Reversible Regulation of Promoter and Enhancer Histone Landscape by DNA Methylation in Mouse Embryonic Stem Cells.
DNA methylation is one of a number of modes of epigenetic gene regulation. Here, we profile the DNA methylome, transcriptome, and global occupancy of histone modifications (H3K4me1, H3K4me3, H3K27me3, and H3K27ac) in a series of mouse embryonic stem cells (mESCs) with varying DNA methylation levels to study the effects of DNA methylation on deposition of histone modifications. We find that genome-wide DNA demethylation alters occupancy of histone modifications at both promoters and enhancers. This is reversed upon remethylation by Dnmt expression. DNA methylation promotes H3K27me3 deposition at bivalent promoters, while opposing H3K27me3 at silent promoters. DNA methylation also reversibly regulates H3K27ac and H3K27me3 at previously identified tissue-specific enhancers. These effects require DNMT catalytic activity. Collectively, our data show that DNA methylation is essential and instructive for deposition of specific histone modifications across regulatory regions, which together influences gene expression patterns in mESCs.
Department of Human Genetics and Broad Stem Cell Research Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Interdepartmental Doctoral Program, University of California Los Angeles, Los Angeles, CA 90095, USA.
Andrew D
AD
King
Department of Human Genetics and Broad Stem Cell Research Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; Division of Oral Biology and Medicine, School of Dentistry, University of California Los Angeles, Los Angeles, CA 90095, USA.
Kevin
K
Huang
Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA.
Liudmilla
L
Rubbi
Department of Chemistry, University of California Riverside, Riverside, CA 92521, USA.
Shuo
S
Liu
Division of Oral Biology and Medicine, School of Dentistry, University of California Los Angeles, Los Angeles, CA 90095, USA.
Cun-Yu
CY
Wang
Department of Chemistry, University of California Riverside, Riverside, CA 92521, USA.
Yinsheng
Y
Wang
Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA.
Matteo
M
Pellegrini
Department of Human Genetics and Broad Stem Cell Research Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA. Electronic address: gfan@mednet.ucla.edu.
Guoping
G
Fan
D000818:Animals; D002460:Cell Line; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D042421:Histone Code; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D011401:Promoter Regions, Genetic
D006657:Histones; D004248:DNA (Cytosine-5-)-Methyltransferases
DNA methylation; chromatin; embryonic stem cells; enhancers; epigenetics; gene regulation; histone modifications; polycomb; promoters
Nat Genet. 2007 Mar;39(3):311-8
17277777
Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):12979-84
18753622
Nucleic Acids Res. 2010 Jul;38(13):4246-53
20223770
Genes Dev. 2014 Oct 1;28(19):2103-19
25223896
Cell. 2015 Jun 4;161(6):1425-36
26004067
J Biol Chem. 2003 Feb 7;278(6):4035-40
12427740
Genome Biol. 2013 Mar 25;14(3):R25
23531360
Nature. 2011 Dec 14;480(7378):490-5
22170606
Nature. 2012 Aug 2;488(7409):116-20
22763441
J Neurosci Res. 2005 Mar 15;79(6):734-46
15672446
Mol Cell. 2014 Oct 23;56(2):286-97
25263596
Nat Commun. 2015 Feb 18;6:6363
25691127
J Biol Chem. 2002 Oct 11;277(41):38746-54
12138111
Science. 2010 Jul 23;329(5990):444-8
20651149
Nat Genet. 2013 Oct;45(10):1198-206
23995138
Nature. 2006 Feb 16;439(7078):871-4
16357870
Mol Cell. 2003 Sep;12(3):723-34
14527417
Cell. 2013 May 23;153(5):1134-48
23664764
Nat Rev Genet. 2009 May;10(5):295-304
19308066
Cell Rep. 2014 Jun 12;7(5):1456-70
24857660
Cell. 1999 Oct 29;99(3):247-57
10555141
J Biol Chem. 2013 Nov 29;288(48):34287-94
24151070
Bioinformatics. 2011 Jun 1;27(11):1571-2
21493656
Mol Cell. 2015 Jul 2;59(1):89-103
26073541
Nature. 2012 Sep 6;489(7414):75-82
22955617
Bioinformatics. 2013 Jan 1;29(1):15-21
23104886
Nature. 2014 Mar 27;507(7493):455-61
24670763
Nature. 2014 Jul 31;511(7511):606-10
25079557
Cell. 2006 Apr 21;125(2):315-26
16630819
Cell. 2007 May 18;129(4):823-37
17512414
EMBO Rep. 2009 Nov;10(11):1235-41
19834512
Cell. 2015 Jun 4;161(6):1453-67
26046444
Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21931-6
21106759
Nature. 2007 Aug 9;448(7154):714-7
17687327
Mol Cell. 2010 May 28;38(4):576-89
20513432
Cell Stem Cell. 2014 Aug 7;15(2):239-53
24835570
Nature. 2014 Jul 31;511(7511):611-5
25079558
Genome Res. 2012 Jun;22(6):1128-38
22466170
Mol Cell. 2014 Aug 7;55(3):347-60
24999238
Genome Res. 2011 Aug;21(8):1313-27
21636662
Cell. 2015 Jun 4;161(6):1437-52
26046443
Nucleic Acids Res. 2005 Oct 13;33(18):5868-77
16224102
Nature. 2007 Aug 2;448(7153):553-60
17603471
Mol Cell Biol. 2007 Dec;27(24):8748-59
17938196
Nature. 2015 Apr 9;520(7546):243-7
25607372
Mol Cell Biol. 2004 Oct;24(20):8862-71
15456861
Nat Struct Mol Biol. 2008 Mar;15(3):259-67
18311153
Cell Rep. 2014 Nov 20;9(4):1554-66
25453758
Genome Res. 2011 Aug;21(8):1273-83
21632746
Proc Natl Acad Sci U S A. 2014 Aug 19;111(33):E3415-21
25092339
Cell Stem Cell. 2015 Dec 3;17 (6):748-57
26637943
Nature. 2015 Dec 24;528(7583):575-9
26675734
Nature. 2011 Feb 10;470(7333):279-83
21160473
Nature. 2013 Aug 22;500(7463):477-81
23925113
Elife. 2015 Apr 07;4:e06205
25848745
Mol Cell. 2015 Nov 19;60(4):584-96
26590716
Cell Stem Cell. 2011 Jun 3;8(6):676-87
21624812
Nature. 2011 Mar 3;471(7336):68-73
21289626
Mol Cell. 2015 Apr 16;58(2):216-31
25818644
Nat Genet. 2007 Apr;39(4):457-66
17334365
Cell. 2010 Oct 29;143(3):470-84
21029866
Nat Commun. 2016 Jan 13;7:10291
26759081
Cell Stem Cell. 2008 Feb 7;2(2):160-9
18371437
Mol Cell Biol. 2003 Aug;23(16):5594-605
12897133
Nature. 2015 Jan 29;517(7536):640-4
25383530