Histone deacetylases, typified by class I Rpd3 in the yeast Saccharomyces cerevisiae, have historically been associated with gene repression. We now demonstrate that Hos2, another member of the class I family, binds to the coding regions of genes primarily during gene activation, when it specifically deacetylates the lysines in H3 and H4 histone tails. Moreover, Hos2 is pref-erentially associated with genes of high activity genome-wide. We also show that Hos2 and an associated factor, Set3, are necessary for efficient transcrip-tion. Therefore, our data indicate that, in contrast to other class I histone deacetylases, Hos2 is directly required for gene activation. Histone deacetylases such as Rpd3 and Hda1 can act locally at promoters or globally throughout the genome to repress gene activ-ity (1–5). In yeast, Rpd3 is required for deacetylation of all lysines examined in the core histones H3, H4, H2A, and H2B excep
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