Epigenetic regulation is a newly appreciated and fundamentally important set of gene control mechanisms that profoundly influences chromatin function. Histone lysine and arginine methylation, demethylation, and the detection of these methyl marks are components of a "histone code" that underlies epigenetic regulation. Epigenetic regulators modulate the structure, function, and access of the mammalian genome to regulate transcription. Hundreds of epigenetic effectors have been identified, many of which are enzymes that catalyze reversible chromatin modifications. Many of these enzymes contain distinct functional domains, within the same polypeptide, for both creating (or removing) and binding to a given methyl mark. To date, most if not all available structural knowledge of these chromatin (de)modifying enzymes comes from the structures of individual domains. To approach a more complete understanding of the mechanisms of epigenetic regulation, we need to understand how these different functional domains work, both individually and in concert. The central goal of this proposal is to understand the interactions and spatial relationships between such domains by determining structures spanning multiple domains of several complementary epigenetic regulators. Such information will help us to address whether the "writer" and "reader" domains act on the same histone, and whether there are any inter-domain interactions that can influence/regulate their target specificity. Importantly, broader themes may be recognized because several distinct epigenetic regulators will be studied in parallel. I propose here four new specific aims that are designed to answer four related questions. (1) How does a lysine methylation mark for repression spread? (2) How does an existing methyl mark prevent the modification of neighboring residues in histones? (3) How are the histone marks of repression connected to DNA methylation? (4) How are the local methyl marks of repression removed within a nucleosome?
Epigenetic regulation is a newly appreciated and fundamentally important set of gene control mechanisms that profoundly influences chromatin function, which has direct relevance to a large number of human diseases. An increasing number of chromatin modifying and de-modifying enzymes have been associated with neurodegenerative disorders, metabolic diseases, inflammation, and, most notably, cancer. Thus, structural and biochemical studies directed against this emerging class of gene regulatory enzymes may provide a method for the development of highly selective therapeutic agents that promise entirely novel approaches for the treatment of human diseases. In this proposal, we will explore questions of dynamic regulation (creating and removing) of histone lysine modifications, modification- and position-specific interactions, and biochemical crosstalk between modifications by several distinct epigenetic regulators.
|Upadhyay, Anup K; Rotili, Dante; Han, Ji Woong et al. (2012) An analog of BIX-01294 selectively inhibits a family of histone H3 lysine 9 Jumonji demethylases. J Mol Biol 416:319-27|
|Chang, Yanqi; Horton, John R; Bedford, Mark T et al. (2011) Structural insights for MPP8 chromodomain interaction with histone H3 lysine 9: potential effect of phosphorylation on methyl-lysine binding. J Mol Biol 408:807-14|
|Horton, John R; Upadhyay, Anup K; Hashimoto, Hideharu et al. (2011) Structural basis for human PHF2 Jumonji domain interaction with metal ions. J Mol Biol 406:1-8|
|Chang, Yanqi; Sun, Lidong; Kokura, Kenji et al. (2011) MPP8 mediates the interactions between DNA methyltransferase Dnmt3a and H3K9 methyltransferase GLP/G9a. Nat Commun 2:533|
|Upadhyay, Anup K; Cheng, Xiaodong (2011) Dynamics of histone lysine methylation: structures of methyl writers and erasers. Prog Drug Res 67:107-24|
|Cheng, Xiaodong; Blumenthal, Robert M (2011) Introduction--Epiphanies in epigenetics. Prog Mol Biol Transl Sci 101:1-21|
|Esteve, Pierre-Olivier; Chang, Yanqi; Samaranayake, Mala et al. (2011) A methylation and phosphorylation switch between an adjacent lysine and serine determines human DNMT1 stability. Nat Struct Mol Biol 18:42-8|
|Chang, Yanqi; Levy, Dan; Horton, John R et al. (2011) Structural basis of SETD6-mediated regulation of the NF-kB network via methyl-lysine signaling. Nucleic Acids Res 39:6380-9|
|Upadhyay, Anup K; Horton, John R; Zhang, Xing et al. (2011) Coordinated methyl-lysine erasure: structural and functional linkage of a Jumonji demethylase domain and a reader domain. Curr Opin Struct Biol 21:750-60|
|Zhao, Jing; Du, Yuhong; Horton, John R et al. (2011) Discovery and structural characterization of a small molecule 14-3-3 protein-protein interaction inhibitor. Proc Natl Acad Sci U S A 108:16212-6|
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