DOT1L inhibition reveals a distinct subset of enhancers dependent on H3K79 methylation.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
26 06 2019
26 06 2019
Historique:
received:
14
08
2018
accepted:
05
06
2019
entrez:
28
6
2019
pubmed:
28
6
2019
medline:
17
8
2019
Statut:
epublish
Résumé
Enhancer elements are a key regulatory feature of many important genes. Several general features including the presence of specific histone modifications are used to demarcate potentially active enhancers. Here we reveal that putative enhancers marked with H3 lysine 79 (H3K79) di or trimethylation (me2/3) (which we name H3K79me2/3 enhancer elements or KEEs) can be found in multiple cell types. Mixed lineage leukemia gene (MLL) rearrangements (MLL-r) such as MLL-AF4 are a major cause of incurable acute lymphoblastic leukemias (ALL). Using the DOT1L inhibitor EPZ-5676 in MLL-AF4 leukemia cells, we show that H3K79me2/3 is required for maintaining chromatin accessibility, histone acetylation and transcription factor binding specifically at KEEs but not non-KEE enhancers. We go on to show that H3K79me2/3 is essential for maintaining enhancer-promoter interactions at a subset of KEEs. Together, these data implicate H3K79me2/3 as having a functional role at a subset of active enhancers in MLL-AF4 leukemia cells.
Identifiants
pubmed: 31243293
doi: 10.1038/s41467-019-10844-3
pii: 10.1038/s41467-019-10844-3
pmc: PMC6594956
doi:
Substances chimiques
Benzimidazoles
0
EPZ-5676
0
Histones
0
DOT1L protein, human
EC 2.1.1.-
Methyltransferases
EC 2.1.1.-
Histone-Lysine N-Methyltransferase
EC 2.1.1.43
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Pagination
2803Subventions
Organisme : RCUK | Medical Research Council (MRC)
ID : MC_UU_12009
Pays : International
Organisme : Medical Research Council
ID : MC_UU_12009/15
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L008963/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_15065
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12009/11
Pays : United Kingdom
Organisme : RCUK | MRC | Medical Research Foundation
ID : MC_UU_12009/6
Pays : International
Organisme : RCUK | Medical Research Council (MRC)
ID : MC_UU_12009/6
Pays : International
Organisme : Wellcome Trust (Wellcome)
ID : 106130/Z/14/Z
Pays : International
Organisme : Medical Research Council
ID : G1000729
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12009/6
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00016/6
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00016/11
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_U137961146
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00016/14
Pays : United Kingdom
Références
Nat Struct Mol Biol. 2016 Jul;23(7):673-81
pubmed: 27294782
Science. 2018 Jul 27;361(6400):
pubmed: 29930091
Cancer Cell. 2010 Feb 17;17(2):198-212
pubmed: 20153263
Nat Genet. 2012 Jan 08;44(2):148-56
pubmed: 22231485
Nat Rev Cancer. 2010 Oct;10(10):721-8
pubmed: 20844554
Cell. 2013 Apr 11;153(2):307-19
pubmed: 23582322
Bioinformatics. 2009 Aug 15;25(16):2078-9
pubmed: 19505943
Chromosoma. 2014 Aug;123(4):355-71
pubmed: 24789118
Nat Protoc. 2017 Dec;12(12):2478-2492
pubmed: 29120462
Bioessays. 2018 Oct;40(10):e1800078
pubmed: 30144132
Elife. 2019 May 24;8:
pubmed: 31124784
Cell. 2005 Apr 22;121(2):167-78
pubmed: 15851025
Blood. 2013 Mar 28;121(13):2533-41
pubmed: 23361907
Cancer Res. 1986 Jul;46(7):3642-7
pubmed: 3458526
Nat Methods. 2016 Jan;13(1):74-80
pubmed: 26595209
Blood. 2007 Dec 15;110(13):4445-54
pubmed: 17855633
Trends Cell Biol. 2018 Aug;28(8):608-630
pubmed: 29759817
Bioinformatics. 2014 Apr 1;30(7):923-30
pubmed: 24227677
Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21931-6
pubmed: 21106759
Cancer Cell. 2011 Jul 12;20(1):66-78
pubmed: 21741597
Blood. 2018 Jun 14;131(24):2661-2669
pubmed: 29724899
Cell Rep. 2015 Dec 29;13(12):2715-27
pubmed: 26711339
Nature. 2019 Jan;565(7740):448-453
pubmed: 30626972
Curr Opin Genet Dev. 2009 Dec;19(6):541-9
pubmed: 19854636
Cell Rep. 2017 Jan 10;18(2):482-495
pubmed: 28076791
Proc Natl Acad Sci U S A. 2011 Sep 20;108(38):15751-6
pubmed: 21896721
Nat Genet. 2018 Sep;50(9):1296-1303
pubmed: 30038397
Cell. 2012 Jun 8;149(6):1233-44
pubmed: 22682246
Cancer Cell. 2016 Nov 14;30(5):737-749
pubmed: 27846391
Br J Haematol. 1994 Feb;86(2):275-83
pubmed: 8199015
Nat Commun. 2018 Sep 21;9(1):3849
pubmed: 30242161
Cell. 2013 Nov 7;155(4):934-47
pubmed: 24119843
Nat Commun. 2018 Dec 19;9(1):5378
pubmed: 30568163
Science. 2018 Jul 27;361(6400):412-415
pubmed: 29930094
Blood. 2013 Aug 8;122(6):1017-25
pubmed: 23801631
Mol Cell. 2009 Sep 11;35(5):626-41
pubmed: 19682934
Cell Rep. 2013 Jan 31;3(1):116-27
pubmed: 23352661
Cell. 2013 Apr 11;153(2):320-34
pubmed: 23582323
Curr Biol. 2002 Jun 25;12(12):1052-8
pubmed: 12123582
Bioinformatics. 2010 Jan 1;26(1):139-40
pubmed: 19910308
Nature. 2011 Feb 10;470(7333):279-83
pubmed: 21160473
Cancer Cell. 2008 Nov 4;14(5):355-68
pubmed: 18977325
Nat Methods. 2013 Dec;10(12):1213-8
pubmed: 24097267
Science. 2018 Sep 28;361(6409):1341-1345
pubmed: 30262496
Development. 2016 Aug 15;143(16):2994-3001
pubmed: 27402708
Nat Methods. 2012 Feb 28;9(3):215-6
pubmed: 22373907
Nature. 2009 May 7;459(7243):108-12
pubmed: 19295514
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Blood. 2017 Apr 20;129(16):2217-2223
pubmed: 28179274
Nat Med. 2015 Apr;21(4):335-43
pubmed: 25822366
Nat Genet. 2007 Mar;39(3):311-8
pubmed: 17277777
Cell. 2014 Oct 23;159(3):543-57
pubmed: 25417106
Cancer Res. 2005 Dec 15;65(24):11367-74
pubmed: 16357144
FASEB J. 2018 Oct;32(10):5737-5750
pubmed: 29763382
Mol Cell Biol. 2008 Apr;28(8):2825-39
pubmed: 18285465
Methods Mol Biol. 2009;538:409-23
pubmed: 19277579
Exp Hematol. 2017 Mar;47:64-75
pubmed: 27856324
Nat Genet. 2014 Feb;46(2):205-12
pubmed: 24413732
Cell Rep. 2014 Nov 6;9(3):1163-70
pubmed: 25437568
Leukemia. 2013 Nov;27(11):2165-76
pubmed: 23628958