Research Summary

Our group investigates mechanisms, regulation, and biological functions of methyl group addition to proteins and RNA. Methylation, a common post-transcriptional and post-translational modification, has a profound effect on the regulation of fundamental biological processes such as gene expression, cellular localization, and RNA structure and function. Deregulation of methylation is associated with a wide range of diseases. The enzymatic regulation of methyl group addition and removal provides an opportunity for therapeutic intervention. We seek to understand the molecular mechanisms that control methylation, and develop chemical probes to interrogate the pathophysiological function of enzymes that regulate this modification. Specifically, our research focuses on the following areas:

Regulation and Small Molecule Inhibition of Jumonji Histone Demethylases
Jumonji histone demethylases, a family of epigenetic “erasers”, catalyze the removal of methyl marks from lysine residues in proteins. Jumonji demethylases are complex proteins that, in addition to the catalytic domain, often contain one or more chromatin “reader” domains. The reader modules commonly interact with chromatin, and this interaction can be modulated by chromatin modifications. We investigate the functional cross-talk between chromatin recognition and demethylation in the jumonji family to understand how chromatin context impacts methyl mark removal, and consequently transcription. Furthermore, we are interested in understanding how additional regulatory inputs, such as metabolism and cellular signaling cascades, influence chromatin methylation and transcriptional regulation. In addition, our lab is actively involved in the development of small molecule inhibitors of the jumonji demethylases that can be used as cellular probes of their function. We use both rational design and high-throughput screening to identify starting scaffolds, and further optimize these scaffolds through iterative cycles of chemical synthesis and testing their potency and selectivity. Our goal is to use these molecules to inhibit aberrant demethylation caused by misregulation of demethylases in disease models.

Mechanisms and Cellular Roles of RNA Methylation
Methylation of RNA is the abundant post-transcriptional modification identified in various types of RNAs. Despite its prevalence, the functional role of methylation is poorly understood. We are interested in elucidating the mechanisms responsible for RNA methylation, and understanding the role this modification plays in controlling the cellular function of RNA. We are particularly interested in 2-methyl and 8-methyladenosine modifications, catalyzed by related enzymes that utilize an unusual mechanism to achieve methylation. Incorporation of 2-methyladenosine into RNA has been implicated in the regulation of translational fidelity, although the mechanisms by which this is achieved are yet to be elucidated. In contrast, 8-methyladenosine formation is responsible for resistance to five chemically distinct classes of antibiotics that target the peptidyltransferase center of the bacterial ribosome, including linezolid. We investigate catalytic mechanisms, substrate recognition, and evolution of function in enzymes that carry out these methylations. Our goal is to determine the impact of methylation on the cellular function of substrate RNA.

Research Funding

  • September 14, 2018 - August 31, 2022 - Radical SAM-dependent methylation in antibiotic resistance, Principal Investigator. Sponsor: NIH/NIAID, Sponsor Award ID: R01AI137270
  • September 15, 2015 - August 31, 2019 - Allosteric Regulation in the KDM5 Family of Histone Demethylases, Principal Investigator. Sponsor: NIH, Sponsor Award ID: R01GM114044
  • June 15, 2011 - May 31, 2016 - Radical SAM Methytransferases, Principal Investigator. Sponsor: NIH, Sponsor Award ID: R01AI095393
  • March 1, 1982 - May 31, 2015 - Bio-Organic Biomedical Mass Spectrometry Resource, Co-Investigator. Sponsor: NIH, Sponsor Award ID: P41RR001614


University of Belgrade, Belgrade, Serbia BSc 07/2000 Chemistry
University of Illinois, Urbana, IL PhD 05/2005 Chemistry
Harvard Medical School, Boston, MA Postdoc 06/2008 Biochemistry

Honors & Awards

  • 2000
    Serbian Chemical Society Outstanding Undergraduate Student Award
  • 2001
    University of Illinois Teachers Rated as Excellent
  • 2003
    Procter and Gamble Predoctoral Fellowship
  • 2004
    University of Illinois Pines Predoctoral Fellowship
  • 2005
    Damon Runyon Cancer Research Foundation Postdoctoral Fellowship
  • 2007
    NIH Pathway to Independence Award
  • 2009
    Kimmel Scholar Award
  • 2010
    V Foundation Scholar Award
  • 2011
    Basil O'Connor Starter Scholar Award, March of Dimes
  • 2011
    NSF CAREER Award
  • 2011
    Searle Scholar Award
  • 2014
    UCSF Excellence in Teaching Award

Selected Publications

  1. Longbotham JE, Chio CM, Dharmarajan V, Trnka MJ, Torres IO, Goswami D, Ruiz K, Burlingame AL, Griffin PR, Fujimori DG. Histone H3 binding to the PHD1 domain of histone demethylase KDM5A enables active site remodeling. Nat Commun. 2019 01 09; 10(1):94.  View on PubMed
  2. Stojkovic V, Chu T, Therizols G, Weinberg DE, Fujimori DG. miCLIP-MaPseq, a Substrate Identification Approach for Radical SAM RNA Methylating Enzymes. J Am Chem Soc. 2018 06 13; 140(23):7135-7143.  View on PubMed
  3. Stojkovic V, Fujimori DG. Mutations in RNA methylating enzymes in disease. Curr Opin Chem Biol. 2017 Dec; 41:20-27.  View on PubMed
  4. Fitzsimmons CM, Fujimori DG. Determinants of tRNA Recognition by the Radical SAM Enzyme RlmN. PLoS One. 2016; 11(11):e0167298.  View on PubMed
  5. Stojkovic V, Noda-Garcia L, Tawfik DS, Fujimori DG. Antibiotic resistance evolved via inactivation of a ribosomal RNA methylating enzyme. Nucleic Acids Res. 2016 Oct 14; 44(18):8897-8907.  View on PubMed
  6. Fujimori DG, Conway SJ. Editorial overview: Chemical genetics and epigenetics. Curr Opin Chem Biol. 2016 08; 33:vi-vii.  View on PubMed
  7. Liu YC, Fujimori DG, Weissman JS. Htm1p-Pdi1p is a folding-sensitive mannosidase that marks N-glycoproteins for ER-associated protein degradation. Proc Natl Acad Sci U S A. 2016 07 12; 113(28):E4015-24.  View on PubMed
  8. Pack LR, Yamamoto KR, Fujimori DG. Opposing Chromatin Signals Direct and Regulate the Activity of Lysine Demethylase 4C (KDM4C). J Biol Chem. 2016 Mar 18; 291(12):6060-70.  View on PubMed
  9. Korczynska M, Le DD, Younger N, Gregori-Puigjané E, Tumber A, Krojer T, Velupillai S, Gileadi C, Nowak RP, Iwasa E, Pollock SB, Ortiz Torres I, Oppermann U, Shoichet BK, Fujimori DG. Docking and Linking of Fragments To Discover Jumonji Histone Demethylase Inhibitors. J Med Chem. 2016 Feb 25; 59(4):1580-98.  View on PubMed
  10. Torres IO, Fujimori DG. Functional coupling between writers, erasers and readers of histone and DNA methylation. Curr Opin Struct Biol. 2015 Dec; 35:68-75.  View on PubMed
  11. Lu J, Trnka MJ, Roh SH, Robinson PJ, Shiau C, Fujimori DG, Chiu W, Burlingame AL, Guan S. Improved Peak Detection and Deconvolution of Native Electrospray Mass Spectra from Large Protein Complexes. J Am Soc Mass Spectrom. 2015 Dec; 26(12):2141-51.  View on PubMed
  12. Stojkovic V, Fujimori DG. Radical SAM-Mediated Methylation of Ribosomal RNA. Methods Enzymol. 2015; 560:355-76.  View on PubMed
  13. Torres IO, Kuchenbecker KM, Nnadi CI, Fletterick RJ, Kelly MJ, Fujimori DG. Histone demethylase KDM5A is regulated by its reader domain through a positive-feedback mechanism. Nat Commun. 2015 Feb 17; 6:6204.  View on PubMed
  14. Dumesic PA, Homer CM, Moresco JJ, Pack LR, Shanle EK, Coyle SM, Strahl BD, Fujimori DG, Yates JR, Madhani HD. Product binding enforces the genomic specificity of a yeast polycomb repressive complex. Cell. 2015 Jan 15; 160(1-2):204-18.  View on PubMed
  15. Fujimori DG. Radical SAM-mediated methylation reactions. Curr Opin Chem Biol. 2013 Aug; 17(4):597-604.  View on PubMed
  16. Shiau C, Trnka MJ, Bozicevic A, Ortiz Torres I, Al-Sady B, Burlingame AL, Narlikar GJ, Fujimori DG. Reconstitution of nucleosome demethylation and catalytic properties of a Jumonji histone demethylase. Chem Biol. 2013 Apr 18; 20(4):494-9.  View on PubMed
  17. Le DD, Cortesi AT, Myers SA, Burlingame AL, Fujimori DG. Site-specific and regiospecific installation of methylarginine analogues into recombinant histones and insights into effector protein binding. J Am Chem Soc. 2013 Feb 27; 135(8):2879-82.  View on PubMed
  18. McCusker KP, Medzihradszky KF, Shiver AL, Nichols RJ, Yan F, Maltby DA, Gross CA, Fujimori DG. . Covalent Intermediate in the Catalytic Mechanism of the Radical S-Adenosyl-l-methionine Methyl Synthase RlmN Trapped by Mutagenesis. J Am Chem Soc. 2012; 134(43):18074-81.  View on PubMed
  19. McCusker KP, Medzihradszky KF, Shiver AL, Nichols RJ, Yan F, Maltby DA, Gross CA, Fujimori DG. Covalent intermediate in the catalytic mechanism of the radical S-adenosyl-L-methionine methyl synthase RlmN trapped by mutagenesis. J Am Chem Soc. 2012 Oct 31; 134(43):18074-81.  View on PubMed
  20. Le DD, Fujimori DG. Protein and nucleic acid methylating enzymes: mechanisms and regulation. Curr Opin Chem Biol. 2012 Dec; 16(5-6):507-15.  View on PubMed

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