: Cytotherapy. 2008;10(4):406-16
references.pmid: 18574773
references.citation: Cell. 1994 Jul 29;78(2):191-201
references.pmid: 7913880
references.citation: Cell. 2008 Jun 13;133(6):1106-17
references.pmid: 18555785
references.citation: Mol Cell Biol. 2001 Apr;21(7):2249-58
references.pmid: 11259575
references.citation: Nature. 2006 May 18;441(7091):349-53
references.pmid: 16625203
references.citation: Nat Cell Biol. 2008 Nov;10(11):1291-300
references.pmid: 18931660
references.citation: Nature. 2010 Mar 11;464(7286):306-10
references.pmid: 20075857
references.citation: Blood. 1997 Jun 1;89(11):3945-50
references.pmid: 9166831
references.citation: Mol Cell Proteomics. 2010 May;9(5):838-50
references.pmid: 20150217
references.citation: Ann N Y Acad Sci. 2007 Jun;1106:114-42
references.pmid: 17442773
references.citation: Mol Cell Biol. 2007 May;27(10):3769-79
references.pmid: 17339329
references.citation: EMBO J. 2003 Oct 15;22(20):5323-35
references.pmid: 14532106
references.citation: Mol Cell Biol. 2006 Apr;26(7):2560-9
references.pmid: 16537902
references.citation: EMBO J. 2004 Oct 13;23(20):4061-71
references.pmid: 15385962
references.citation: Mol Cell Biol. 2001 Jul;21(13):4330-6
references.pmid: 11390661