title: A SIRT1-LSD1 corepressor complex regulates Notch target gene expression and development.
abstract: Epigenetic regulation of gene expression by histone-modifying corepressor complexes is central to normal animal development. The NAD(+)-dependent deacetylase and gene repressor SIRT1 removes histone H4K16 acetylation marks and facilitates heterochromatin formation. However, the mechanistic contribution of SIRT1 to epigenetic regulation at euchromatic loci and whether it acts in concert with other chromatin-modifying activities to control developmental gene expression programs remain unclear. We describe here a SIRT1 corepressor complex containing the histone H3K4 demethylase LSD1/KDM1A and several other LSD1-associated proteins. SIRT1 and LSD1 interact directly and play conserved and concerted roles in H4K16 deacetylation and H3K4 demethylation to repress genes regulated by the Notch signaling pathway. Mutations in Drosophila SIRT1 and LSD1 orthologs result in similar developmental phenotypes and genetically interact with the Notch pathway in Drosophila. These findings offer new insights into conserved mechanisms of epigenetic gene repression and regulation of development by SIRT1 in metazoans.
authors: Massachusetts General Hospital Cancer Center and Harvard Medical School, Building 149, 13th Street, Charlestown, MA 02129, USA.
authors: Peter
authors: P
authors: Mulligan
authors: Fajun
authors: F
authors: Yang
authors: Luisa
authors: L
authors: Di Stefano
authors: Jun-Yuan
authors: JY
authors: Ji
authors: Jian
authors: J
authors: Ouyang
authors: Joy L
authors: JL
authors: Nishikawa
authors: Debra
authors: D
authors: Toiber
authors: Madhura
authors: M
authors: Kulkarni
authors: Qun
authors: Q
authors: Wang
authors: S Hani
authors: SH
authors: Najafi-Shoushtari
authors: Raul
authors: R
authors: Mostoslavsky
authors: Steven P
authors: SP
authors: Gygi
authors: Grace
authors: G
authors: Gill
authors: Nicholas J
authors: NJ
authors: Dyson
authors: Anders M
authors: AM
authors: Näär
references: Nature. 2007 Apr 19;446(7138):882-7
references: 17392792
references: Cell Mol Life Sci. 2009 May;66(10):1631-46
references: 19165418
references: Curr Biol. 2007 May 1;17(9):808-12
references: 17462898
references: Cell. 2004 Dec 29;119(7):941-53
references: 15620353
references: Genes Dev. 2011 Jan 1;25(1):17-28
references: 21205864
references: Nature. 2008 Jan 31;451(7178):587-90
references: 18235502
references: Mol Cell. 2009 Apr 24;34(2):145-54
references: 19394292
references: Development. 2009 Mar;136(6):879-89
references: 19234061
references: EMBO J. 2007 Jul 11;26(13):3169-79
references: 17581637
references: Development. 2004 Mar;131(5):965-73
references: 14973298
references: J Mol Neurosci. 2006;29(3):227-39
references: 17085781
references: Cell. 2007 Feb 23;128(4):693-705
references: 17320507
references: Nature. 2003 Apr 17;422(6933):735-8
references: 12700765
references: Mol Cell Biol. 2005 Dec;25(23):10433-41
references: 16287856
references: Mol Cell Biol. 2002 Aug;22(15):5296-307
references: 12101226
references: Genes Dev. 1998 Aug 1;12(15):2269-77
references: 9694793
references: Chem Biol. 2006 Jun;13(6):563-7
references: 16793513
references: J Biol Chem. 2001 Oct 19;276(42):38837-43
references: 11483616
references: Mol Cell. 2007 Jan 12;25(1):15-30
references: 17218268
references: Annu Rev Pathol. 2008;3:587-613
references: 18039126
references: Genes Dev. 2010 Jul 1;24(13):1403-17
references: 20595232
references: Oncogene. 2010 Sep 2;29(35):4896-904
references: 20562920
references: Nature. 2008 Jan 31;451(7178):583-6
references: 18235501
references: Int J Dev Biol. 2009;53(2-3):303-22
references: 19378253
references: Nucleic Acids Res. 1983 Mar 11;11(5):1475-89
references: 6828386
references: EMBO Rep. 2002 Sep;3(9):840-5
references: 12223465
references: Oncogene. 2008 Sep 1;27(38):5115-23
references: 18758480
references: EMBO J. 2002 Sep 16;21(18):4927-37
references: 12234932
references: PLoS One. 2009 Aug 24;4(8):e6728
references: 19701455
references: Genes Dev. 1995 Nov 1;9(21):2598-608
references: 7590238
references: Mol Cell. 2009 Sep 24;35(6):782-93
references: 19782028
references: Nature. 2010 Aug 26;466(7310):1105-9
references: 20622856
references: Proc Natl Acad Sci U S A. 2005 Feb 8;102(6):1859-64
references: 15684044
references: Mol Cell. 2005 Sep 16;19(6):857-64
references: 16140033
references: PLoS Genet. 2006 Mar;2(3):e40
references: 16596166
references: J Med Chem. 2005 Dec 15;48(25):8045-54
references: 16335928
references: Nature. 2005 Sep 15;437(7057):432-5
references: 16079794
references: EMBO J. 1998 Apr 1;17(7):2067-78
references: 9524128
references: Nat Rev Mol Cell Biol. 2008 Mar;9(3):206-18
references: 18292778
references: Curr Biol. 2001 May 15;11(10):789-92
references: 11378391
references: Genetics. 2004 Nov;168(3):1477-89
references: 15579700
references: Structure. 2006 Mar;14(3):457-68
references: 16531230
references: Development. 2005 Aug;132(15):3333-44
references: 15975935
references: J Neurosci. 2010 Jul 21;30(29):9695-707
references: 20660252
references: Cell Mol Life Sci. 2009 Mar;66(5):773-87
references: 19011757
references: Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10794-9
references: 12960381
references: Mol Cell Biol. 2005 Dec;25(23):10379-90
references: 16287852
references: Exp Cell Res. 1994 Sep;214(1):189-97
references: 8082721
references: Methods Enzymol. 2003;370:430-44
references: 14712665
references: Proc Natl Acad Sci U S A. 2002 May 28;99(11):7420-5
references: 12032298
references: Nat Protoc. 2006;1(2):729-48
references: 17406303
references: Int J Biol Sci. 2009;5(2):147-52
references: 19173036
references: Curr Biol. 2004 Oct 26;14(20):1812-21
references: 15498488
references: Cell. 2010 Oct 15;143(2):212-24
references: 20888037
references: Nature. 2007 Nov 15;450(7168):440-4
references: 18004385
references: Science. 2006 Feb 10;311(5762):844-7
references: 16469925
references: Genes Dev. 2002 Jun 1;16(11):1339-44
references: 12050112
references: Nat Rev Cancer. 2010 Jul;10(7):457-69
references: 20574448
references: Cell. 1994 Oct 21;79(2):273-82
references: 7954795
references: Mol Cell. 2004 Oct 8;16(1):93-105
references: 15469825
references: Mol Cell. 2008 Dec 5;32(5):718-26
references: 19061646
references: Oncogene. 2007 Aug 13;26(37):5505-20
references: 17694090
references: Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4568-73
references: 12676992
references: Genes Dev. 2010 Mar 15;24(6):590-601
references: 20231316
references: Int J Biochem Cell Biol. 2007;39(9):1593-607
references: 17336131
references: Mech Dev. 2009 Jan-Feb;126(1-2):68-79
references: 18992810
references: Nat Cell Biol. 2008 Apr;10(4):385-94
references: 18344989