H3K36 methylation antagonizes PRC2-mediated H3K27 methylation.
H3K27 methylation mediated by the histone methyltransferase complex PRC2 is critical for transcriptional regulation, Polycomb silencing, Drosophila segmentation, mammalian X chromosome inactivation, and cancer. PRC2-mediated H3K27 methylation can spread along the chromatin and propagate the repressive chromatin environment; thus, chromatin components that antagonize the activity of PRC2 are important for restraining Polycomb silencing. Here we report that in HeLa cells, H3 histones unmethylated at Lys-36 are mostly methylated at Lys-27, with the exception of newly synthesized H3. In addition, K27me3 rarely co-exists with K36me2 or K36me3 on the same histone H3 polypeptide. Moreover, PRC2 activity is greatly inhibited on nucleosomal substrates with preinstalled H3K36 methylation. These findings collectively identify H3K36 methylation as a chromatin component that restricts the PRC2-mediated spread of H3K27 methylation. Finally, we provide evidence that the controversial histone lysine methyltransferase Ash1, a known Trithorax group protein that antagonizes Polycomb silencing in vivo, is an H3K36-specific dimethylase, not an H3K4 methylase, further supporting the role of H3K36 methylation in antagonizing PRC2-mediated H3K27 methylation.
From the State Key Laboratory of Plant Physiology and Biochemistry, College of Biological Sciences, China Agricultural University, Beijing 100094, China,; the National Institute of Biological Sciences, Beijing 102206, China.
Wen
W
Yuan
the National Institute of Biological Sciences, Beijing 102206, China,; the Graduate Program, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China, and.
Mo
M
Xu
From the State Key Laboratory of Plant Physiology and Biochemistry, College of Biological Sciences, China Agricultural University, Beijing 100094, China,; the National Institute of Biological Sciences, Beijing 102206, China.
Chang
C
Huang
the National Institute of Biological Sciences, Beijing 102206, China,; the Life Science College, Beijing Normal University, Beijing 100875, China.
Nan
N
Liu
the National Institute of Biological Sciences, Beijing 102206, China.
She
S
Chen
the National Institute of Biological Sciences, Beijing 102206, China,. Electronic address: zhubing@nibs.ac.cn.
Bing
B
Zhu
D000818:Animals; D004330:Drosophila; D006367:HeLa Cells; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008745:Methylation; D009707:Nucleosomes / Q000201:enzymology* / Q000235:genetics
D006657:Histones; D009707:Nucleosomes; D011495:Histone-Lysine N-Methyltransferase
PLoS Genet. 2010 Jan;6(1):e1000805
20062800
Cell. 2006 Apr 21;125(2):301-13
16630818
J Biol Chem. 2009 Jun 5;284(23):15701-7
19332550
Cell. 2002 Oct 18;111(2):185-96
12408863
Curr Opin Genet Dev. 2004 Apr;14(2):155-64
15196462
EMBO J. 2001 Dec 17;20(24):7137-48
11742990
Genetics. 1989 Mar;121(3):517-25
2497049
Cell. 2005 Jun 17;121(6):873-85
15960975
EMBO Rep. 2004 Apr;5(4):373-7
15031712
Cell. 2007 Nov 16;131(4):633-6
18022353
Curr Opin Cell Biol. 2008 Jun;20(3):266-73
18439810
Gene. 2007 Aug 1;397(1-2):161-8
17544230
Cell. 2007 Feb 23;128(4):707-19
17320508
Cell. 2007 Feb 23;128(4):693-705
17320507
Cell Res. 2009 Oct;19(10):1217-20
19770845
Mol Cell Biol. 2007 Dec;27(24):8466-79
17923682
Nat Genet. 2006 Jun;38(6):700-5
16732288
Annu Rev Genet. 2009;43:559-99
19886812
Mol Cell Proteomics. 2009 Oct;8(10):2266-84
19654425
Science. 2002 Nov 1;298(5595):1039-43
12351676
Nat Rev Mol Cell Biol. 2009 Oct;10(10):697-708
19738629
J Biol Chem. 2005 May 6;280(18):17732-6
15760899
Mol Cell Biol. 2008 Jan;28(1):468-86
17967882
J Biol Chem. 2009 Dec 4;284(49):34283-95
19808676
Cell. 2002 Oct 18;111(2):197-208
12408864
Genes Dev. 2002 Nov 15;16(22):2893-905
12435631
Nat Protoc. 2007;2(4):933-8
17446892
J Biol Chem. 2010 Jan 29;285(5):3341-50
19940157
J Proteome Res. 2010 Jan;9(1):393-403
19888749
Nature. 2009 Oct 8;461(7265):762-7
19767730
Cell. 2007 May 18;129(4):823-37
17512414
Cell. 2007 Mar 9;128(5):1003-12
17350582
Science. 2010 Apr 2;328(5974):94-8
20360108
Nature. 2002 Oct 24;419(6909):857-62
12397363
Genes Dev. 2006 Aug 1;20(15):2041-54
16882982
Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11535-40
13679578
Genes Dev. 2008 Oct 15;22(20):2799-810
18923078
Cell. 2007 Oct 5;131(1):58-69
17884155
Science. 2003 Apr 4;300(5616):131-5
12649488
Nature. 2006 May 18;441(7091):349-53
16625203
Nat Cell Biol. 2008 Nov;10(11):1291-300
18931660
Nat Protoc. 2007;2(6):1445-57
17545981
EMBO J. 2007 Dec 12;26(24):4974-84
18007591