The Homeodomain Protein NK-3 Recruits Groucho and a Histone Deacetylase Complex to Repress Transcription*
- From the ‡Laboratory of Molecular Cardiology, NHLBI, National Institutes of Health, Bethesda, Maryland 20892 and the§Department of Radiation Medicine, Georgetown University, Washington, D. C. 20007
Abstract
Transcriptional repression by sequence-specific DNA binding factors is mediated by the recruitment of a corepressor complex to the promoter region. The NK-3 homeodomain protein is a transcriptional repressor that recruits the nuclear protein kinase, homeodomain interacting protein kinase 2 (HIPK2). Here we show that HIPK2 is a component of a corepressor complex containing Groucho and a histone deacetylase complex. Groucho, like HIPK2, acts as a corepressor for NK-3 and binds to NK-3 and HIPK2. Moreover, HIPK2 appears to regulate the corepressor activity of Groucho. Transcriptional repression by NK-3 and Groucho is relieved by the histone deacetylase inhibitor trichostatin A, and both NK-3 and Groucho directly interact with the histone deacetylase HDAC1 that is associated with mSin3Ain vivo. Recruitment of the histone deacetylase complex by NK-3 decreases the acetylated histones that are associated with the target gene promoter. These results indicate that NK-3 represses transcription by recruiting a complex containing Groucho and a histone deacetylase complex that leads to histone modification on chromatin and suggest that HIPK2 may play a regulatory role in the corepressor complex formation.
Footnotes
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↵* This work was supported by a grant from the NHLBI, National Institutes of Health, Intramural Program (to Y. K.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵‖ To whom correspondence should be addressed: Bldg. 10, Rm. 8N228, NHLBI, National Institutes of Health, Bethesda, MD 20892. E-mail: yongsok@helix.nih.gov.
- Abbreviations:
- HIPK2
-
homeodomain interacting protein kinase 2
- aa
-
amino acid(s)
- CAT
-
chloramphenicol acetyltransferase
- CHIP
-
chromatin immunoprecipitation
- GFP
-
green fluorescent protein
- GRO
-
Groucho
- GST
-
glutathioneS-transferase
- HDAC
-
histone deacetylase
- PCR
-
polymerase chain reaction
- TSA
-
trichostatin A
-
- Received August 23, 1999.
- Revision received September 20, 1999.
- The American Society for Biochemistry and Molecular Biology, Inc.
