Karen C. Glass, Ph.D.
B.S., Microbiology, University of Massachusetts, Amherst, MA (- Dr. Steven J. )
Ph.D., Microbiology & Molecular Genetics, University of Vermont, Burlington, VT (- Dr. Christopher S. )
Postdoctoral, Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA (- Dr. Harry F. )
Postdoctoral, Pharmacology, University of Colorado Denver, Denver, CO (- Dr. Tatiana G. )
Courses Taught at ACPHS
Principles of Pharmacology and Medicinal Chemistry
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.
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
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.
Selected Publications/Conference presentations
Avvakumov, N, Lalonde, ME, Saksouk, N, Landry, AJ, Paquet, E, Glass, KC, Ullah, M, Doyon, Y, Cayrou, C, Robitaille, G, Côté, V, Richard, D, Yang, XJ, Kutateladze, TG and Côté, J. Conserved Molecular Interactions Within Myst-ING Acetyltransferase Complexes That Regulate Cell Proliferation (submitted February 2011).
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. *These authors contributed equally to the work.
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.
Champagne KS and Kutateladze TG. (2009) Structural insight into histone recognition by the ING PHD fingers. Current Drug Targets. 10:432-41.
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. 33:248-256. *These authors contributed equally to the work.
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. 33:257-265. *These authors contributed equally to the work.
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: 1371-6.
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: 303-12.
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.
Champagne KS, Piscitelli E, Francklyn CS. (2006) Substrate recognition by the hetero-octameric ATP phosphoribosyltransferase from L. lactis. Biochemistry 45:14933-43.
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: 34096-34104.
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.
Department of Pharmaceutical Sciences (2010). Albany College of Pharmacy and Health Sciences (Vermont Campus), Colchester, VT. "Structural Insights into the Role of PHD Fingers in Epigenetics and Disease."
Department of Pharmacology, Postdoctoral Summer Seminar Series. (2009) UC Denver, Aurora, CO. "The role PHD fingers in chromatin remodeling and disease."
Department of Pharmacology, Postdoctoral Summer Seminar Series. (2008) UC Denver, Aurora, CO. "The role PHD fingers in chromatin remodeling and disease."
Department of Biomolecular Structure (2008) UC Denver, Aurora, CO. “The role of ING4 and ING5 tumor suppressors in chromatin remodeling.”
Department of Pharmacology, Postdoctoral Summer Seminar Series. (2007) UCHSC, Aurora, CO. "The role of ING4 and ING5 tumor suppressors in chromatin remodeling."
International Conference on Aminoacyl-tRNA Synthetases: Ancient Molecules for Future Biology and Medicine. (2004) Seoul National University, Seoul, Korea. “A Histidyl-tRNA Synthetase Paralog with a Role in Histidine Biosynthesis.”
Ribo Club, Faculte de Medecine, Universite de Sherbrooke, Sherbrooke, QC, Canada. (2004) “A Histidyl-tRNA Synthetase-like Domain Involved in the Regulation of ATP-Phosphoribosyl Transferase from Lactococcus lactis.”
Structural Biology Supergroup, Seminar Series. (2004) UVM, Burlington, VT. “The Macromolecular Structure of ATP-Phosphoribosyl Transferase from Lactococcus lactis: Implications for Regulation by a Histidyl-tRNA Synthetase Paralog.”
VT DOE EPSCoR Retreat. (2002) Burlington, VT. “Structural Studies on an ATP Phosphoribosyl Transferase from Lactococcus lactis.”
American Crystallography Association, annual conference. (2001) Los Angeles, CA. "Structural Studies of an ATP-Phosphoribosyl Transferase from Lactococcus lactis."
Honors and Achievements
Poster presentation award. University of Colorado Denver Postdoctoral Research Day. 2010.
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). 2008.
Travel award from the University of Vermont (UVM) graduate college for a tRNA Synthetase conference, Seoul, Korea. 2004.
American Crystallography Association student travel grant, ACA meeting, Los Angeles, CA. 2001.
Graduated with honors, Magna Cum Laude. 1999.
Golden Key National Honors Society, member. 1997.
Alpha Lambda Delta, a national academic honors society for freshmen in the top 10% of their class, member. 1996.
Previous Positions or Appointments
11/06-8/10 - Postdoctoral Research Fellow, Advisor- Dr. Tatiana G. Kutateladze, University of Colorado at Denver, Aurora, CO
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
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-present Member, National Postdoctoral Association 2007-present Member, Colorado Bioscience Association Introduction to General Biology for Majors, Metropolitan State College of Denver. Course number Biol 1080. Advisor- Dr. Fordyce Lux III, Chair, Department of Biology, MSCD. 2010. 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, ACPHS
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-present Member, National Postdoctoral Association
2007-present Member, Colorado Bioscience Association
Introduction to General Biology for Majors, Metropolitan State College of Denver. Course number Biol 1080. Advisor- Dr. Fordyce Lux III, Chair, Department of Biology, MSCD. 2010.
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, ACPHS