Areas of Interest
The Trievel laboratory uses a combination of structural and biochemical approaches to study the structures, substrate specificities, and mechanisms of a variety of enzymes, with a particular focus on enzymes involved in gene regulation. Techniques used in the lab include crystallography, enzymology, calorimetry and high throughput screening. Current projects include:
1) Structural and biochemical studies of chromatin modifying enzymes: Our laboratory utilizes biochemical and structural approaches to investigate the mechanisms of enzymes that catalyze chromatin modifications with a particular emphasis on SET domain lysine methyltransferases. We are also developing new assays and reagents that will facilitate high-throughput characterization of these enzymes. Our collective efforts are yielding insights into the molecular mechanisms underlying the establishment and maintenance of chromatin modification states and will furnish new avenues for developing novel therapeutics that target lysine methyltransferases to treat cancer and other protein methylation-linked diseases.
2) Structural and functional characterization of Nocturnin, a deadenylase linked to obesity: Obesity is a growing worldwide epidemic that impacts the health and lifespan of affected individuals, increasing the risk of cardiovascular disease, high blood pressure, diabetes, and certain cancers. Discovering the underlying genetic and biochemical mechanisms that control metabolism and adipogenesis is fundamental to developing new therapeutics to combat this epidemic and to preventing diseases associated with obesity. Previous studies have revealed multiple genes in mammals that contribute to obesity, including the gene encoding Nocturnin. Mice bearing a knockout of the Nocturnin gene are resistant to diet-induced obesity, suggesting that this protein regulates specific genes that control fat uptake and metabolism. Nocturnin shares sequence homology with deadenylases that regulate the translation of mRNAs by degrading their 3' polyadenosine tails. In collaboration with Dr. Aaron Goldstrohm (University of Minnesota) and Dr. Peter Freddolino (UM Department of Biological Chemistry), we determined the first crystal structure of Nocturnin, revealing a protein fold and active site that is conserved in related deadenylases. Tethered function reporter assays demonstrate that Nocturnin represses translation in cells and that this repression is dependent on the structure of the 3' end of the mRNA. Together, these results demonstrate that Nocturnin functions as an exoribonuclease that can degrade mRNAs to inhibit protein expression and provide a foundation for elucidating Nocturnin’s biological functions in regulating fat metabolism and adipogenesis.
3) Discovery and development of novel therapeutics to treat chronic kidney disease: Chronic kidney disease (CKD) ranks among the most common and deadly non-communicable degenerative diseases, affecting ~10% of the world population. At present there are no cures or medications available to combat CKD, and patients are typically treated through chronic dialysis or kidney transplants. To address this unmet clinical need, our laboratory is collaborating with Dr. Mathias Kretzler (UM Department of Internal Medicine), Dr. Jeanne Stuckey (UM Department of Biological Chemistry and the Life Sciences Institute), and Dr. Vincent Groppi (UM Center for the Discover of New Medicines and the Life Sciences Institute) to investigate a target for treating CKD. Our research team recently established an academic-industrial collaboration with AstraZeneca Pharmaceuticals with the overall goal of developing the first in class drug to treat CKD.
Graduate Program Affiliations
Biological Chemistry Graduate Program
Biophysics Graduate Program
Cellular Biotechnology Training Program
Cellular & Molecular Biology Program
Chemical Biology Doctoral Program
Chemical Biology Interface Training Program
Honors & Awards
Margaret C. Etter Early Career Award, American Crystallographic Association, 2010
Basic Science Research Award, University of Michigan Medical School, 2010
NIH Fellowship Award for Research Excellence, 2004
Keystone Symposium Scholarship, 2003
Intramural Research Training Fellowship, National Institutes of Health, 2000–2003
Howard Hughes Medical Institute Predoctoral Fellowship, 1996–2000
Structural and Functional Characterization of Sulfonium Carbon-Oxygen Hydrogen Bonding in the Deoxyamino Sugar Methyltransferase TylM1.
Fick RJ, Horowitz S, McDole BG, Clay MC, Mehl RA, Al-Hashimi HM, Scheiner S, Trievel RC.
Biochemistry. 2019; 58: 2152–9.
Crystallographic and Computational Characterization of Methyl Tetrel Bonding in S-Adenosylmethionine-Dependent Methyltransferases.
Trievel RC, Scheiner S.
Molecules. 2018; 23: 2965.
The structure of human Nocturnin reveals a conserved ribonuclease domain that represses target transcript translation and abundance in cells.
Abshire ET, Chasseur J, Bohn JA, Del Rizzo PA, Freddolino PL, Goldstrohm AC, Trievel RC.
Nucleic Acids Res. 2018; 46: 6257–70.
Water-Mediated Carbon-Oxygen Hydrogen Bonding Facilitates S-Adenosylmethionine Recognition in the Reactivation Domain of Cobalamin-Dependent Methionine Synthase.
Fick RJ, Clay MC, Vander Lee L, Scheiner S, Al-Hashimi H, Trievel RC.
Biochemistry. 2018; 57: 3733–40.
Sulfur-Oxygen Chalcogen Bonding Mediates AdoMet Recognition in the Lysine Methyltransferase SET7/9.
Fick RJ, Kroner GM, Nepal B, Magnani R, Horowitz S, Houtz RL, Scheiner S, Trievel RC.
ACS Chem Biol. 2016; 11: 748–54.
Frequent side chain methyl carbon-oxygen hydrogen bonding in proteins revealed by computational and stereochemical analysis of neutron structures.
Yesselman JD, Horowitz S, Brooks CL 3rd, Trievel RC.
Proteins. 2015; 83: 403–10.
Manipulating unconventional CH-based hydrogen bonding in a methyltransferase via noncanonical amino acid mutagenesis.
Horowitz S, Adhikari U, Dirk LM, Del Rizzo PA, Mehl RA, Houtz RL, Al-Hashimi HM, Scheiner S, Trievel RC.
ACS Chem Biol. 2014; 9: 1692–7.
Conservation and functional importance of carbon-oxygen hydrogen bonding in AdoMet-dependent methyltransferases.
Horowitz S, Dirk LM, Yesselman JD, Nimtz JS, Adhikari U, Mehl RA, Scheiner S, Houtz RL, Al-Hashimi HM, Trievel RC.
J Am Chem Soc. 2013; 135: 15536–48.
Structural and functional analysis of JMJD2D reveals molecular basis for site-specific demethylation among JMJD2 demethylases.
Krishnan S, Trievel RC.
Structure. 2013; 21: 98–108.
Structure, mechanism, and regulation of polycomb-repressive complex 2.
Moritz LE, Trievel RC.
J Biol Chem. 2018; 293: 13805–14.
Molecular basis for substrate recognition by lysine methyltransferases and demethylases.
Del Rizzo PA, Trievel RC.
Biochim Biophys Acta. 2014; 1839: 1404–15.
An overview of chromatin modifications.
Fick RJ, Trievel RC.
Biopolymers. 2013; 99: 95–7.
Carbon-oxygen hydrogen bonding in biological structure and function.
Horowitz S, Trievel RC.
J Biol Chem. 2012; 287: 41576–82.
For a list of publications from PubMed, click HERE