Evan M. Cornett, PhD
Phone: (317) 278-4503
980 W. Walnut St.
Walther Hall, R3 C549
Indianapolis, IN 46202
- Assistant Professor of Biochemistry & Molecular Biology, Department of Biochemistry and Molecular Biology, IU School of Medicine
- Associate member
Indiana University Melvin and Bren Simon Cancer Center, Experimental and Developmental Therapeutics
More than one-sixth of the human proteome contains methylation on a lysine residue, yet little is known about the function of these lysine methylation events. In general, it is appreciated that post-translational modifications (PTMs) are molecular signals, strung together to create signaling cascades that regulate nearly every cellular process. Lysine methylation was discovered around the same time as phosphorylation, yet our understanding of lysine methylation signaling lags decades behind. Mapping phosphorylation signaling cascades helped spur the development of kinase inhibitors that revolutionized targeted medicine and similar efforts toward mapping lysine methylation signaling networks has the potential to provide similar impact. My lab will apply in vitro and cellular biochemistry, chemical biology, and proteomics approaches to map lysine methylation signaling networks and study the function of lysine methylation on non-histone proteins. I am particularly interested in understanding how lysine methylation regulates the circadian clock. The circadian clock is intricately connected to human health, and knowledge of the clock’s basic molecular mechanisms is critical to understand it’s full impact and rationalize how the clock can be leveraged for therapeutic gain. I recently discovered that the cancer-associated lysine methyltransferase SMYD2 methylates the nuclear localization signal of the circadian regulatory protein PER2, and that SMYD2 plays a regulatory role in circadian clock gene expression. The immediate goals of my independent lab are will be to (1) determine the mechanism through which SMYD2-dependent methylation of PER2 regulates the circadian clock, (2) to map lysine methylation events on other core circadian clock proteins, and (3) profile the selectivity of candidate lysine methyltransferase and lysine demethylase enzymes that also regulate the circadian program. The technological and conceptual advances I have made thus far place me in a unique position to make immediate impacts in the lysine methylation signaling field. It is important to note that many of the regulators of lysine methylation, lysine methyltransferases and lysine demethylases, are dysregulated in many human cancers. In fact, some are already being pursued as targets with small-molecule inhibitors in preclinical and clinical trials (targeting EZH2, DOT1L, MLL1). These studies have primarily focused on the roles we understand for these proteins in regulating epigenetic processes by modifying histone proteins. However, it has become evident that the function of lysine methyltransferases is more often than not through the combination of methylation of histone and non-histone proteins. In order to understand why these molecules succeed or fail in the clinic, and to advance molecules targeting other lysine methylation regulators, more complete understanding of their substrates will be critical. Additionally, my lab will focus on connections between lysine methylation and the circadian clock. The circadian clock in recent years has become a new route for treating some human cancers ( ie: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924733/ ). The long-term goal of my research group is to collaborate with other labs in the IUSCC and abroad to apply our basic findings to achieve new avenues for anticancer treatments.
Post-doctoral Fellowship - Van Adnel Research Institute, Grand Rapids, MI 07/2019
Ph.D. - University of Central Florida, Orlando, FL 05/2015