Groucho-mediated repression may result from a histone deacetylase-dependent increase in nucleosome density.
Groucho (Gro) is a Drosophila melanogaster transcriptional corepressor that directly interacts with the histone deacetylase Rpd3. Although previous studies suggest that this interaction is required for repression of Gro-responsive reporters in cultured cells, the in vivo significance of this interaction and the mechanism by which it leads to repression remain largely unexplored. In this study, we show that Gro is partially dependent on Rpd3 for repression, supporting the idea that Rpd3-mediated repression is one mode of Gro-mediated repression. We demonstrate that Gro colocalizes with Rpd3 to the chromatin of a target gene and that this is accompanied by the deacetylation of specific lysines within the N-terminal tails of histones H3 and H4. Gro overexpression leads to wing patterning defects and ectopic repression in the wing disc of transcription directed by the vestigial quadrant enhancer. These effects are reversed by the histone deacetylase inhibitors TSA and HC-Toxin and by the reduction of Rpd3 gene dosage. Furthermore, repression of the vestigial quadrant enhancer is accompanied by a Gro-mediated increase in nucleosome density, an effect that is reversed by histone deacetylase inhibitors. We propose a model in which Gro-mediated histone deacetylation results in increased nucleosome density leading to transcriptional repression.
Winkler
Clint J
CJ
Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California, United States of America.
Ponce
Alberto
A
Courey
Albert J
AJ
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D002843:Chromatin / Q000378:metabolism; D029721:Drosophila Proteins / Q000502:physiology; D004331:Drosophila melanogaster; D056284:Histone Deacetylase 1 / Q000502:physiology; D006655:Histone Deacetylases / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D009707:Nucleosomes / Q000378:metabolism*; D012097:Repressor Proteins / Q000502:physiology*
D051792:Basic Helix-Loop-Helix Proteins; D002843:Chromatin; D029721:Drosophila Proteins; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases; D006657:Histones; D009707:Nucleosomes; D012097:Repressor Proteins; C091023:gro protein, Drosophila; C512966:HDAC1 protein, Drosophila
J Biol Chem. 2002 Dec 27;277(52):51049-57
12397081
Genes Dev. 2001 Nov 1;15(21):2786-96
11691830
Nature. 1996 Jul 11;382(6587):133-8
8700202
Nature. 1998 Oct 8;395(6702):604-8
9783586
EMBO J. 1997 May 15;16(10):2883-91
9184232
Mol Cell. 2000 Feb;5(2):367-75
10882077
Proc Natl Acad Sci U S A. 2009 Oct 13;106(41):17314-9
19805071
Genes Dev. 1999 Sep 1;13(17):2218-30
10485845
Mol Cell Biol. 1996 Jun;16(6):2670-7
8649374
Nat Genet. 2002 Nov;32(3):378-83
12379856
Mol Cell Biol. 2005 Dec;25(23):10433-41
16287856
Endocrine. 2006 Jun;29(3):435-44
16943582
Proc Natl Acad Sci U S A. 2008 Dec 23;105(51):20072-6
19104040
Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15771-6
17898168
Mol Cell Biol. 2008 Apr;28(8):2792-802
18285466
Br J Cancer. 2006 Mar 27;94(6):771-5
16508633
Mech Dev. 1993 Jul;42(1-2):67-76
8369224
Trends Plant Sci. 2008 Mar;13(3):137-44
18314376
PLoS Biol. 2008 Dec 23;6(12):2928-39
19108605
Development. 2003 Sep;130(17):4001-10
12874122
J Biol Chem. 1996 Dec 20;271(51):33026-31
8955148
J Biol Chem. 1997 Oct 17;272(42):26604-10
9334241
Cell. 1992 Feb 21;68(4):709-19
1739976
Mol Cell Biol. 1998 Aug;18(8):4629-38
9671473
Development. 2008 Jun;135(12):2183-92
18506030
Cell. 2004 Jun 11;117(6):721-33
15186774
J Biol Chem. 1999 Nov 19;274(47):33194-7
10559189
EMBO J. 1999 Oct 15;18(20):5622-33
10523306
Mol Cell. 2009 Sep 24;35(6):782-93
19782028
Annu Rev Biochem. 1998;67:545-79
9759497
Development. 2008 Mar;135(5):829-37
18216172
Proc Natl Acad Sci U S A. 1999 Jan 19;96(2):535-40
9892668
Cancer Res. 2005 Nov 15;65(22):10214-22
16288009
J Biol Chem. 2003 Jun 27;278(26):24217-24
12697747
Development. 1997 May;124(10):1919-28
9169839
Mol Cell Biol. 1995 Dec;15(12):6923-31
8524259
Proc Natl Acad Sci U S A. 1981 Jan;78(1):143-6
6264428
Proc Natl Acad Sci U S A. 1999 Jun 8;96(12):6797-801
10359792
Mol Cell. 2007 Oct 26;28(2):291-303
17964267
Science. 2009 Jul 31;325(5940):626-8
19644123
Dev Biol. 2007 Mar 1;303(1):347-61
17188260
Nucleic Acids Res. 2000 Nov 1;28(21):4189-96
11058116
Genomics. 2005 Nov;86(5):606-17
16137856
Mol Cell Biol. 1998 Dec;18(12):7259-68
9819412
Cancer Res. 2006 Feb 1;66(3):1294-301
16452182
Mol Cell Biol. 2004 May;24(10):4341-50
15121853
Cell. 1994 Dec 2;79(5):805-15
8001118
Genes Dev. 1991 Dec;5(12B):2481-95
1752439
Cancer Res. 2008 Jun 1;68(11):4116-22
18519670
EMBO J. 2001 Oct 15;20(20):5725-36
11598015
Eur J Biochem. 1993 Aug 15;216(1):343-52
8365415
J Biol Chem. 2008 Sep 5;283(36):24881-8
18611861