Dynamic transitions in chromatin stmcture are key elements to normal pattems of transcriptional activation in vivo. This Program of Projects is designed to fill a void in our understanding of how histone chaperones, in conjunction with histone acetylti'ansferases (HATs), contribute to the regulation of chromatin structure. Our approaches are broad and multi-pronged, spanning from in vivo genetic and molecular studies, to in viti'o biochemical and sti'uctural investigations. These innovative studies are highly synergistic and are dependent on the services provided by three Cores Facilities. The three Research Projects will pursue three common hypotheses.
The aims proposed in the Stargell Project specifically address tiie contributions of chaperones and HATs to gene expression programs in vivo. The Stargell Project will test tiie first hypothesis (histone mobilization by chaperones is linked to histone acetylation) by determining whetiier there are specific in vivo contributions to gene expression, chromatin organization and histone mobility that are distinct for different chaperones and HAT family members. To test the second hypothesis (histone chaperones interact with histone acetyltransferases), we will determine if chaperones are required for HAT activity in vivo (or vice versa), and whether physical interactions can be detected. For hypothesis 3 (histone chaperones fijnction beyond the mono-nucleosome), we will investigate the potential roles of histone chaperone in particular steps in transcription (PIC formation, elongation, etc.), and assay chaperone complexes purified from yeast cells for their in vitro capabilities. Our work will provide a detailed picture of the influence of histone chaperones and histone acetylation on the dynamic nature of chromatin during the activation of gene expression in vivo. Taken together, this Program of Projects will explore transitions in chromatin and the links between histone chaperones and HATs. The results generated will profoundly impact our understanding of how genome accessibility is regulated.
Chromatin is a major obstacle to regulatory proteins, which must have access to DNA to allow for proper gene expression. Histone chaperones and acetyltransferases change chromatin stmcture, thus facilitating normal gene expression. The studies proposed here on these proteins are highly relevant to tiie human condition since many diseases are directly linked to abenant gene expression (i.e. cancer).
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