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EMBO reports 6, 5, 445–451 (2005)
doi:10.1038/sj.embor.7400391
Published online: 15 April 2005
The histone-binding code of nuclear receptor co-repressors matches the substrate specificity of histone deacetylase 3
Helen B Hartman*, Jiujiu Yu*, Theresa Alenghat, Takahiro Ishizuka & Mitchell A Lazar
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Division of Endocrinology, Diabetes and Metabolism, Department of Medicine and Department of Genetics, and The Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, 611 CRB, 415 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA
To whom correspondence should be addressed
Mitchell A Lazar Tel: +1 215 898 0198; Fax: +1 215 898 5408; E-mail: lazar@mail.med.upenn.edu
* These authors contributed equally to this work
Received 18 November 2004; Accepted 16 March 2005; Published online 15 April 2005.
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Abstract
Ligands for nuclear receptors facilitate the exchange of co-repressors for coactivators, leading to chromatin modifications that favour the activation of gene transcription. Here, we show that the repressed state of an endogenous retinoic acid-regulated gene is quickly re-established after ligand removal. As expected, repression is characterized by recruitment of N-CoR/SMRT–HDAC3 (histone deacetylase 3) co-repressor complexes, leading to local histone hypoacetylation. The achievement of the repressed state involves the ordered deacetylation of lysines in H4 tails. This order is determined by the inherent substrate specificity of HDAC3, and unexpectedly predicts the binding preference of N-CoR/SMRT for submaximally acetylated H4 tails. The match between the specificity of acetyl-histone deacetylation by HDAC3 and the histone-binding preference of N-CoR/SMRT allows the co-repressor complex to stabilize and propagate repression of nuclear hormone receptor gene targets.
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