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Jordan L. Meier, Ph.D.

Jordan L. Meier, Ph.D.

  • Center for Cancer Research
  • National Cancer Institute
Chemical Biology Laboratory

RESEARCH SUMMARY

Epigenetic mechanisms—factors other than an individual’s DNA sequence—play a critical role in the regulation of gene expression and undergo routine disruption in cancer. Dr. Meier’s work focuses on the development of chemical approaches to study epigenetic signaling and its relationship to cellular metabolism. The goal of these studies is to better elucidate the underlying logic linking gene expression and metabolism, and apply this knowledge towards new approaches to cancer therapy, diagnosis, and chemoprevention.

Areas of Expertise

1) chemistry 2) biochemistry 3) assay development 4) metabolism 5) epigenetics 6) chemical proteomics

Publications

Selected Key Publications

A Systems Chemoproteomic Analysis of Acyl-CoA/Protein Interaction Networks

Levy MJ, Montgomery DC, Sardiu ME, Montano JL, Bergholtz SE, Nance KD, Thorpe AL, Fox SD, Lin Q, Andresson T, Florens L, Washburn MP, Meier JL.
Cell Chem Biol. 27(3): 322-33, 2020. [ Journal Article ]

Epigenetic regulation by endogenous metabolite pharmacology

Kulkarni RA, Montgomery DC, Meier JL.
Curr Opin Chem Biol. 51: 30-39, 2019. [ Journal Article ]

A chemoproteomic portrait of the oncometabolite fumarate

Kulkarni RA, Bak DW, Wei D, Bergholtz SE, Briney CA, Shrimp JH, Alpsoy A, Thorpe AL, Bavari AE, Crooks DR, Levy M, Florens L, Washburn MP, Frizzell N, Dykhuizen EC, Weerapana E, Linehan WM, Meier JL.
Nat Chem Biol. 15(4): 391-400, 2019. [ Journal Article ]

Bioorthogonal pro-metabolites for profiling short chain fatty acylation

Sinclair WR, Shrimp JH, Zengeya TT, Kulkarni RA, Garlick JM, Luecke H, Worth AJ, Blair IA, Snyder NW, Meier JL.
Chem Sci. 9(5): 1236-41, 2018. [ Journal Article ]

Discovering Targets of Non-enzymatic Acylation by Thioester Reactivity Profiling

Kulkarni RA, Worth AJ, Zengeya TT, Shrimp JH, Garlick JM, Roberts AM, Montgomery DC, Sourbier C, Gibbs BK, Mesaros C, Tsai YC, Das S, Chan KC, Zhou M, Andresson T, Weissman AM, Linehan WM, Blair IA, Snyder NW, Meier JL.
Cell Chem Biol. 24(2): 231-42, 2017. [ Journal Article ]

Job Vacancies

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Team

Postdoctoral Fellow (CRTA)
David Lee Bartee, Ph.D.
Postbaccalaureate Fellow (CRTA)
Keri M. Bryson
Postbaccalaureate Fellow (CRTA)
Jared A. Grooms
Postdoctoral Fellow (Visiting)
Isita Jhulki, Ph.D.
Postdoctoral Fellow (Visiting)
Yihang Jing, Ph.D.
Postbaccalaureate Fellow (CRTA)
Courtney Link
Postbaccalaureate Fellow (CRTA)
Susana Najera
Postdoctoral Fellow (CRTA)
Kellie Nance, Ph.D.
Postdoctoral Fellow (CRTA)
Minervo Perez, Ph.D.
Postdoctoral Fellow (Visiting)
Supuni Thalalla Gamage, Ph.D.

Covers

Radar screen showing fumarates in view

A Chemoproteomic Portrait of the Oncometabolite Fumarate

Published Date

Hereditary cancer disorders often provide an important window into novel mechanisms supporting tumor growth. Understanding these mechanisms thus represents a vital goal. Toward this goal, here we report a chemoproteomic map of fumarate, a covalent oncometabolite whose accumulation marks the genetic cancer syndrome hereditary leiomyomatosis and renal cell carcinoma (HLRCC). We applied a fumarate-competitive chemoproteomic probe in concert with LC–MS/MS to discover new cysteines sensitive to fumarate hydratase (FH) mutation in HLRCC cell models. Analysis of this dataset revealed an unexpected influence of local environment and pH on fumarate reactivity, and enabled the characterization of a novel FH-regulated cysteine residue that lies at a key protein–protein interface in the SWI-SNF tumor-suppressor complex. Our studies provide a powerful resource for understanding the covalent imprint of fumarate on the proteome and lay the foundation for future efforts to exploit this distinct aspect of oncometabolism for cancer diagnosis and therapy.

Citation

Rhushikesh A. Kulkarni, Daniel W. Bak, Darmood Wei, Sarah E. Bergholtz, Chloe A. Briney, Jonathan H. Shrimp, Aktan Alpsoy, Abigail L. Thorpe, Arissa E. Bavari, Daniel R. Crooks, Michaella Levy, Laurence Florens, Michael P. Washburn, Norma Frizzell, Emily C. Dykhuizen, Eranthie Weerapana, W. Marston Linehan and Jordan L. Meier

Nature Chemical Biology, 201915 (4), 391.

Rubin's vase indicating oncometabolite detection

Photoinducible Oncometabolite Detection

Published Date

Dysregulated metabolism can fuel cancer by altering the production of bioenergetic building blocks and directly stimulating oncogenic gene-expression programs. However, relatively few optical methods for the direct study of metabolites in cells exist. To address this need and facilitate new approaches to cancer treatment and diagnosis, herein we report an optimized chemical approach to detect the oncometabolite fumarate. Our strategy employs diaryl tetrazoles as cell-permeable photoinducible precursors to nitrileimines. Uncaging these species in cells and cell extracts enables them to undergo 1,3-dipolar cycloadditions with endogenous dipolarophile metabolites such as fumarate to form pyrazoline cycloadducts that can be readily detected by their intrinsic fluorescence. The ability to photolytically uncage diaryl tetrazoles provides greatly improved sensitivity relative to previous methods, and enables the facile detection of dysregulated fumarate metabolism through biochemical activity assays, intracellular imaging, and flow cytometry. Our studies showcase an intersection of bioorthogonal chemistry and metabolite reactivity that can be applied for biological profiling, imaging, and diagnostics.

Citation

Rhushikesh A. Kulkarni  Chloe A. Briney, Daniel R. Crooks, Sarah E. Bergholtz, Chandrasekhar Mushti, Stephen J. Lockett, Andrew N. Lane, Teresa W.‐M. Fan, Rolf E. Swenson, W. Marston Linehan and Jordan L. Meier ChemBioChem, 201920 (3), 360.

Chemical biology takes to the skies as drones to deliver drugs and visualize biological processes

Pharmacology by Chemical Biology

Published Date

The real voyage of discovery consists not in seeking new landscapes, but in having new eyes.

~ Marcel Proust

Pharmacology is a science deeply rooted not only in manipulating physiology but also in defining the mechanism of therapeutic compounds so that they may be more precisely deployed. For example, studies by Sydney Farber revealed the potential of antifolates as drugs for the treatment of childhood leukemia, which led to mechanistic efforts that defined dihydrofolate reductase as a drug target. This discovery in turn enabled the development of novel anticancer and antibacterial agents, as well as new methods for probing biology using inducible dimerization. In this special issue of Molecular Pharmaceutics, “Pharmacology by Chemical Biology”, we highlight a diverse collection of chemical advances which may be used to treat disease or study drug action, and thus impact our understanding of pharmacology.

Citation

See: Pharmacology by Chemical Biology by Jordan L. Meier and Martin J. Schnermann in Molecular Pharmaceutics, 2018, 15 (3), 703-704.

Image shows RNA illuminated with a light bulb

Profiling Cytidine Acetylation with Specific Affinity and Reactivity

Published Date

The human acetyltransferase NAT10 has recently been shown to catalyze formation of N4-acetylcytidine (ac4C), a minor nucleobase known to alter RNA structure and function. In order to better understand the role of RNA acetyltransferases in biology and disease, here we report the development and application of chemical methods to study ac4C. First, we demonstrate that ac4C can be conjugated to carrier proteins using optimized protocols. Next, we describe methods to access ac4C-containing RNAs, enabling the screening of anti-ac4C antibodies. Finally, we validate the specificity of an optimized ac4C affinity reagent in the context of cellular RNA by demonstrating its ability to accurately report on chemical deacetylation of ac4C. Overall, these studies provide a powerful new tool for studying ac4C in biological contexts, as well as new insights into the stability and half-life of this highly conserved RNA modification. More broadly, they demonstrate how chemical reactivity may be exploited to aid the development and validation of nucleobase-targeting affinity reagents designed to target the emerging epitranscriptome.

Citation

See: Profiling Cytidine Acetylation with Specific Affinity and Reactivity by Wilson R. Sinclair, Daniel Arango, Jonathan H. Shrimp, Thomas T. Zengeya, Justin M. Thomas, David C. Montgomery, Stephen D. Fox, Thorkell Andresson, Shalini Oberdoerffer, and Jordan L. Meier in ACS Chemical Biology, 201712 (12), 2922-2926.

Cover image of Cell Chemical Biology

Discovering Targets of Non-enzymatic Acylation by Thioester Reactivity Profiling

Published Date

The cover image illuminates the non-enzymatic “ghost writers” of lysine acylation. Meier et al. detail the development of a chemoproteomic strategy that harnesses thioester reactivity to discover candidate cellular targets of non-enzymatic acylation. Application of this approach reveals that glycolytic enzymes can be strongly inhibited by reactive thioesters, including the fatty acid precursor malonyl-CoA. This study provides new insights into the metabolic regulation of lysine acetylation, and highlights the utility of reactivity-based methods to define and manipulate non-enzymatic protein modifications in complex biological settings. 

Cover art by Scientific Publications, Graphics & Media, Frederick National Laboratory for Cancer Research.

Citation

See: Discovering Targets of Non-enzymatic Acylation by Thioester Reactivity Profiling by Rhushikesh A. Kulkarni, Andrew J. Worth, Thomas T. Zengeya, Jonathan H. Shrimp, Julie M. Garlick, Allison M. Roberts, David C. Montgomery, Carole Sourbier, Benjamin K. Gibbs, Clementina Mesaros, Yien Che Tsai, Sudipto Das, King C. Chan, Ming Zhou, Thorkell Andresson, Allan M. Weissman, W. Marston Linehan, Ian A. Blair, Nathaniel W. Snyder, Jordan L. Meier in Cell Chemical Biology201724 (2), 231-242.

Cover of Chemistry & Biology, Volume 22, Number 8, August 20, 2015

Metabolic regulation of histone acetyltransferases by endogenous Acyl-CoA cofactors

Published Date

Unraveling the metabolic regulation of lysine acetyltransferases (KATs). Montgomery et al. detail the application of a competitive chemoproteomic strategy to quantitatively characterize the interactions of acyl-CoA metabolites with cellular KAT enzymes. These studies reveal KATs are strongly inhibited by lipid-derived CoA analogs, an interaction that may have implications for the metabolic regulation of epigenetic signaling, and highlight the power of chemoproteomics to rapidly characterize metabolic-epigenetic interactions in complex biological contexts. 

Cover design by Scientific Publications, Graphics & Media, Frederick National Laboratory for Cancer Research.

Citation

See: Metabolic Regulation of Histone Acetyltransferases by Endogenous Acyl-CoA Cofactors by David C. Montgomery#, Alexander W. Sorum#, Laura Guasch, Marc C. Nicklaus and Jordan L. Meier in Chemistry & Biology201522, 1030-1039.

#Co-first author