Karen C. Glass, Ph.D.

Bio: 

Education

B.S.,  Microbiology, University of Massachusetts, Amherst, MA (Advisor- Dr. Steven J. Sandler)                                                                                        

Ph.D., Microbiology & Molecular Genetics, University of Vermont, Burlington, VT (Advisor- Dr. Christopher S. Francklyn)                          

Postdoctoral, Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA (Advisor- Dr. Harry F. Noller)

Postdoctoral, Pharmacology, University of Colorado Denver, Denver, CO (Advisor- Dr. Tatiana G. Kutateladze)

 

Courses Taught at ACPHS

Infectious Disease

Cardiovascular PTPM

Principles of Pharmacology and Medicinal Chemistry

Molecular Biology

Macromolecular Structure 

 

Research Interests

My research focuses on understanding the molecular mechanisms underlying chromatin dynamics and its role in the regulation of diverse cellular process including gene transcription and replication. High field Nuclear Magnetic Resonance (NMR) spectroscopy, X-ray crystallography, and biochemical and molecular biology approaches are utilized determine the three-dimensional structures and functions of chromatin binding proteins implicated in heart disease, cancer and other human diseases.

The human genome is compacted into chromatin, allowing nearly three meters of DNA to fit into the small volume of the nucleus. Chromatin is composed of DNA and proteins, and this DNA-protein complex is the template for a number of essential cell processes including transcription and replication. Understanding the role of chromatin’s higher order structure in transcriptional control is important as loss of this regulation underlies many disease processes.

The basic structural unit of chromatin is the nucleosome. Nucleosomes are comprised of 147 base pairs of DNA wrapped around a core histone octamer. The histone octamer core contains two molecules of each histone H2A, H2B, H3 and H4. Each of these core histones contains two separate functional domains; a modular domain which interacts with the DNA and other histones, and a flexible tail domain that protrudes from the nucleosome. The tail domains can be modified by the reversible addition of chemical moieties such as acetyl-, methyl- and phospho- groups.

Modifications on the histone tail have been shown to be important in altering chromatin structure, facilitating access for DNA-binding transcription factors, but they also act as markers allowing non-histone proteins to interact with the chromatin. The “Histone Code Hypothesis” suggests that histone tail modifications constitute an epigenetic (beyond genes) code, which is read by other proteins. It postulates that these proteins, and protein complexes are able to recognize/read distinct tail modifications, just like a language or code. This consequently triggers downstream events resulting in a unique and specific biological outcome, such as: cell death, cell cycle regulation, and the transcription, repair or replication of DNA.  

We are investigating the structure and function of chromatin binding domains, including the bromodomain, which interact specifically with acetylated histones.  There are about 60 human bromodomain-containing proteins, and these nuclear proteins have a wide variety of biological activities (1). Bromodomains bind to specific acetylation marks on histone tail (Figure 1), and tether associated proteins and enzymatic complexes to histones to regulate chromatin structure and gene expression (2). For example, the BRPF1 bromodomain is a subunit of the MOZ/MORF Histone Acetyltransferase (HAT) complex that plays an important role in hematopoiesis (blood development) (Figure 2) (3). Chromosomal translocations of the MOZ gene are associated with the development of acute myeloid leukemia (4,5).  We have found that the bromodomain, and other epigenetic reader domains within this complex, are essential for targeting the MOZ HAT to its chromatin substrates, and regulate its histone acetylation activity (6-8). It is thought that disruption of MOZ’s acetylation activity causes aberrant gene expression and transformation to the leukemic phenotype. Unlike genetic changes in cancer, epigenetic changes are potentially reversible. Recently it has become evident that chromatin reader domains, such as the PHD fingers and bromodomains found in the MOZ HAT complex, are druggable with small molecules. Bromodomain inhibitors are rapidly being developed to treat disease, and selective inhibition of epigenetic regulators is now recognized as a valuable therapeutic avenue (9). 

However, how these protein modules differentiate between various histone marks to read the histone code is unknown. The focus of my research is aimed at determining the structures of chromatin binding domains, including the bromodomain and PHD finger, in complex with the histone tail to elucidate how histone tail modifications are recognized. This research will aid in a deeper understanding of how chromatin remodeling complexes are targeted to the chromatin and regulate gene expression.  A greater understanding of how these molecular signaling pathways function and are regulated will provide insights into how they can be therapeutically manipulated, and may help to identify new diagnostic markers and targets to prevent and treat disease.

References

  1. Filippakopoulos, P., Picaud, S., Mangos, M., Keates, T., Lambert, J. P., Barsyte-Lovejoy, D., Felletar, I., Volkmer, R., Muller, S., Pawson, T., Gingras, A. C., Arrowsmith, C. H., and Knapp, S. (2012) Histone recognition and large-scale structural analysis of the human bromodomain family. Cell 149, 214-231
  2. Lubula, M. Y., Eckenroth, B. E., Carlson, S., Poplawski, A., Chruszcz, M., and Glass, K. C. (2014) Structural insights into recognition of acetylated histone ligands by the BRPF1 bromodomain. FEBS Lett 
  3. Poplawski, A., Hu, K., Lee, W., Natesan, S., Peng, D., Carlson, S., Shi, X., Balaz, S., Markley, J. L., and Glass, K. C. (2014) Molecular Insights into the Recognition of N-Terminal Histone Modifications by the BRPF1 Bromodomain. J Mol Biol 426, 1661-1676
  4. Kitabayashi, I., Aikawa, Y., Yokoyama, A., Hosoda, F., Nagai, M., Kakazu, N., Abe, T., and Ohki, M. (2001) Fusion of MOZ and p300 histone acetyltransferases in acute monocytic leukemia with a t(8;22)(p11;q13) chromosome translocation. Leukemia 15, 89-94
  5. Carapeti, M., Aguiar, R. C., Goldman, J. M., and Cross, N. C. (1998) A novel fusion between MOZ and the nuclear receptor coactivator TIF2 in acute myeloid leukemia. Blood 91, 3127-3133
  6. Champagne, K. S., Saksouk, N., Pena, P. V., Johnson, K., Ullah, M., Yang, X. J., Cote, J., and Kutateladze, T. G. (2008) The crystal structure of the ING5 PHD finger in complex with an H3K4me3 histone peptide. Proteins 72, 1371-1376
  7. Lalonde, M. E., Avvakumov, N., Glass, K. C., Joncas, F. H., Saksouk, N., Holliday, M., Paquet, E., Yan, K., Tong, Q., Klein, B. J., Tan, S., Yang, X. J., Kutateladze, T. G., and Cote, J. (2013) Exchange of associated factors directs a switch in HBO1 acetyltransferase histone tail specificity. Genes Dev 27, 2009-2024
  8. Carlson, S., and Glass, K. C. (2014) The MOZ Histone Acetyltransferase in Epigenetic Signaling and Disease. Journal of cellular physiology 
  9. Filippakopoulos, P., and Knapp, S. (2014) Targeting bromodomains: epigenetic readers of lysine acetylation. Nature reviews. Drug discovery 13, 337-356

Research Grants

  • 2R15GM104865-02 (Glass, KC), 1/1/2016-12/31/2018 National Institute of General Medical Sciences of the National Institutes of Health  “Mechanisms of chromatin binding and selection by family IV bromodomains”, funding is pending (impact score: 10, percentile: 1%).
  • R15GM104865 (Glass, KC), 1/13 - 12/15 National Institute of General Medical Sciences of the National Institutes of Health "A unique double PHD finger and bromodomain in epigenetic signaling"
  • 10BGIA3420014 (Glass, KC),  7/10-6/12 American Heart Association PMA Beginning Grant-in-Aid “The Structural Role of PHD Finger Domains in Chromatin Remodeling”
  • F32 GM083462 (Champagne, KS), 7/08-8/10 National Research Service Award, postdoctoral fellowship “The Structural Role of PHD Finger Domains in Chromatin Remodeling”
  • 08-049-01-GMC (Champagne, KS) (Terminated on 6/30/2008), 01/08-12/10 American Cancer Society, postdoctoral fellowship “The Structural Role of PHD Finger Domains in Chromatin Remodeling” 
  • Vermont DOE EPSCoR graduate research fellowship. 2001-2003.
  • Howard Hughes grant for undergraduate research. 1999. 
  • Honors Research Grant for undergraduate thesis research. 1998.

Publications

Link to the Current List of Published Work in My Bibliography:

http://www.ncbi.nlm.nih.gov/sites/myncbi/karen.glass.1/bibliography/41158764/public/?sort=date&direction=ascending 

(Please note name change in 2009 from Champagne KS to Glass KC).

  1. Hassan HE, Carlson S, Abdallah I, Buttolph T, Glass KC, Fandy TE. (2014) Curcumin and Dimethoxycurcumin Induced Epigenetic Changes in Leukemia Cells. Pharmaceutical Research, 32(3):863-75. PMID: 25186441 
  2. Lubula MY, Eckenroth BE, Carlson S, Poplawski A, Chruszcz M, and Glass KC (2014) Structural insights into recognition of acetylated histone ligands by the BRPF1 bromodomain. FEBS Lett, 588(21):3844-54. PMID: 25281266
  3. Carlson S and Glass KC. (2014) The MOZ Histone Acetyltransferase in Epigenetic Signaling and Disease. J Cell Physiol, Nov;229(11):1571-4. (Cover) PMID: 24633655
  4. Lubula M, Poplawski A and Glass KC (2014) Crystallization and preliminary X-ray diffraction analysis of the BRPF1 bromodomain in complex with its H2AK5ac and H4K12ac histone peptide ligands. Acta Cryst F, 70(Pt 10):1389-93. PMID: 25286946
  5. Poplawski A, Hu K, Lee W, Natesan S, Peng D, Carlson S, Shi X, Balaz S, Markley JL, Glass KC. (2014) Molecular Insights into the Recognition of N-Terminal Histone Modifications by the BRPF1 Bromodomain. J Mol Biol, 426(8): 1661-1676. PMID: 24333487
  6. Lee W, Hu K, Tonelli M, Bahrami A, Neuhardt E, Glass KC and Markley JL. (2013) Fast automated protein NMR data collection and assignment by ADAPT-NMR on Bruker spectrometers. J Magn Reson, Aug 236:83-88. PMID: 24091140
  7. Lalonde ME, Avvakumov N, Glass KC, Joncas FH, Saksouk N, Holliday M, Paquet E, Yan K, Tong Q, Klein BJ, Tan S, Yang XJ, Kutateladze TG and Côté J. (2013) Exchange of associated factors directs a switch in HBO1 acetyltransferase histone tail specificity. Genes Dev, Sep 15;27(18):2009-24. PMID: 24065767
  8. Yuan CC, Matthews AG, Jin Y, Chen CF, Chapman BA, Ohsumi TK, Glass KC, Kutateladze TG, Borowsky ML, Struhl K, Oettinger MA. (2012) Histone H3R2 symmetric dimethylation and histone H3K4 trimethylation are tightly correlated in eukaryotic genomes. Cell Rep, Feb 23;1(2):83-90. PMID: 22720264
  9. Avvakumov N, Lalonde ME, Saksouk N, Paquet E, Glass KC, Landry AJ, Doyon Y, Cayrou C, Robitaille GA, Richard DE, Yang XJ, Kutateladze TG and Côté J. (2012) Conserved Molecular Interactions within the HBO1 Acetyltransferase Complexes Regulate Cell Proliferation. Mol Cell Biol, Feb;32(3):689-703. PMID: 22144582
  10. Hom, RA, Chang, PY, Roy, S*, Musselman, CA*, Glass, KC*, Selezneva, AI, Gozani, O, Ismagilov, RF, Cleary, MI and Kutateladze, TG. (2010) Molecular mechanism of MLL PHD3 and RNA recognition by the Cyp33 RRM domain. J Mol Biol, Jul 9;400(2):145-54. PMID: 20460131 *These authors contributed equally to the work.
  11. Roy S, Musselman CA, Kachirskaia I, Hayashi R, Glass KC, Nix JC, Gozani O, Appella E, Kutateladze TG.  (2010) Structural insight into p53 recognition by the 53BP1 tandem Tudor domain.  J Mol Biol, 14;398(4):489-96. PMID: 20307547
  12. Champagne KS and Kutateladze TG.  (2009) Structural insight into histone recognition by the ING PHD fingers. Current Drug Targets. 10(5):432-41. PMID: 19442115
  13. Hung T*, Binda O*, Champagne KS*, Kuo AJ, Johnson K, Chang HY, Simon MD, Kutateladze TG and Gozani O.  (2009) ING4-mediated crosstalk between histone H3K4 trimethylation and H3 acetylation attenuates cellular transformation. Mol Cell, 33(2):248-256. PMID: 19187765 *These authors contributed equally to the work
  14. Saksouk N, Avvakumov N*, Champagne KS*, Hung T*, Doyon Y, Cayrou C, Paquet E, Ulla M, Landry AJ, Côté V, Yang XJ, Gozani O, Kutateladze TG and Côté J.  (2009) HBO1 HAT complexes target chromatin throughout gene coding regions via multiple PHD finger interactions with histone H3 tail.  Mol Cell, 33(2):257-265. PMID: 19187766 *These authors contributed equally to the work.
  15. Champagne KS, Saksouk N, Peña PV, Johnson K, Ullah M, Yang XJ, Côté J, Kutateladze TG. (2008) The crystal structure of the ING5 PHD finger in complex with an H3K4me3 histone peptide.  Proteins, 72(4): 1371-6. PMID: 18623064
  16. Peña PV, Hom RA, Hung T, Lin H, Kuo AJ, Wong RP, Subach OM, Champagne KS, Zhao R, Verkhusha VV, Li G, Gozani O, Kutateladze TG. (2008) Histone H3K4me3 binding is required for the DNA repair and apoptotic activities of ING1 tumor suppressor.  J Mol Biol, 380(2): 303-12. PMID: 18533182
  17. Matthews AG, Kuo AJ, Ramón-Maiques S, Han S, Champagne KS, Ivanov D, Gallardo M, Carney D, Cheung P, Ciccone DN, Walter KL, Utz PJ, Shi Y, Kutateladze TG, Yang W, Gozani O, Oettinger MA. (2007) RAG2 PHD finger couples histone H3 lysine 4 trimethylation with V(D)J recombination. Nature, Dec 13; 450 (7172): 1106-10. PMID: 18033247
  18. Champagne KS, Piscitelli E, Francklyn CS. (2006) Substrate recognition by the hetero-octameric ATP phosphoribosyltransferase from L. lactis. Biochemistry, 45(50): 14933-43. PMID: 17154531
  19. Champagne KS, Sissler M, Larrabee Y, Doublié S, Francklyn CS. (2005) Activation of the hetero-octameric ATP phosphoribosyl transferase through subunit interface rearrangement by a tRNA synthetase paralog.  J Biol Chem, 280(40): 34096-34104. PMID: 16051603
  20. Bovee ML, Champagne KS, Demeler B, Francklyn CS. (2002) The Quaternary Structure of the HisZ-HisG N-1-(5’-Phosphoribosyl)-ATP Transferase from Lactococcus lactis.  Biochemistry, 41: 11838-11846. PMID: 12269828

National Presentations/Invited Seminars

  1. Epigenetic Signaling and Breast Cancer. Invited talk for panel session on Environmental Endocrine Disruptors and Their Impact on Weight, Metabolism, and Cancer that included Frances Carr, PhD, Karen Glass, PhD, and Janet Gray, PhD. The 18th Annual Women's Health and Breast Cancer Conference, Burlington, VT, October 2, 2015.
  2. Molecular Basis of Histone Recognition by the MOZ HAT Complex. Invited talk presenter Karen C. Glass, and session chair of Transcriptional Regulation. GTC Bio Conference on Epigenomics and Novel Therapeutic Targets, May 21-22, 2015, Boston, MA.
  3. Molecular Basis of Histone Acetyllysine Recognition by the BRPF1 Bromodomain. Glass KC, Lubula MY, Poplawski A, Carlson S, Eckenroth BE, Hu K, Lee W, Peng D, Chruszcz M, Shi X and Markley JL. Poster presenter Karen C. Glass at the Keystone Symposia on Epigenetics and Cancer, Keystone, CO, Jan 26, 2015.
  4. Identifying Target Genes of the MOZ Complex in Normal and Disease States. Carlson S, Gordon JA, Zaidi SK, Bond JP, Fandy TE and Glass KC. Poster presenter Karen C. Glass at the Vermont Cancer Center Clinical & Translational Research Symposium, Burlington, Vermont, Nov 21, 2014.
  5. Molecular Basis of Histone Recognition by the MOZ HAT Complex. Invited seminar presenter Karen C. Glass. Department of Pharmacology, University of Vermont, Burlington, VT, May 15, 2014.
  6. Molecular Basis of Histone Recognition by the MOZ HAT Complex. Co-organizer, session chair and invited talk presenter Karen C. Glass. Vermont Cancer Center Clinical & Translational Research Symposium on Epigenetics and Cancer, Fletcher Allen Health Care, Burlington, VT, November 2013.
  7. Molecular Basis of Histone Recognition by the MOZ HAT Complex. Invited seminar presenter Karen C. Glass. Vermont Cancer Center Grand Rounds, Burlington, VT, June 18th, 2013.
  8. Structural Insights into the Role of PHD Fingers in the MOZ/MORF and HBO1 HATs. Karen C. Glass1, Nehmé Saksouk2, Pedro V. Peña3, Tiffany Hung4, Mukta Ullah5, Xiang-Jiao Yang5, Jacques Côté2, Or Gozani4 and Tatiana G. Kutateladze3. Poster Presenter Karen Glass, American Society of Biochemistry and Molecular Biology annual meeting, San Diego, CA. April 21-25, 2013. *Poster award winner 
  9. Molecular Basis of Histone Acetyllysine Recognition by the BRPF1 Bromodomain. Amanda Poplawski, Kiafeng Hu, Woonghee Lee, Danni Peng, Samuel Carlson, Xiaobing Shi, Milo Westler and Karen C. Glass. Poster presenter and invited short talk by Karen C. Glass, American Society of Biochemistry and Molecular Biology annual meeting, Boston, MA. April 20-24, 2013.
  10. A unique combination of chromatin reader domains in epigenetic signaling. Invited seminar presenter Karen C. Glass. Department of Environmental Pathology, University of Vermont, Burlington, VT. March 11, 2013.
  11.  Structural Insights into the Role of PHD Fingers in the MOZ/MORF and HBO1 HATs. Karen C. Glass, Nehmé Saksouk, Pedro V. Peña, Tiffany Hung, Mukta Ullah, Xiang-Jiao Yang, Jacques Côté, Or Gozani and Tatiana G. Kutateladze. Poster Presenter Karen C. Glass, 2nd Epigenetics in Drug Discovery Conference, Boston, MA. May 30-31, 2012.
  12. A Unique Combination of Chromatin Reader Domains in Epigenetic Signaling. Invited seminar presenter Karen C. Glass. Department of Chemistry, SUNY Plattsburgh, Plattsburgh, NY. April 10, 2012.
  13.  Structural Insights into the Role of PHD Fingers in the MOZ/MORF and HBO1 HATs. Karen C. Glass1, Nehmé Saksouk2, Pedro V. Peña3, Tiffany Hung4, Mukta Ullah5, Xiang-Jiao Yang5, Jacques Côté2, Or Gozani4 and Tatiana G. Kutateladze3. Poster presenter Karen Glass, Vermont Cancer Center, Clinical & Translational Research Symposium on DNA Repair and Cancer, University of Vermont, Burlington, VT. November 11, 2011. *Poster award winner
  14. The role of ING4 and ING5 tumor suppressors in chromatin remodeling and disease. Karen C. Glass1, Nehmé Saksouk2, Pedro V. Peña3, Kyle Johnson3, Tiffany Hung4, Mukta Ullah5, Xiang-Jiao Yang5, Jacques Côté2, Or Gozani4 and Tatiana G. Kutateladze3. Short talk and poster presenter Karen Glass, FASEB Summer Research Conferences, Histone Deacetylases & Reversible Acetylation in Signaling & Disease, Steamboat Springs, CO. June 26 – July 1, 2011.
  15.  The Role of ING4 And ING5 Tumor Suppressors in Chromatin Remodeling and Disease. Karen C. Glass1, Nehmé Saksouk2, Pedro V. Peña3, Kyle Johnson3, Tiffany Hung4, Mukta Ullah5, Xiang-Jiao Yang5, Jacques Côté2, Or Gozani4 and Tatiana G. Kutateladze3. Poster presenter Karen Glass, Vermont Cancer Center, Clinical & Translational Research Symposium on Inflammation and Cancer, University of Vermont, Burlington, VT. November 5, 2010. *Poster award winner

Honors and Achievements

  • 2014    ACPHS Researcher of the year award
  • 2012    ASBMB annual meeting thematic best poster in the Gene Regulation category
  • 2012    ASBMB childcare grant recipient
  • 2011    Poster presentation award winner in the Faculty/Staff category. Vermont Cancer Center's
  • 2011    Clinical and Translational Research Symposium: DNA Repair & Cancer.
  • 2010    Poster presentation award winner in the Faculty/Staff category. Vermont Cancer Center's Clinical and Translational Research Symposium: Inflammation & Cancer.
  • 2010    Poster presentation award. University of Colorado Denver Postdoctoral Research Day.
  • 2008    Post-Doctoral Award for Outstanding Achievement, Department of Pharmacology, University of Colorado Denver (UC Denver), School of Medicine.
  • 2008    Keystone Symposia Scholarship, ‘Molecular Basis for Chromatin Modifications and Epigenetic Phenomena’, Snowmass, CO.
  • 2008    American Heart Association, postdoctoral fellowship (declined).
  • 2004    Travel award from the University of Vermont (UVM) graduate college for a tRNA Synthetase conference, Seoul, Korea.
  • 2001    American Crystallography Association student travel grant, ACA meeting, Los Angeles, CA.
  • 1999    Graduated with honors, Magna Cum Laude.
  • 1997    Golden Key National Honors Society, member.
  • 1996    Alpha Lambda Delta, a national academic honors society for freshmen in the top 10% of their class, member.

Current and Previous Post-Graduate Positions

  • 08/11-present - Adjunct Assistant Professor, Department of Biochemistry, University of Vermont, College of Medicine, Burlington, VT
  • 11/06-8/10 - Postdoctoral Research Fellow, Advisor- Dr. Tatiana G. Kutateladze, University of Colorado at Denver, Aurora, CO
  • 2010 - Affiliate Faculty, Metropolitan State College of Denver.   Introduction to General Biology for Majors, Course number Biol 1080. Advisor- Dr. Fordyce Lux III, Chair, Department of Biology, MSCD.
  • 11/05-11/06 - Postdoctoral Research Fellow, Advisor- Dr. Harry F. Noller, University of California Santa Cruz, Santa Cruz, CA
  • 06/98-08/98 - Summer Undergraduate Research Student, Advisor- Dr. Jeffrey P. Bond, University of Vermont, Burlington, VT

Professional Affiliations:

  • 2014-Present Member, UVM Cellular and Molecular Biology Program
  • 2013-Present Member, UVM Graduate Faculty
  • 2012-present ACPHS Research Active Graduate Faculty Member
  • 2011-present Full Member, University of Vermont Cancer Center
  • 2011-present Member, American Society for Biochemistry and Molecular Biology
  • 2011-present Member, American Crystallography Association
  • 2010-present Member, American Crystallography Association
  • 2009-2010 Member, National Postdoctoral Association
  • 2007-2010 Member, Colorado Bioscience Association

ACPHS COMMITTEES:

  • 2015-present Member, Research Committee
  • 2015-present Member, Faculty Senate
  • 2012-present Member, ACPHS Graduate Faculty Curriculum Committee (Chair from 2012-2015)
  • 2010-2015 Member, ACPHS Academic Standings Committee
  • 2014-2015 Member, Pharmacy Admissions & Academic Standards committee (PAASC), ACPHS

     

     

     

     

     

     

     

     

     

     

Assistant Professor
Department of Pharmaceutical Sciences - Vermont Campus