Characterization of an antagonistic switch between histone H3 lysine 27 methylation and acetylation in the transcriptional regulation of Polycomb group target genes.
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.
Pasini
Diego
D
Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
Malatesta
Martina
M
Jung
Hye Ryung
HR
Walfridsson
Julian
J
Willer
Anton
A
Olsson
Linda
L
Skotte
Julie
J
Wutz
Anton
A
Porse
Bo
B
Jensen
Ole Nørregaard
ON
Helin
Kristian
K
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
D006657:Histones; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; C494163:Suz12 protein, mouse; D063151:Polycomb Repressive Complex 2; D051548:Histone Acetyltransferases; D008239:Lysine
Mol Cancer Ther. 2007 Sep;6(9):2391-8
17876038
Nat Protoc. 2006;1(4):2082-7
17487198
Cell. 2009 Dec 24;139(7):1290-302
20064375
Science. 2002 Nov 1;298(5595):1039-43
12351676
Development. 2009 Sep;136(18):3131-41
19700617
Cell. 2002 Oct 18;111(2):197-208
12408864
Cell. 2002 Oct 18;111(2):185-96
12408863
EMBO J. 2000 Sep 1;19(17):4655-64
10970858
Proc Natl Acad Sci U S A. 2001 May 22;98(11):6348-53
11371647
Genes Dev. 2008 May 15;22(10):1345-55
18483221
Cell. 2007 Nov 16;131(4):633-6
18022353
Nature. 1999 Jan 14;397(6715):164-8
9923679
EMBO J. 2003 Oct 1;22(19):5186-96
14517256
Nat Immunol. 2003 Feb;4(2):124-31
12496962
EMBO J. 2007 Mar 21;26(6):1637-48
17332741
Cell. 2004 Oct 15;119(2):157-67
15479634
Cell. 1998 May 1;93(3):361-72
9590171
Genes Dev. 2004 May 1;18(9):965-74
15132992
Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11606-11
14500907
Development. 2007 Jan;134(2):223-32
17185323
Cell. 2009 Dec 24;139(7):1303-14
20064376
EMBO J. 2006 Jul 12;25(13):3110-22
16763550
Cancer Cell. 2003 Sep;4(3):197-207
14522254
Cancer Cell. 2007 Jun;11(6):513-25
17560333
Cell. 2006 Apr 21;125(2):301-13
16630818
Genes Dev. 2006 May 1;20(9):1123-36
16618801
Eur J Haematol. 2008 Dec;81(6):475-80
18778367
Nature. 2007 Aug 2;448(7153):553-60
17603471
Genes Dev. 2002 Nov 15;16(22):2893-905
12435631
Curr Biol. 2005 May 24;15(10):942-7
15916951
Cancer Cell. 2006 Oct;10(4):257-68
17045204
Nature. 2002 Oct 10;419(6907):624-9
12374981
Mol Cell. 2008 Jun 20;30(6):755-66
18514006
Blood. 2002 Jan 1;99(1):121-9
11756161
Nat Cell Biol. 2004 Jan;6(1):67-72
14647293
Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2468-73
12589020
Nat Rev Genet. 2007 Jan;8(1):9-22
17173055
Mol Cell. 2005 Dec 22;20(6):845-54
16359901
Trends Genet. 1998 May;14(5):178-83
9613201
J Biol Chem. 2003 May 23;278(21):19134-40
12624111
Cell Biol Int. 1998;22(6):397-400
10328847
Blood. 2004 Mar 1;103(5):1823-8
14615372
Cell. 2007 Feb 23;128(4):735-45
17320510
Mol Cell Biol. 2004 Jan;24(2):741-56
14701746
Cell. 1996 Jun 14;85(6):853-61
8681380
J Cell Biochem. 2005 Jun 1;95(3):429-36
15786493
Mech Dev. 2000 Jul;95(1-2):133-45
10906457
Trends Endocrinol Metab. 2002 Mar;13(2):55-60
11854019
Cytotherapy. 2008;10(4):406-16
18574773
Cell. 1994 Jul 29;78(2):191-201
7913880
Cell. 2008 Jun 13;133(6):1106-17
18555785
Mol Cell Biol. 2001 Apr;21(7):2249-58
11259575
Nature. 2006 May 18;441(7091):349-53
16625203
Nat Cell Biol. 2008 Nov;10(11):1291-300
18931660
Nature. 2010 Mar 11;464(7286):306-10
20075857
Blood. 1997 Jun 1;89(11):3945-50
9166831
Mol Cell Proteomics. 2010 May;9(5):838-50
20150217
Ann N Y Acad Sci. 2007 Jun;1106:114-42
17442773
Mol Cell Biol. 2007 May;27(10):3769-79
17339329
EMBO J. 2003 Oct 15;22(20):5323-35
14532106
Mol Cell Biol. 2006 Apr;26(7):2560-9
16537902
EMBO J. 2004 Oct 13;23(20):4061-71
15385962
Mol Cell Biol. 2001 Jul;21(13):4330-6
11390661