Now that the human genome has been sequenced, we must leam to understand the information that is encoded by its stmctural organization. How and when a particular gene is read by the cell's machinery is vital to all aspects of cell life, differentiation, and death. Several complex mechanisms are devoted to decoding the information that is inherent in each gene's stmctural organization. Histone acetyltransferases (HATs) are enzymes that posttranslationally acetylate lysine side chains of histones and other proteins. Histone chaperones are a diverse group of acidic proteins with roles in histone binding, nucleosome assembly and disassembly. The emerging concept that HAT and chaperone activities act synergistically to modulate chromatin stmcture v^dll be addressed in the Luger Project by combining x-ray crystallography mth methods in biophysics, enzymology, molecular biology, and biochemistry. The proposed studies are augmented and complemented through the participation of the other two Projects within this POI, and are dependent on the services provided by the three Cores. The three Projects of the POI will pursue three common aims. The Luger Project will test the first hypothesis ("histone mobilization by chaperones requires histone acetylation") by kinetically and thermodynamically quantifying the effects of histone acetylation on chaperone-histone interaction and nucleosome stability.
This aim will also uncover functional and mechanistic differences between different histone chaperones with diverging biological functions. To test the second hypothesis ("histone chaperones regulate histone acetyltransferases"), we will stmcturally and functionally characterize the interaction between chaperones and HATs using x-ray crystallography and enzymology. Our contribution to hypothesis 3 ("histone chaperones function beyond the mononucleosome") will involve a biophysical characterization of the effect of chromatin compaction on chaperone function. Together, the experiments in this Project will yield unprecedented quantitative insight into the interconnection of histone acetylation, nucleosome assembly, and nucleosome disassembly.
A detailed knowledge of the mechanisms that regulate chromatin stmcture is a prerequisite for understanding how misguided compaction/decompaction of highly condensed genomic DNA may lead to disease through misregulation of gene transcription. This project adresses the interconnection between two seemingly unrelated activities involved in the modulation of chromatin stmcture
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