Global analysis of H3K4 methylation defines MLL family member targets and points to a role for MLL1-mediated H3K4 methylation in the regulation of transcriptional initiation by RNA polymerase II.
A common landmark of activated genes is the presence of trimethylation on lysine 4 of histone H3 (H3K4) at promoter regions. Set1/COMPASS was the founding member and is the only H3K4 methylase in Saccharomyces cerevisiae; however, in mammals, at least six H3K4 methylases, Set1A and Set1B and MLL1 to MLL4, are found in COMPASS-like complexes capable of methylating H3K4. To gain further insight into the different roles and functional targets for the H3K4 methylases, we have undertaken a genome-wide analysis of H3K4 methylation patterns in wild-type Mll1(+/+) and Mll1(-)(/)(-) mouse embryonic fibroblasts (MEFs). We found that Mll1 is required for the H3K4 trimethylation of less than 5% of promoters carrying this modification. Many of these genes, which include developmental regulators such as Hox genes, show decreased levels of RNA polymerase II recruitment and expression concomitant with the loss of H3K4 methylation. Although Mll1 is only required for the methylation of a subset of Hox genes, menin, a component of the Mll1 and Mll2 complexes, is required for the overwhelming majority of H3K4 methylation at Hox loci. However, the loss of MLL3/MLL4 and/or the Set1 complexes has little to no effect on the H3K4 methylation of Hox loci or their expression levels in these MEFs. Together these data provide insight into the redundancy and specialization of COMPASS-like complexes in mammals and provide evidence for a possible role for Mll1-mediated H3K4 methylation in the regulation of transcriptional initiation.
Wang
Pengfei
P
Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA.
Lin
Chengqi
C
Smith
Edwin R
ER
Guo
Hong
H
Sanderson
Brian W
BW
Wu
Min
M
Gogol
Madelaine
M
Alexander
Tara
T
Seidel
Christopher
C
Wiedemann
Leanne M
LM
Ge
Kai
K
Krumlauf
Robb
R
Shilatifard
Ali
A
D000818:Animals; D002843:Chromatin / Q000378:metabolism; D021901:DNA, Intergenic / Q000378:metabolism; D005786:Gene Expression Regulation; D005801:Genes, Homeobox; D016678:Genome / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012319:RNA Polymerase II / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D004268:DNA-Binding Proteins
D002843:Chromatin; D021901:DNA, Intergenic; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D008239:Lysine; D051788:Myeloid-Lymphoid Leukemia Protein; D011518:Proto-Oncogene Proteins; D012319:RNA Polymerase II; C484898:Men1 protein, mouse; C510652:Kmt2c protein, mouse; D004268:DNA-Binding Proteins
Genes Dev. 2008 Dec 15;22(24):3403-8
19141473
Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8603-8
15941828
Semin Cancer Biol. 2005 Jun;15(3):175-88
15826832
Mol Cell. 2003 Mar;11(3):709-19
12667453
Mol Cell. 2004 Feb 27;13(4):587-97
14992727
Nature. 2009 Mar 26;458(7237):529-33
19212323
Nature. 2005 Jan 27;433(7024):434-8
15647753
Nature. 2006 Jul 6;442(7098):100-3
16728977
EMBO J. 1992 May;11(5):1825-36
1582411
Nat Genet. 1996 Feb;12(2):154-8
8563753
Proc Natl Acad Sci U S A. 1999 Dec 7;96(25):14372-7
10588712
Nat Genet. 1996 Feb;12(2):149-53
8563752
Cell. 2007 Nov 16;131(4):633-6
18022353
Mol Cell. 2003 Jan;11(1):267-74
12535539
Nature. 2006 Jul 6;442(7098):86-90
16728976
PLoS Genet. 2006 Apr;2(4):e51
16604156
Blood. 1997 Mar 15;89(6):1922-30
9058712
Cell Stem Cell. 2008 Jan 10;2(1):72-82
18371423
Oncogene. 2001 Sep 10;20(40):5695-707
11607819
Nature. 1995 Nov 30;378(6556):505-8
7477409
Proc Natl Acad Sci U S A. 2005 Oct 11;102(41):14765-70
16199523
Mol Cell Biol. 2007 Dec;27(24):8466-79
17923682
Development. 2006 Oct;133(19):3787-96
16943279
BMC Bioinformatics. 2008 Jan 29;9:67
18230172
Annu Rev Genet. 1998;32:495-519
9928489
J Biol Chem. 2005 Dec 16;280(50):41725-31
16253997
Nature. 2006 Jul 6;442(7098):96-9
16728974
Mol Cell Biol. 2004 Jul;24(13):5639-49
15199122
Proc Natl Acad Sci U S A. 2001 Nov 6;98(23):12902-7
11687631
Mol Cell Biol. 2007 Jan;27(2):709-20
17088385
Mol Cell. 2002 Nov;10(5):1107-17
12453418
Oncogene. 2003 Jun 5;22(23):3655-68
12789274
Cell. 2007 Dec 14;131(6):1084-96
18083099
Curr Opin Cell Biol. 2008 Jun;20(3):341-8
18508253
Nat Genet. 2005 Oct;37(10):1090-7
16155569
Development. 1998 Nov;125(22):4349-58
9778495
EMBO J. 2001 Dec 17;20(24):7137-48
11742990
Development. 2006 Apr;133(8):1423-32
16540515
Annu Rev Biochem. 2006;75:243-69
16756492
J Cell Biochem. 2005 Jun 1;95(3):429-36
15786493
Genome Res. 2002 Jun;12(6):996-1006
12045153
Mol Cell Biol. 2008 Dec;28(24):7337-44
18838538
Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):749-54
15640349
Nat Genet. 2007 Mar;39(3):311-8
17277777
Cell. 1992 Jan 24;68(2):283-302
1346368
Cell. 2006 May 19;125(4):703-17
16713563
Mol Cell Biol. 2007 Mar;27(5):1889-903
17178841
Nat Protoc. 2006;1(2):729-48
17406303
Cell. 2007 Oct 5;131(1):58-69
17884155
Mol Cell. 2006 Jan 6;21(1):51-64
16387653
Proc Natl Acad Sci U S A. 2008 May 27;105(21):7472-7
18495928
Curr Biol. 2004 Nov 23;14(22):2063-9
15556871
Cell. 2005 Jan 28;120(2):169-81
15680324
Dev Cell. 2007 Oct;13(4):580-92
17925232
J Biol Chem. 2002 Mar 29;277(13):10753-5
11805083
Mol Cell. 2007 Nov 30;28(4):665-76
18042460
Nat Rev Genet. 2009 Mar;10(3):161-72
19204718
Mol Cell. 2003 Mar;11(3):721-9
12667454
Methods. 2003 Dec;31(4):265-73
14597310
J Biol Chem. 2007 Jul 13;282(28):20395-406
17500065