title: Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation.
abstract: Acetylation of histones at DNA regulatory elements plays a critical role in transcriptional activation. Histones are also modified by other acyl moieties, including crotonyl, yet the mechanisms that govern acetylation versus crotonylation and the functional consequences of this "choice" remain unclear. We show that the coactivator p300 has both crotonyltransferase and acetyltransferase activities, and that p300-catalyzed histone crotonylation directly stimulates transcription to a greater degree than histone acetylation. Levels of histone crotonylation are regulated by the cellular concentration of crotonyl-CoA, which can be altered through genetic and environmental perturbations. In a cell-based model of transcriptional activation, increasing or decreasing the cellular concentration of crotonyl-CoA leads to enhanced or diminished gene expression, respectively, which correlates with the levels of histone crotonylation flanking the regulatory elements of activated genes. Our findings support a general principle wherein differential histone acylation (i.e., acetylation versus crotonylation) couples cellular metabolism to the regulation of gene expression.
authors.affiliation: Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Sabari
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Zhanyun
authors.initials: Z
authors.lastname: Tang
authors.affiliation: Ben May Department of Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.affiliation: Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Yong-Gonzalez
authors.affiliation: Proteomics Resource Center, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Henrik
authors.initials: H
authors.lastname: Molina
authors.affiliation: Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Ha Eun
authors.initials: HE
authors.lastname: Kong
authors.affiliation: Ben May Department of Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Lunzhi
authors.initials: L
authors.lastname: Dai
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Miho
authors.initials: M
authors.lastname: Shimada
authors.affiliation: Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Cross
authors.affiliation: Ben May Department of Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Yingming
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Roeder
authors.affiliation: Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA. Electronic address: alliscd@rockefeller.edu.
authors.forename: C David
authors.initials: CD
authors.lastname: Allis
mesh_terms: D000106:Acetate-CoA Ligase / Q000235:genetics / Q000378:metabolism; D000107:Acetylation; D000214:Acyl Coenzyme A / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002474:Cell-Free System; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D000214:Acyl Coenzyme A; D006657:Histones; D008070:Lipopolysaccharides; D012333:RNA, Messenger; C010701:crotonyl-coenzyme A; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; C000595379:ACSS2 protein, human; D000106:Acetate-CoA Ligase
references.citation: Genet Mol Res. 2008;7(2):342-56
references.pmid: 18551400
references.citation: Mol Cell. 2002 Apr;9(4):811-21
references.pmid: 11983172
references.citation: Cell. 2009 Jul 10;138(1):114-28
references.pmid: 19596239
references.citation: Immunity. 2010 Mar 26;32(3):317-28
references.pmid: 20206554
references.citation: Nature. 2011 May 19;473(7347):337-42
references.pmid: 21593866
references.citation: Cell. 2011 Sep 16;146(6):1016-28
references.pmid: 21925322
references.citation: Mol Cell Proteomics. 2012 May;11(5):100-7
references.pmid: 22389435
references.citation: ACS Chem Biol. 2012 Jun 15;7(6):947-60
references.pmid: 22571489
references.citation: Cell. 2012 Jul 20;150(2):279-90
references.pmid: 22817891
references.citation: Cell. 2013 Mar 28;153(1):56-69
references.pmid: 23540690
references.citation: Cell. 2013 Jul 18;154(2):297-310
references.pmid: 23870121
references.citation: Nature. 2013 Oct 24;502(7472):489-98
references.pmid: 24153302
references.citation: ACS Chem Biol. 2013 Dec 20;8(12):2607-21
references.pmid: 24228614
references.citation: Nat Chem Biol. 2014 May;10(5):365-70
references.pmid: 24681537
references.citation: Cell. 2014 Jul 3;158(1):84-97
references.pmid: 24995980
references.citation: Cell Metab. 2014 Aug 5;20(2):306-19
references.pmid: 24998913
references.citation: Cell. 2004 Jun 11;117(6):735-48
references.pmid: 15186775
references.citation: Nat Struct Mol Biol. 2007 Nov;14(11):1025-40
references.pmid: 17984965
references.citation: Nat Protoc. 2007;2(6):1445-57
references.pmid: 17545981
references.citation: Mol Cell Proteomics. 2007 May;6(5):812-9
references.pmid: 17267393
references.citation: Methods Enzymol. 1999;304:675-96
references.pmid: 10372390
references.citation: Cell. 1996 Mar 22;84(6):843-51
references.pmid: 8601308
references.citation: J Biol Chem. 1977 Jan 25;252(2):504-7
references.pmid: 13070
references.citation: Science. 2009 May 22;324(5930):1076-80
references.pmid: 19461003