Faculty: Emery H. Bresnick
| Dept: | Professor, Cell & Regenerative Biology |
|---|---|
| Contact: | 4009 WIMR, L4 608-265-6446 ehbresni@wisc.edu |
| Training Areas: | Molecular & Env Toxicology Biostatistics (Affiliate Trainer) Molecular & Cellular Pharmacology Cell & Molecular Biology Biomolecular Chemistry Cancer Biology Biotechnology Pathology & Laboratory Medicine Hematology MD/PhD Translational Cardiovasc Science |
Research Interests
Figure 1
We use multidisciplinary, integrative approaches to understand important biological processes, including stem/progenitor cell function, blood cell development (hematopoiesis), and vascular biology. Such approaches include genomics, proteomics, chemical genetics, and computational analysis, as well as traditional molecular, cellular, and biochemical methodologies. In addition to elucidating biological principles, we aim to develop innovative therapeutic strategies based on targeting novel mechanisms.
A major project is to dissect mechanisms that regulate hematopoietic stem cell differentiation into specific progenitor cells, which in turn, form the specific blood cell types. Defining such mechanisms has enormous importance, as deviations from hematopoietic programs lead to the development of leukemias, lymphomas, myelodysplasias and additional blood disorders. Furthermore, while hematopoietic stem cells are routinely transplanted to treat diverse diseases, their therapeutically desirable long-term repopulating activity is poorly understood and cannot be readily modulated. Thus, we are analyzing the function and regulation of GATA transcription factors that control hematopoietic stem cell function, hematopoiesis, the function of specific blood cell types, and additional important biological processes. We demonstrated that GATA-1 and GATA-2 select a small subset of DNA motifs within the genome and function via multiple mechanisms to control target gene expression. Transcriptional profiling and chromatin immunoprecipitation coupled with microarray analysis have identified a large cohort of novel GATA factor target genes, including genes encoding proteins that bear no obvious similarity to known proteins. Loss-of-function and gain-of-function studies are being conducted in mice, zebrafish, and cultured cells to elucidate GATA factor networks, which will provide fundamental insights into mechanisms of development and cellular differentiation. Furthermore, this knowledge can be exploited to develop novel approaches to therapeutically modulate hematopoietic stem cells, hematopoiesis, and blood cell malignancies.
Another program focuses on the transcriptional control of hemoglobin synthesis. These studies address fundamental mechanistic questions on how chromatin modification/remodeling regulates transcription of endogenous loci. Whereas a great deal is known about DNA assembly into nucleosomal filaments and higher-order chromatin structure, many questions remain unanswered regarding how dynamic changes in chromatin structure are orchestrated during development and cellular differentiation.
We have defined a novel multistep chromatin domain activation mechanism and are continuing to establish precisely how broad regions of repressed chromatin are converted into transcriptionally permissive and active chromatin. We are also interested in understanding the molecular underpinnings of hemoglobinopathies, which result from dysregulation of transcriptional mechanisms that control hemoglobin synthesis, and devising strategies to treat such diseases.
Based on our discovery of an endogenous suppressor of angiogenesis, which functions via a novel multi-component mechanism, we are developing strategies to inhibit and promote angiogenesis, the process whereby new blood vessels develop from preexisting vasculature. Angiogenesis is a fascinating process that has crucial physiological functions and underlies specific pathophysiologies, such as cancer, macular degeneration, and diabetic retinopathy, which affects millions of people worldwide. Anti-angiogenic therapy has emerged as an efficacious strategy to treat these diseases and holds enormous promise for promoting vascularization of bioengineered tissues to prevent tissue rejection, facilitating the repair of ischemic damage in the heart, and facilitating the repair of stroke-induced damage in the central nervous system. Furthermore, as GATA-2 has important functions in vascular endothelium and its deregulation is linked to human coronary artery disease, we are also defining how GATA-2 functions in the context of the vascular system. This work, in conjunction with studies on Notch receptor structure/function analyses, constitutes emerging efforts in vascular biology.
Go to the Bresnick Lab website.
Honors & Awards
- 2009 - Editor, The Open Leukemia Journal
- 2008 - Naito Foundation Lecture
- 2007 - Distinguished Alumnus, University of Michigan School of Medicine, Department of Pharmacology
- 2005 - Chair, NIH Erythrocyte and Leukocyte Biology Study Section
- 2005 - Member of Molecular and Cellular Biology Editorial Board
- 2002 - Associate Editor, Journal of Cellular Physiology
- 2002 - Member of Nucleic Acids Research Editorial Board
- 2002 - Member of Journal of Biological Chemistry Editorial Board
- 2002 - Romnes Faculty Scholar
- 2001 - NIH Hematology II Study Section Member
- 2000 - Vilas Associate Award
- 1997 - National Institutes of Health K02 Career Development Award
- 1997 - Leukemia Society of America Scholar Award
- 1996 - Shaw Scientist Award
- 1994 - Pharmaceutical Manufacturers of America Foundation Faculty Development Award
Recent Invited Lectures
- 5th International GATA factor meeting, Sendai, Japan, 2010
- 17th International Hemoglobin Switching Meeting, Oxford, 2010
- NIH (NIDDK), Laboratory of Cellular and Developmental Biology, 2010
- European Hematology Association, Barcelona, 2010
- British Society of Hematology, Brighton, UK, 2009
- Weatherall Institute of Molecular Medicine, Oxford University, 2009
- Red Cell Gordon Conference, University of New England, 2009
- Naito Foundation Symposium: Nuclear Dynamics and RNA, Japan, 2008
- 16th International Hemoglobin Switching Meeting, Asilomar, CA, 2008
- American Society of Hematology, San Francisco, CA, 2008
- University of Montreal, September, 2007
- Red Cell Gordon Conference, France, 2007
- Loyola University, Cardinal Bernardin Cancer Center, 2007
- 4th International GATA factor meeting, Capri, Italy, 2007
- Johns Hopkins University School of Medicine, Department of Pharmacology and Molecular Sciences, 2007
- Yale University, Department of Genetics, 2006
- 15th International Hemoglobin Switching Meeting, Oxford, 2006
- Yale University, Center for Molecular Hematology, 2006
- Kansas University School of Medicine, 2006
Recent Study Section Service
- Chair, NIH Erythrocyte Biology Special Emphasis Panel, 2010
- American Heart Association Basic Cell and Molecular Biology 4 Study Section, 2009
- Chair, NIH Erythrocyte and Leukocyte Biology Study Section, 2005-2007
- Member of NIH Study Section Erythrocyte and Leukocyte Biology, 2003-2007
Other Links
Selected Publications
- Kang YA, Sanalkumar R, O'Geen H, Linnemann AK, Chang CJ, Bouhassira EE, Farnham PJ, Keles S, Bresnick EH (2012). Autophagy driven by a master regulator of hematopoiesis. Mol Cell Biol. 32(1):226-39. PMID: 22025678
- Linnemann AK, O'Geen H, Keles S, Farnham PJ, Bresnick EH (2011). Genetic framework for GATA factor function in vascular biology. Proc Natl Acad Sci U S A. 108(33):13641-6. PMID: 21808000
- Chung D, Kuan PF, Li B, Sanalkumar R, Liang K, Bresnick EH, Dewey C, Kele_ S (2011). Discovering transcription factor binding sites in highly repetitive regions of genomes with multi-read analysis of ChIP-Seq data. PLoS Comput Biol. 7(7):e1002111.PMID: 21779159
- Mysliwiec MR, Bresnick EH, Lee Y (2011). Endothelial Jarid2/Jumonji is required for normal cardiac development and proper Notch1 expression. J Biol Chem. 286(19):17193-204. PMID: 21402699
- Lee HY, Johnson KD, Boyer ME, Bresnick EH (2011). Relocalizing genetic loci into specific subnuclear neighborhoods. J Biol Chem. 286(21):18834-44. PMID: 21398517
- Fujiwara T, Lee HY, Sanalkumar R, Bresnick EH (2010). Building multifunctionality into a complex containing master regulators of hematopoiesis. Proc Natl Acad Sci U S A.107(47):20429-34. PMID: 21059912
- Bresnick EH, Lee HY, Fujiwara T, Johnson KD, Keles S (2010).GATA switches as developmental drivers. J Biol Chem. 285(41):31087-93. PMID: 20670937
- Pope NJ, Bresnick EH (2010). Differential coregulator requirements for function of the hematopoietic transcription factor GATA-1 at endogenous loci. Nucleic Acids Res. 38(7):2190-200. PMID: 20047963
- Fujiwara T, Lee HJ,, Kumar S, and Bresnick EH. (2010) Building Multifunctionality into a Complex Containing Master Regulators of Hematopoiesis. Proc. Natl. Acad. Sci. USA, In Press
- Bresnick EH, Lee HY, Fujiwara T, Johnson KD, and Keles S. (2010) GATA switches as developmental drivers. (minireview) J. Biol. Chem. 285:31087-31093.
- Snow, J.W., Trowbridge, J.J., Fujiwara, T., Emambokus, N., Grass, J.A., Orkin, S.H., and Bresnick, E.H. (2010) A single cis-element mediates repression of the key developmental regulator GATA-2. PLOS Genet., 9;6(9). PMID: 20838598.
- Fujiwara T, O'Geen H, Keles S, Blahnik K, Linnemann AK, Kang YA, Choi K, Farnham PJ, Bresnick EH. (2009) Discovering hematopoietic mechanisms through genome-wide analysis of GATA factor chromatin occupancy. Mol Cell. 36(4):667-81. PMID: 19941826.
- Lee HY, Johnson KD, Fujiwara T, Boyer ME, Kim SI, Bresnick EH. (2009) Controlling hematopoiesis through sumoylation-dependent regulation of a GATA factor. Mol Cell. 36(6):984-95. PMID: 20064464.
- Kim SI, Bultman SJ, Kiefer CM, Dean A, and Bresnick EB. (2009). BRG1 requirement for long-range interaction of a locus control region with a downstream promoter. PNAS USA. 106:2259-2264. PMID 19171905
- Wozniak RJ, Keles S, Lugus JJ, Young KH, Boyer ME, Tran TM, Choi K, Bresnick EH. (2008). Molecular hallmarks of endogenous chromatin complexes containing master regulators of hematopoiesis. Mol Cell Biol. 28:6681-6694.
- Scherzer CR, Grass JA, Liao Z, Pepivani I, Zheng B, Eklund AC, Ney PA, Ng J, McGoldrick M, Mollenhauer B, Bresnick EH, and Schlossmacher MG. (2008). GATA transcription factors directly regulate the Parkinson's disease-linked gene alpha-synuclein. Proc. Natl. Acad. Sci. 105, 10907-10912
- Lurie LJ, Boyer ME, Grass JA, Bresnick EH. (2008). Differential GATA factor stabilities: implications for chromatin occupancy by structurally similar transcription factors. Biochemistry. 47:859-869. PMID 18154321