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
|Chen, Xu; D'Arcy, Sheena; Radebaugh, Catherine A et al. (2016) Histone Chaperone Nap1 Is a Major Regulator of Histone H2A-H2B Dynamics at the Inducible GAL Locus. Mol Cell Biol 36:1287-96|
|White, Alison E; Hieb, Aaron R; Luger, Karolin (2016) A quantitative investigation of linker histone interactions with nucleosomes and chromatin. Sci Rep 6:19122|
|Chatterjee, Nilanjana; North, Justin A; Dechassa, Mekonnen Lemma et al. (2015) Histone Acetylation near the Nucleosome Dyad Axis Enhances Nucleosome Disassembly by RSC and SWI/SNF. Mol Cell Biol 35:4083-92|
|Brehove, Matthew; Wang, Tao; North, Justin et al. (2015) Histone core phosphorylation regulates DNA accessibility. J Biol Chem 290:22612-21|
|Kuo, Yin-Ming; Henry, Ryan A; Huang, Liangqun et al. (2015) Utilizing targeted mass spectrometry to demonstrate Asf1-dependent increases in residue specificity for Rtt109-Vps75 mediated histone acetylation. PLoS One 10:e0118516|
|Mattiroli, Francesca; D'Arcy, Sheena; Luger, Karolin (2015) The right place at the right time: chaperoning core histone variants. EMBO Rep 16:1454-66|
|Groocock, Lynda M; Nie, Minghua; Prudden, John et al. (2014) RNF4 interacts with both SUMO and nucleosomes to promote the DNA damage response. EMBO Rep 15:601-8|
|Muthurajan, Uma M; Hepler, Maggie R D; Hieb, Aaron R et al. (2014) Automodification switches PARP-1 function from chromatin architectural protein to histone chaperone. Proc Natl Acad Sci U S A 111:12752-7|
|Blakeslee, Weston W; Wysoczynski, Christina L; Fritz, Kristofer S et al. (2014) Class I HDAC inhibition stimulates cardiac protein SUMOylation through a post-translational mechanism. Cell Signal 26:2912-20|
|Chodaparambil, Jayanth V; Pate, Kira T; Hepler, Margretta R D et al. (2014) Molecular functions of the TLE tetramerization domain in Wnt target gene repression. EMBO J 33:719-31|
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