Faculty

Post-translational modifications of proteins play pivotal roles in governing a myriad of biological functions within the cell. Gene expression, the cell cycle, intracellular signaling cascades, cytoskeletal organization, and numerous metabolic pathways are just a few examples of cellular functions that are controlled by covalent modifications. Our laboratory is interested in understanding how protein modifications within the nucleus impact transcription and other genomic processes. Histones, the major scaffolding proteins that organize genomic DNA in chromatin, are enriched in modifications such as acetylation, methylation, phosphorylation and ubiquitination. Transcription factors and other components of the transcriptional machinery are subject to similar types of covalent modifications in vivo. These modifications collectively act as molecular switches that can either activate or repress gene expression, depending on the pattern of modifications established within a given gene locus. Aberrant histone modifications have been directly linked to carcinogenesis, underscoring the fundamental importance of these pathways in governing faithful gene expression.

Our laboratory is currently investigating protein lysine methyltransferases (KMTs) and demethylases (KDMs) that dynamically regulate the methylation status of lysine residues in histones and other nuclear proteins. These enzymes function in a concerted manner to govern transcription, heterochromatin structure, DNA damage response, cell cycle progression, differentiation, and development. Using structural and biochemical approaches, we have characterized the molecular basis of substrate recognition for several representative KMTs and KDMs in order to elucidate the mechanisms by which they control site- and state-specific lysine methylation in histones and non-histone proteins. A thorough understanding of these specificities is fundamental to human health as aberrant KMT and KDM activities have been clinically correlated with the onset and progression of a broad spectrum of cancers, including prostate, breast, lung, hepatic, and colorectal cancers. We envision that our research will provide a molecular basis for developing KMT- and KDM-specific inhibitors as new classes of chemotherapeutics and will also impact gene therapy and stem cell research due to the central role of epigenetic gene regulation to these fields.

Awards

Representative Publications

1. Krishnan S., Collazo E., Ortiz-Tello P.A., and Trievel R.C., “Purification and assay protocols for obtaining highly active Jumonji C demethylases”, Anal. Biochem., 2012, 420, 48.

2. Horowitz S., Yesselman J.D., Al-Hashimi H.M., and Trievel R.C., “Direct evidence for methyl group coordination by carbon-oxygen hydrogen bonds in the lysine methyltransferase SET7/9” J. Biol. Chem., 2011, 286, 18658.

3. Del Rizzo P.A., Couture J.-F., Dirk L.M., Strunk B.S., Roiko M.S., Brunzelle J.S., Houtz R.L., and Trievel R.C., “SET7/9 catalytic mutants reveal the role of active site water molecules in lysine multiple methylation” J. Biol. Chem., 2010, 285, 31849.

4. Couture J.-F., Dirk L.M., Brunzelle J.S., Houtz R.L., and Trievel R.C., “Structural origins for the product specificity of SET domain protein methyltransferases” Proc. Natl. Acad. Sci. U. S. A., 2008, 105, 20659.

5. Couture, J.-F., Collazo, E., Ortiz-Tello, P.A., Brunzelle, J.S., and Trievel, R.C., "Specificity and Mechanism of JMJD2A, a trimethyllysine-specific histone demethylase", Nat. Struct. Mol. Biol., 2007, 14, 689.

6. Couture, J.-F., Collazo, E. and Trievel, R.C., "Molecular recognition of histone H3 by the WD40 protein WDR5", Nat. Struct. Mol. Biol., 2006, 13, 698.

7. Couture, J.-F., Hauk, G., Thompson, M.J., Blackburn, G.M. and Trievel, R.C., "Catalytic roles for carbon-oxygen hydrogen bonding in SET domain lysine methyltransferases", J. Biol. Chem., 2006, 281, 19280.

8. Couture, J.-F., Collazo, E., Hauk, G. and Trievel, R.C., "Structural basis for the methylation site specificity of SET7/9", Nat. Struct. Mol. Biol., 2006, 13, 140.

9. Couture, J.-F., Collazo, E., Brunzelle, J.S. and Trievel, R.C., "Structural and functional analysis of SET8, a histone H4 Lys-20 methyltransferase", Genes Dev., 2005, 19, 1455.

10. Collazo, E., Couture, J.F., Bulfer, S. and Trievel, R.C., "A coupled fluorescent assay for histone methyltransferases", Anal. Biochem., 2005, 342, 86

11. Trievel, R.C., Beach, B.M., Dirk, L.M., Houtz, R.L. and Hurley, J.H., "Structure and Catalytic Mechanism of a SET Domain Protein Methyltransferase", Cell, 2002, 111, 91.