No abstract

Post-translational modifications of histones, in general, and acetylation/deacetylation, in particular, can dramatically alter gene expression in eukaryotic cells. In humans, four highly homologous class I HDAC enzymes (HDAC1, HDAC2, HDAC3, and HDAC8) have been identified to date. Although HDAC3 shares some structural and functional similarities with other class I HDACs, it exists in multisubunit complexes separate and different from other known HDAC complexes, implying that individual HDACs might function in a distinct manner. In this current study, to understand further the cellular function of HDAC3 and to uncover possible unique roles this protein may have in gene regulation, we performed a detailed analysis of HDAC3 using deletion mutations. Surprisingly, we found that the non-conserved C-terminal region of HDAC3 is required for both deacetylase and transcriptional repression activity. In addition, we discovered that the central portion of the HDAC3 protein possesses a nuclear export signal, whereas the C-terminal part of HDAC3 contributes to the protein's localization in the nucleus. Finally, we found that HDAC3 forms oligomers in vitro and in vivo and that the N-terminal portion of HDAC3 is necessary for this property. These data indicate that HDAC3 comprises separate, non-overlapping domains that contribute to the unique properties and function of this protein.Post-translational modification of nucleosomal histones can convert regions of chromosomes into transcriptionally active or inactive chromatin. The best understood post-translational modification of histones is the acetylation of ⑀-amino groups on conserved lysine residues in the histones' N-terminal tail domains. In addition to its effect on transcription, acetylation of core histones has been correlated with many important cellular processes, including chromatin assembly, DNA repair, and recombination (1-7).In general, the status of histone acetylation in a cell is regulated by histone acetyltransferases and histone deacetylases (HDACs).1 In humans, HDACs are divided into three categories (8 -11): the class I RPD3-like proteins (HDAC1, HDAC2, HDAC3, and HDAC8); the class II HDA1-like proteins (HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10); and the class III SIR2-like proteins. The recent availability of the human genome sequence revealed the possibility of additional HDACs whose class assignment has yet to be determined (12). Because class I HDACs are ubiquitously expressed, whereas most class II HDACs are tissue-specific, it has been proposed that the class I enzymes may be important in the regulation of housekeeping genes (13,14). By far, the most thoroughly studied human HDACs are the two founding members of the class I enzymes, HDAC1 and the closely related HDAC2 protein. HDAC1 and HDAC2 exist together in at least three distinct multiprotein complexes called the Sin3, the NuRD/NRD/Mi2, and the CoREST complexes (15-22). In addition, many transcription factors interact directly with HDAC1/2 and thus may target HDAC1/2 to specific promoters (8,...