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Gene expression is in part controlled by chromatin remodeling factors and the acetylation state of nucleosomal histones. The latter process is regulated by histone acetyltransferases and histone deacetylases (HDACs). Previously, three human and five yeast HDAC enzymes had been identified. These can be categorized into two classes: the first class represented by yeast Rpd3-like proteins and the second by yeast Hda1-like proteins. Human HDAC1, HDAC2, and HDAC3 proteins are members of the first class, whereas no class II human HDAC proteins had been identified. The amino acid sequence of Hda1p was used to search the GenBank/expressed sequence tag databases to identify partial sequences from three putative class II human HDAC proteins. The corresponding full-length cDNAs were cloned and defined as HDAC4, HDAC5, and HDAC6. These proteins possess certain features present in the conserved catalytic domains of class I human HDACs, but also contain additional sequence domains. Interestingly, HDAC6 contains an internal duplication of two catalytic domains, which appear to function independently of each other. These class II HDAC proteins have differential mRNA expression in human tissues and possess in vitro HDAC activity that is inhibited by trichostatin A. Coimmunoprecipitation experiments indicate that these HDAC proteins are not components of the previously identified HDAC1 and HDAC2 NRD and mSin3A complexes. However, HDAC4 and HDAC5 associate with HDAC3 in vivo. This finding suggests that the human class II HDAC enzymes may function in cellular processes distinct from those of HDAC1 and HDAC2.