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The Orphan Nuclear Receptor TR2 Interacts Directly with Both Class I and Class II Histone Deacetylases

Department of Pharmacology (P.J.F., M.F., L.-N.W.) University of Minnesota Medical School, Minneapolis, Minnesota 55455; and Molecular Oncology Program (E.S.), H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, Florida 33612

Address all correspondence and requests for reprints to: Dr. Li-Na Wei, Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church Street S.E., Minneapolis, Minnesota 55455. E-mail: weixx009{at}maroon.tc.umn.edu

A combination of in vivo and in vitro assays was employed to describe the ligand-independent interaction of the orphan nuclear receptor TR2 and histone deacetylase proteins. The repressive effect of TR2 on transcription of a luciferase reporter driven by a promoter containing a direct repeat-5 (DR5) derived from the human RARß gene was suppressed by the addition of the histone deacetylase inhibitor trichostatin A. Immunoprecipitation with FLAG-epitope (MDYKDDDDK)-tagged histone deacetylase proteins was used to demonstrate that TR2 and histone deacetylases 3 or 4 are present in the same immunoprecipitated complex. Deacetylase activity was demonstrated for these coimmunoprecipitates, further confirming the in vivo interaction of TR2 and histone deacetylases. Immunoprecipitation with anti-TR2 antibody was used to demonstrate interaction of TR2 with endogenously expressed histone deacetylases 3 and 4 in COS-1 cells. Dissection of TR2 domains showed that the DNA binding domain of the receptor was responsible for interaction with both histone deacetylases 3 and 4 in glutathione-S-transferase pull-down assays, while the ligand binding domain did not interact. The pull-down data were confirmed with far Western blots that also showed a direct interaction between labeled histone deacetylase proteins and TR2. It is suggested that repression mediated by unliganded TR2 is mediated, in part, by a direct interaction of this receptor with histone deacetylase proteins.

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