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).
|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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