Raymond Trievel, Ph.D.

Associate Professor, Biological Chemistry

Ofc: 4301C MSRB III

Lab: 4315 MSRB III

1150 W. Medical Center Drive

Ann Arbor, MI  48109-5606

 

(734) 647-0889

Appointments

Biological Chemistry, Medical School
Biophysics, College of Literature, Science, and the Arts

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 particularly 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 providea 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.

http://www.uofmhealth.org/news/archive/201711/michigan-medicine-enters-drug-discovery-collaboration

 

Laboratory Members

Elizabeth Abshire, Biological Chemistry Graduate Student, AHA Predoctoral Fellow
Jean-Marc Fontaine, Research Scientist
Ethan Madison, Undergraduate Student
 

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
 

Lab Alumni

Stacie Bulfer (Biological Chemistry Graduate Student, 2005-2010) – Senior Scientist, Deciphera Pharmaceuticals
 
Jennifer Chasseur (Undergraduate Student, 2015-2017) – Master’s Student, University of Michigan Public Policy Program
 
Jean-Francois Couture (Postdoctoral Fellow, 2004-2007) – Professor of Biochemistry, Microbiology and Immunology, University of Ottawa
 
Paul Del Rizzo (Postdoctoral Fellow, 2008-2013) – Research Scientist, Cayman Chemical
 
Robert Fick (Biological Chemistry Graduate Student 2012-2017)
 
Glenn Hauk (Biochemistry Undergraduate Student, 2004) – Postdoctoral Fellow, Johns Hopkins University (James Berger)
 
Scott Horowitz (Biophysics Graduate Student, 2009-2013) – Assistant Professor of Chemistry & Biochemistry, University of Denver
 
Swathi Krishnan (Biological Chemistry Graduate Student, 2009-2012) – Research Specialist, Calicolabs
 
Jennifer Nimtz (Biochemistry Undergraduate Student, 2011-2012) – DO, Orthopedic Medicine, Michigan State University
 
 

Honors & Awards

2010 Margaret C. Etter Early Career Award, American Crystallographic Association
2010 University of Michigan Basic Science Research Award
2004 NIH Fellowship Award for Research Excellence
2003 Keystone Symposium Scholarship
2000-2003 Intramural Research Training Fellowship, National Institutes of Health
1996-2000 Howard Hughes Medical Institute Predoctoral Fellowship
 
 

Published Articles or Reviews

Select Research Articles

Abshire ET, Chasseur J, Bohn JA, Del Rizzo PA, Freddolino PL, Goldstrohm AC, and Trievel RC. (2018) The structure of human Nocturnin reveals a conserved ribonuclease domain that represses target transcript translation and abundance in cells. Nucleic Acids Res.46, 6257-70.

Fick RJ, Clay MC, Vander Lee L, Scheiner S, Al-Hashimi H, and Trievel RC. (2018) Water-Mediated Carbon-Oxygen Hydrogen Bonding Facilitates S-Adenosylmethionine Recognition in the Reactivation Domain of Cobalamin-Dependent Methionine Synthase. Biochemistry.57, 3733-40.

Fick RJ, Kroner GM, Nepal B, Magnani R, Horowitz S, Houtz RL, Scheiner S, Trievel RC. (2016) Sulfur-Oxygen Chalcogen Bonding Mediates AdoMet Recognition in the Lysine Methyltransferase SET7/9. ACS Chem Biol. 11, 748-54.

Horowitz S, Adhikari U, Dirk LM, Del Rizzo PA, Mehl RA, Houtz RL, Al-Hashimi HM, Scheiner S, and Trievel RC. (2014) Manipulating Unconventional CH-Based Hydrogen Bonding in a Methyltransferase via Noncanonical Amino Acid Mutagenesis. ACS Chem Biol. 9, 1692-7.

Horowitz S, Dirk LM, Yesselman JD, Nimtz JS, Adhikari U, Mehl RA, Scheiner S, Houtz RL, Al-Hashimi HM, and Trievel RC. (2013) Conservation and functional importance of carbon-oxygen hydrogen bonding in AdoMet-dependent methyltransferases. J Am Chem Soc. 135, 15536-48.

Krishnan S and Trievel RC. (2013) Structural and functional analysis of JMJD2D reveals molecular basis for site-specific demethylation among JMJD2 demethylases. Structure. 21, 98-108.

Krishnan S, Collazo E, Ortiz-Tello PA, and Trievel RC. (2012) Purification and assay protocols for obtaining highly active Jumonji C demethylases, Anal Biochem. 420, 48-53.

Horowitz S, Yesselman JD, Al-Hashimi HM, and Trievel RC. (2011) Direct evidence for methyl group coordination by carbon-oxygen hydrogen bonds in the lysine methyltransferase SET7/9. J. Biol. Chem. 286, 18658-63.

Bulfer SL, McQuade TJ, Larsen MJ, and Trievel RC. (2011) Application of a high-throughput fluorescent acetyltransferase assay to identify inhibitors of homocitrate synthase. Anal Biochem. 410, 133-40.

Del Rizzo PA, Couture J-F, Dirk LM, Strunk BS, Roiko MS, Brunzelle JS, Houtz RL, and Trievel RC. (2010) SET7/9 catalytic mutants reveal the role of active site water molecules in lysine multiple methylation. J. Biol. Chem. 285, 31849-58.

Bulfer SL, Scott EM, Pillus L, and Trievel RC. (2010) Structural basis for L-lysine feedback inhibition of homocitrate synthase. J Biol Chem. 285, 10446-53.

Bulfer SL, Scott EM, Couture JF, Pillus L, Trievel RC. (2009) Crystal structure and functional analysis of homocitrate synthase, an essential enzyme in lysine biosynthesis. J Biol Chem. 284, 35769-80.

Couture J-F, Dirk LM, Brunzelle JS, Houtz RL, and Trievel RC. (2008) Structural origins for the product specificity of SET domain protein methyltransferases. Proc Natl Acad Sci USA. 105, 20659-64.

Couture J-F, Collazo E, Ortiz-Tello PA, Brunzelle JS, and Trievel RC. (2007) Specificity and Mechanism of JMJD2A, a trimethyllysine-specific histone demethylase. Nat Struct Mol Biol. 14, 689-95.

Couture J-F, Collazo E, and Trievel RC. (2006) Molecular recognition of histone H3 by the WD40 protein WDR5. Nat Struct Mol Biol. 13, 698-703.

Couture J-F, Hauk G, Thompson MJ, Blackburn GM, and Trievel RC. (2006) Catalytic roles for carbon-oxygen hydrogen bonding in SET domain lysine methyltransferases, J Biol Chem. 281, 19280-7.

Couture J-F, Collazo E, Hauk G, and Trievel RC. (2006) Structural basis for the methylation site specificity of SET7/9. Nat Struct Mol Biol. 13, 140-6.

Couture J-F, Collazo E, Brunzelle JS, and Trievel RC. (2005) Structural and functional analysis of SET8, a histone H4 Lys-20 methyltransferase. Genes Dev. 19, 1455-65.

Collazo E, Couture J-F, Bulfer S, and Trievel RC. (2005) A coupled fluorescent assay for histone methyltransferases. Anal Biochem. 342, 86-92.

Invited Reviews

Moritz LE and Trievel RC. (2017) Structure, mechanism, and regulation of polycomb repressive complex 2. J Biol Chem.[Epub ahead of print]

Del Rizzo PA and Trievel RC. (2014) Molecular basis for substrate recognition by lysine methyltransferases and demethylases. Biochim Biophys Acta. Advanced online publication.

Fick RJ and Trievel RC. (2013) An overview of chromatin modifications. Biopolymers. 99, 95-7.

Horowitz S and Trievel RC. (2012) Carbon-oxygen hydrogen bonding in biological structure and function. J Biol Chem. 287, 41576-82.

Del Rizzo PA and Trievel RC. (2011) Substrate and product specificities of SET domain methyltransferases. Epigenetics. 6, 1059-67.

Krishnan S, Horowitz S, and Trievel RC. (2011) Structure and function of histone H3 lysine 9 methyltransferases and demethylases. Chembiochem. 12, 254-63.

For a list of publications from PubMed, click HERE

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