There is a fundamental paradox within the nucleus of every eukaryotlc cell: the genetic material must be organized and compacted, while remaining accessible for readout by the transcription machinery. Histone proteins are at the core of this task and ultimately compact the chromosomal DNA thousands of fold to fit into the nucleus. Genome accessibility can be achieved in part by the actions of histone chaperones and histone acetyltransferases (HATs). Histone chaperones interact directly with histones and can assemble and/or disassemble them on DNA. HATs covalently modify the histones and thereby have the potential to alter chromatin structure. The investigators on this PROGRAM OF PROJECTS have discovered new and exciting linkages between the activities of histone chaperones and histone acetyltransferases. However, virtually nothing is known about the mechanisms by which these proteins work together to manage genome accessibility. The goal of this PROGRAM OF PROJECTS is to determine the molecular interrelationships between the structure and function of HATs and histone chaperones. This will be accomplished by testing three shared hypotheses, which allows for a multi-dimensional and intensive investigation at all levels (genetically, biochemically, thermodynamically, enzymatically, and structurally). In PROJECT 1, we will investigate the biochemical basis for how the histone chaperones and HATs function together to evict histones from a specific promoter DNA template assembled into nucleosomal arrays. In PROJECT 2, we will pursue physicochemical and structural studies related to histone chaperones and their effect on acetylated chromatin. In PROJECT 3, we will use a combination of in vivo yeast genetics and in vitro biochemistry to study the genetic and physical interactions of histone chaperones and HATs. Through the integration of the three research projects, the exchange of information and reagents, and the significant contributions of the Biophysics, Protein Expression and Purification (PEP) and Administrative Cores, the results generated from this Program will profoundly impact our understanding of how genome accessibility is regulated by modulating chromatin dynamics.

Public Health Relevance

The studies described in this proposal will provide important information about the organization of the genome and accessibility of the information encoded in the DNA. These studies on gene expression are directly relevant to processes of cell division, development of multi-cellular organisms, and disease progression (such as cancer).

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Program Projects (P01)
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Special Emphasis Panel (ZRG1-GGG-E (40))
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Preusch, Peter C
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Colorado State University-Fort Collins
Schools of Arts and Sciences
Fort Collins
United States
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Chassé, Maggie H; Muthurajan, Uma M; Clark, Nicholas J et al. (2017) Biochemical and Biophysical Methods for Analysis of Poly(ADP-Ribose) Polymerase 1 and Its Interactions with Chromatin. Methods Mol Biol 1608:231-253
White, Alison E; Hieb, Aaron R; Luger, Karolin (2016) A quantitative investigation of linker histone interactions with nucleosomes and chromatin. Sci Rep 6:19122
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
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
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
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
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
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

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