title: Histone deacetylase 1 (HDAC1), but not HDAC2, controls embryonic stem cell differentiation.
abstract: Histone deacetylases (HDAC) 1 and 2 are highly similar enzymes that help regulate chromatin structure as the core catalytic components of corepressor complexes. Although tissue-specific deletion of HDAC1 and HDAC2 has demonstrated functional redundancy, germ-line deletion of HDAC1 in the mouse causes early embryonic lethality, whereas HDAC2 does not. To address the unique requirement for HDAC1 in early embryogenesis we have generated conditional knockout embryonic stem (ES) cells in which HDAC1 or HDAC2 genes can be inactivated. Deletion of HDAC1, but not HDAC2, causes a significant reduction in the HDAC activity of Sin3A, NuRD, and CoREST corepressor complexes. This reduced corepressor activity results in a specific 1.6-fold increase in histone H3 K56 acetylation (H3K56Ac), thus providing genetic evidence that H3K56Ac is a substrate of HDAC1. In culture, ES cell proliferation was unaffected by loss of either HDAC1 or HDAC2. Rather, we find that loss of HDAC1 affects ES cell differentiation. ES cells lacking either HDAC1 or HDAC2 were capable of forming embryoid bodies (EBs), which stimulates differentiation into the three primary germ layers. However, HDAC1-deficient EBs were significantly smaller, showed spontaneous rhythmic contraction, and increased expression of both cardiomyocyte and neuronal markers. In summary, our genetic study of HDAC1 and HDAC2 in ES cells, which mimic the embryonic epiblast, has identified a unique requirement for HDAC1 in the optimal activity of HDAC1/2 corepressor complexes and cell fate determination during differentiation.
authors.affiliation: Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom.
authors.forename: Oliver M
authors.initials: OM
authors.lastname: Dovey
authors.forename: Charles T
authors.initials: CT
authors.lastname: Foster
authors.forename: Shaun M
authors.initials: SM
authors.lastname: Cowley
mesh_terms: D000818:Animals; D015415:Biomarkers; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic; D056284:Histone Deacetylase 1 / Q000172:deficiency / Q000378:metabolism*; D056464:Histone Deacetylase 2 / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding
chemical_list: D015415:Biomarkers; C484389:Hdac1 protein, mouse; C533424:Hdac2 protein, mouse; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2
references.citation: J Cell Biochem. 2009 Jul 1;107(4):600-8
references.pmid: 19459166
references.citation: Mol Cell Biol. 2005 Aug;25(16):6990-7004
references.pmid: 16055712
references.citation: EMBO Rep. 2001 Apr;2(4):292-7
references.pmid: 11306549
references.citation: Int J Dev Biol. 2009;53(2-3):275-89
references.pmid: 19412887
references.citation: Nat Genet. 2006 May;38(5):566-9
references.pmid: 16642021
references.citation: Mol Cell Biol. 2007 Jul;27(13):4784-95
references.pmid: 17470557
references.citation: Nat Neurosci. 2009 Jul;12(7):829-38
references.pmid: 19503085
references.citation: Nat Med. 2007 Mar;13(3):324-31
references.pmid: 17322895
references.citation: Mol Cell. 2009 Feb 27;33(4):417-27
references.pmid: 19250903
references.citation: Nat Genet. 2009 Jan;41(1):125-9
references.pmid: 19098913
references.citation: Biochim Biophys Acta. 2009 Feb;1793(2):300-11
references.pmid: 18851995
references.citation: Nature. 2009 May 7;459(7243):55-60
references.pmid: 19424149
references.citation: Nat Cell Biol. 2006 Feb;8(2):188-94
references.pmid: 16415856
references.citation: Cell. 2008 Feb 22;132(4):661-80
references.pmid: 18295582
references.citation: Neuroscience. 2006 Dec 28;143(4):939-51
references.pmid: 17084985
references.citation: Nat Cell Biol. 2006 Mar;8(3):285-92
references.pmid: 16462733
references.citation: J Biol Chem. 2005 May 20;280(20):19682-8
references.pmid: 15764815
references.citation: Nat Protoc. 2007;2(6):1445-57
references.pmid: 17545981
references.citation: Curr Opin Genet Dev. 1998 Apr;8(2):140-6
references.pmid: 9610403
references.citation: Proc Natl Acad Sci U S A. 2004 Nov 23;101(47):16659-64
references.pmid: 15537713
references.citation: EMBO J. 2009 Jul 8;28(13):1878-89
references.pmid: 19407812
references.citation: Science. 2000 May 26;288(5470):1422-5
references.pmid: 10827952
references.citation: Cell. 1998 Feb 20;92(4):463-73
references.pmid: 9491888
references.citation: Nature. 1998 Feb 5;391(6667):601-5
references.pmid: 9468140
references.citation: Nature. 2007 Apr 19;446(7138):882-7
references.pmid: 17392792
references.citation: Nature. 2009 May 7;459(7243):113-7
references.pmid: 19270680
references.citation: J Mol Biol. 2001 Apr 20;308(1):27-38
references.pmid: 11302704
references.citation: Proc Natl Acad Sci U S A. 2009 May 12;106(19):7751-5
references.pmid: 19416910
references.citation: Genes Dev. 2007 Jul 15;21(14):1790-802
references.pmid: 17639084
references.citation: Genesis. 2004 Jan;38(1):32-8
references.pmid: 14755802
references.citation: Nat Rev Mol Cell Biol. 2008 Mar;9(3):206-18
references.pmid: 18292778
references.citation: Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1454-8
references.pmid: 11171972
references.citation: Nat Cell Biol. 2009 Oct;11(10):1261-7
references.pmid: 19734887
references.citation: Nat Cell Biol. 2008 Jun;10(6):731-9
references.pmid: 18454139
references.citation: Annu Rev Cell Dev Biol. 2001;17:435-62
references.pmid: 11687496
references.citation: Cancer Res. 2007 Oct 1;67(19):9047-54
references.pmid: 17909008
references.citation: Genes Dev. 2001 Mar 15;15(6):710-23
references.pmid: 11274056
references.citation: Biochem Biophys Res Commun. 2003 Oct 17;310(2):529-36
references.pmid: 14521942
references.citation: EMBO J. 2002 Jun 3;21(11):2672-81
references.pmid: 12032080
references.citation: J Mol Biol. 2008 Sep 12;381(4):816-25
references.pmid: 18653199
references.citation: Proc Natl Acad Sci U S A. 2009 May 12;106(19):7876-81
references.pmid: 19380719
references.citation: Genes Dev. 2003 Oct 1;17(19):2396-405
references.pmid: 14522945
references.citation: Mol Cell Biol. 2006 Nov;26(21):7913-28
references.pmid: 16940178
references.citation: Proc Natl Acad Sci U S A. 2002 May 28;99(11):7420-5
references.pmid: 12032298
references.citation: J Biol Chem. 2001 Mar 2;276(9):6817-24
references.pmid: 11102443
references.citation: Nature. 1998 Feb 5;391(6667):597-601
references.pmid: 9468139
references.citation: Exp Brain Res. 2007 Feb;176(4):672-8
references.pmid: 17216146