The histone H3 and H4 termini help regulate cell cycle progression, gene activity and nucleosome assembly. These functions are likely to be mediated by acetylation and deacetylation of these N terminal tails which may not only affect their interactions with underlying DNA but with other proteins. We have recently discovered the family of five histone deacetylases in yeast which have different and overlapping roles in H3 and H4 acetylation, cell cycle progression and gene activity. Our goal now is to define these roles at a molecular level. We proposed to identify catalytic and regulatory non-catalytic subunits of each of these complexes since these factors may determine deacetylase specificity to different sites in histones, different genes and different stages of the cell cycle. We wish to know the extent to which deacetylase regulates un-induced and induced gene activity and whether this occurs through effects on nucleosome positioning, DNA topology or chromosomal condensation. Since nucleosome structure is disrupted at promoters by activators even before transcription and since histone acetylation provides a logical mechanism for nucleosome disruption, we propose to determine whether a known acetyltransferase (TAF130), that is part of the transcription machinery, disrupts nucleosome at promoters. Finally, we will determine which sites of acetylation in H3 and H4 are important for nucleosome assembly. Understanding gene activity and the cell cycle is central to our knowledge of human disease processes. Chromatin modifications affect both. Moreover, disruption of a histone deacetylase by a drug has been identified as a means of selectively inactivating parasites involved in diseases such as malaria and toxoplasmosis. The molecular characterization of the multiple histone deacetylases in yeast will allow the design of rational approaches to combat these disease states.
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