Abstract
Histone acetyltransferases and deacetylases are recruited by transcription factors and adapter proteins to regulate specific subsets of target genes. We were interested in identifying interaction partners of histone deacetylase 1 (HDAC1) that might be involved in conferring target or substrate specificity. Using the yeast two-hybrid system, we isolated the repressor of estrogen receptor activity (REA) as a novel HDAC1-associated protein. We demonstrated the in vivo interaction of REA with HDAC1 and characterized the respective domains required for their interaction in vitro. In addition, we found that REA also associates with the class II histone deacetylase HDAC5. In luciferase reporter assays, REA decreased transcription, and this repression was sensitive to the deacetylase inhibitor trichostatin A. Finally, we showed that REA specifically interacts with the chicken ovalbumin upstream binding transcription factors and II. The nuclear receptor chicken ovalbumin upstream binding transcription factor I was found to cooperate with REA and histone deacetylases in the repression of target genes. We, therefore, propose a novel function for REA as a mediator of transcriptional repression by nuclear hormone receptors via recruitment of histone deacetylases.
Highlights
Histone acetyltransferases and deacetylases are recruited by transcription factors and adapter proteins to regulate specific subsets of target genes
Mouse receptor activity (REA) was first identified as the murine B-cell receptor-associated protein 37, a protein originally isolated through its physical association with the B lymphocyte IgM antigen receptor [34]
REA as an HDAC-associated Protein—The specificity of histone deacetylases as transcriptional repressors is defined by the recruitment of these enzymes by transcription factors or co-repressor proteins
Summary
□S The on-line version of this article (available at http://www.jbc.org) contains Supplemental Figs. 1 and 2. ** Current address: School of Life Sciences, University of Dundee, Dundee DD1 5 EH, UK. A large number of transcription factors regulate gene expression through the recruitment of histone deacetylase complexes. A direct association between HDACs and nuclear receptors was reported [22], increasing the complexity of the interaction between these two types of partners. Transcription of the murine HDAC1 gene is induced by cooperative phosphorylation and acetylation signals, allowing both growth factor-dependent activation and feedback regulation [25, 26]. Apart from this, specific recruiting factors are required to confer high target specificity upon HDAC1 To this aim, we employed the yeast two-hybrid system to isolate hitherto unknown interaction partners of HDAC1. Our data identify REA as novel HDAC-interacting protein that modulates the activity of a defined subset of nuclear hormone receptors
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