The long-term goal of this project is to distinguish between the individual functions of the eleven known human histone deacetylase (HDAC) proteins. HDAC proteins are transcription factors that repress transcription by deacetylating nucleosomal histones. Studies using small molecule inhibitors of HDAC proteins have demonstrated their importance in cell cycle regulation, tissue differentiation, and cancer formation. In fact, small molecule inhibitors of HDAC proteins are being developed to treat certain diseases, including myeloid leukemia. The nonspecific inhibition of all eleven known human HDAC proteins by small molecule inhibitors, however, complicates the determination of which HDAC plays a causative role in disease development. Rigorous characterization of the biological relevance of each of the known HDAC proteins would aid in development of pharmaceutical agents to treat disease. The short-term goal of this proposal is to focus on characterizing the individual functions of HDAC1. A bioorganic approach will be taken where the small molecule HDAC inhibitor trichostatin will be used to deduce the individual functions of HDAC1. Specifically, mutant protein of HDAC1 that has altered sensitivity to small molecule inhibition will be used to document their individual effects on gene expression. The experiments in this proposal aim to characterize the specific activities of HDAC1 as a first step toward identifying the individual functions of all human HDAC proteins. The proposed project will lay the foundation for the ultimate development of pharmaceutical agents targeting HDAC proteins.
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