Glass Lab

Research focus: to understand how epigenetic signaling regulates gene expression, and how alterations in these pathways are involved in disease development. The lab is investigating the molecular mechanisms driving the recognition of histone post-translational modifications to identify new therapeutic strategies.

Research Overview

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Even though the DNA in all of our cells is nearly the same, it is epigenetic factors, including modifications to DNA, RNA, and chromatin that control the gene expression patterns in different cells, under various environmental conditions, and at specific times (1).  Post-translational modifications on histone tails function as a very complex code for controlling gene expression.  Deciphering this code is at least as important as the genetic code for understanding its role in stem cell programming, maternal effects during fetal development, and potential reversibility in cancer therapies.  However, it is also orders of magnitude more complex (2).  We study the molecular mechanisms driving the recognition of histone modifications, and how combinations of these chemical signals regulate protein interactions on the nucleus in both normal and disease states.

Major research efforts in the lab

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  • To uncover how multiple chromatin reader domains cooperatively regulate the activity of epigenetic regulatory complexes.
  • To reveal how cross-talk between epigenetic marks modulates the function of histone binding proteins and chromatin remodeling enzymes.
  • To identify and functionally characterize how acetyllysine signaling and recognition contributes to the pathogenesis of parasitic infections.
  • To correlate how altered epigenetic modifications influence the progression of cancer, heart, and infectious disease.

Background

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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 contains two molecules of each histone:  H2A, H2B, H3, and H4.  Each of these core histones contains two separate functional domains - a globular 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 groups such as acetyl-, methyl-, and phospho- groups.

Modifications of 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 unique and specific biological outcomes such as cell death; cell cycle regulation; and the transcription, repair, or replication of DNA.

Specific Studies

Epingenetic signaling by histone post-translational modifications
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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 (3).  Bromodomains bind to specific acetylation marks on histone tail and tether associated proteins and enzymatic complexes to histones to regulate chromatin structure and gene expression (4).  However, how these protein modulates differentiate between multiple actylated lysine residues, that are often found alongside other post-translation modifications, to read the histone code is unkown. We recently esablished the molelcular basis of histone acetyllysine recognition by the ATAD2 and ATAD2B bromodomains and discovered that these bromodomains prefer to interact with histones H4, H2A, and the H2A.X histone variant when they contain multiple acetylated lysine residues.  The structural and mechanistic details of histone recognition by bromodomains is crucial for the development of new therapeutic interventions and molecular tools to study a variety of diseases.  Our research has fundamentally advanced our understanding of how bromodomains recognize and select for acetyllysine marks.

Figure 1 - Multiple modifications on individual histone tails...

Bromodomain-containing proteins in cardiovascular and infectious diseases
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Plasmodium falciparum is a unicellular protozoan parasite that causes malaria infections in humans.  Malaria is a significant global health problem that affected 247 million people in 2021, resulting in approximately 619,000 deaths (5).  Unfortunately, this disease disproportionally affects infants and children, and the cases have been expanding since 2016 due to climate changes and drug resistance (5).  In humans, P. falciparum first replicates in the liver cells, and as the disease progresses, it moves into the red blood cells (RBCs) (6).  The symptoms of malaria are associated with repeated rounds of parasite infection, and invasion into the red blood cells (7).  At the red blood cell stage of infection, P. Falciparum consumes the RBCs hemoglobin, preventing it from carrying oxygen to the heart which results in anemic heart failure (8).  In addition, parasitized RBCs stick to the wall of blood vessels in the heart and brain to evade the immune system, which often leads to inflammation and causes blood vessel blockage in these vital organs.  These infection-related complications are directly associated with the invasion of RBCs by the parasite.  The P. falciparum Bromodomain Protein 1 (PfBDP1) is a multi-domain nuclear protein that contains a unique combination of ankyrin repeats (ANK) followed by a bromodomain (BRD) (Fig. 2A).  In-vivo studies have demonstrated that association of PfBDP1 with acetylated chromatin at the promoters of invasion genes promotes their expression, and knockdown of PfBPD1 strongly reduces expression, and blocks the invasion of RBCs (Fig. 2B) (9,10).  The chromatin binding activity of PfBDP1 is thought to play an essential role in the red blood cell invasion process by controlling the expression of genes that are required for cell entry.  Thus, it is imperative to understand the essential factors involved in the P. falciparum RBC invasion process to develop therapeutic interventions.

Figure 2 - Role of PfBDP1 in regulating the expression of invasion related genes

The research focus 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 the 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 identify new diagnostic markers and targets to prevent and treat disease. 

collage of young people's headshots

Addressing research questions through diverse approaches

In the Glass Lab, we are interested in understanding how epigenetic signaling regulates gene expression, and how alterations in these pathways are involved in disease development, particularly cancer and infectious disease. To answer these research questions, we use a diversity of modalities.

Glass Secures UVM’s First NSF Mid-Career Advancement Award Publication link - Dr. Glass Karen C. Glass, Ph.D.

Open Lab Positions
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Undergraduate/Professional Students:  We recruit undergraduates who are enthusiastic to acquire laboratory experience.  Please contact Dr. Karen Glass directly (karen.glass@med.uvm.edu).

Graduate Students:  We recruit graduate students through the UVM Cellular, Molecular and Biomedical Sciences (CMB) Program.  Current graduate students interested in the Glass lab should contact Dr. Karen Glass directly (karen.glass@med.uvm.edu) to inquire about possible rotation projects.

Prospective students should apply through the CMB Program at UVM (http://www.uvm.edu/cmb).  Graduate scholarships are available.

 Postdoctoral positions:  Full-time NIH funded postdoctoral positions are available in the Glass Lab.  Highly motivated Ph.D. scientists with experience in biochemistry, enzymology, crystallography, NMR spectroscopy, or molecular biology are encouraged to apply.  Please email Dr. Karen Glass (karen.glass@uvm.edu) for more information.

Karen C. Glass, Ph.D.

Department of Pharmacology

149 Beaumont Ave., Firestone Medical Research Building 362

Burlington, VT 05405

Phone:  (802) 656-5760

Lab: (802) 656-4988

Lab Alumni

2025
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  • Kiera Malone, Ph.D. in Cellular, Molecular, and Biomedical Sciences 2019-2025 (Current position: Postdoctoral Associate, Van Andel Institute, MI)
  • James Lignos, M.S. in Cellular, Molecular, and Biomedical Sciences 2023-2025 (Current position: Pharmacy Technician)
  • Elizabeth Cook, B.S. and Accelerated MS in Biochemistry, Undergraduate and Masters thesis research (Current position: Biochemistry and Molecular Genetics Ph.D. Graduate Student, University of Louisville, KY)
  • Shannon Wasley, Medical Student Researcher 2024-2025 (Current position:  UVM Larner College of Medical Student)

2024
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  • Ajit Singh, Ph.D., Postdoctoral Associate 2021-2024 (Current position CryoEM Research Project Specialist, The Hormel Institute, University of Minnesota, Medical Research Center)

2023
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  • Margaret Phillips, Ph.D., Postdoctoral Associate 2019-2023 (Current position: NMR Scientist, St. Jude Children's Research Hospital)
  • Brian Boyle, B.S. in Biochemistry, Undergraduate Research (Current position:  Research Associate, Broad Institute of MIT and Harvard)
  • Mirabella Vulikh, B.S. in Biochemistry, Honors Thesis Research (Current position:  Research Associate, Broad Institute of MIT and Harvard)
  • Isabelle Kressy, B.S. in Biochemistry, Senior Thesis Research (Current position:  Research Associate, Broad Institute of MIT and Harvard)
  • Hannah Goldman, Landmark College, VBRN Undergraduate Summer Researcher
  • Ian Orsmond, University of Vermont, UVMCC Undergraduate Summer Researcher

2022 - 2012
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2022

  • Shannah Weller, Community College of Vermont, VBRN Undergraduate Summer Researcher

2021

  • Saleh Alkrimi, M.S. in Pharmaceutical Sciences (Current position: Purification Scientist, Eurofins PPS Insourcing Solutions, NC, USA)
  • Palak Bassi, Pharm D. Student
  • Sam P. Boyson, Technician 2019-2021 (Current position: Ph.D. Graduate student, University of North Carolina Chapel Hill, NC, USA)
  • Sunsik Chang, Pharm D. Student
  • Marina Juan, Pharm D. Student
  • Cameron Montgomery, MS/Pharm D. Student

2020

  • Mulu Y. Lubula, MS, Pharm D. student (Current position: Pharmacist, Kinney Drugs, VT, USA)
  • Lauren Dunn, Saint Michael's College, Undergraduate Summer Researcher (Current position: Ph.D. Graduate student, University of Colorado Denver, CO, USA)

2019 

  • Juliet Obi, M.S. in Pharmaceutical Sciences (Current position: Ph. D. Graduate student, University of Maryland, Baltimore, MD, USA).
  • Kara McGuire, Technician, 2017-2019

2018

  • Chiara Evans, B.S./M.S. in Pharmaceutical Sciences (Current position: Ph.D. Graduate student, Weill Cornell Medicine, NY, USA)
  • Kow Hansen, Pharm.D. student
  • Brittany Allen, Pharm D. student 

2017

  • Jamie Gay, Technician, 2015-17 (Current position: Lab Research Technician, University of Vermont, VT, USA)
  • Jonathan Lloyd, M.S. in Pharmaceutical Sciences (Current position: Research Scientist, Enanta Pharmaceuticals, MA, USA

2016

  • Jennifer Lermond, Pharm.D. student
  • Pabita Shrestha, Pharm.D. student
  • Miranda Wells, Pharm.D. student
  • Theresa Yoon, Pharm.D. student

2015 

  • Samuel Carlson, Technician, 2012-15 (Current position: Ph.D. Graduate student, Harvard Medical School, MA, USA)
  • Emily Macintosh, Pharm.D. student
  • Paul Nguyen, Pharm.D. student
  • Sophia Kim, Pharm.D. student

2014

  • Amy Hsiao, Pharm.D. student
  • Miral Patel, Pharm.D. student
  • Sophia Kim, Pharm.D. student
  • Rosanna LaPier, Pharm.D. student
  • Mulu Lubula, M.S. in Pharmaceutical Sciences (Current position: Pharmacist, Kinney Drugs, VT, USA)

2013

  • Tan-Yi Luk, Pharm.D. student
  • Amanda Poplawaski, Pharm.D. student
  • Rachel Wu, Pharm.D. student

2012

  • Elizabeth Neuhardt, Technician 2011-12 (Current position: Physician Assistant, Monadnock Community Hospital, NH, USA)