Director, UW-Madison Blood Research Program
Ph.D., Univ of Michigan
Postdoctoral Research: National Institutes of Health
(Laboratory of Molecular Biology, NIDDK)
4009 WIMR, L4
1111 Highland Ave
Madison, WI 53705
Stem Cell Biology, Epigenetics, Molecular Hematology, and Vascular Biology: From Fundamental Mechanisms to Translational Medicine
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/epigenetic control of hemoglobin synthesis.
These studies address fundamental mechanistic questions on how chromatin modification/remodeling
regulates transcription of endogenous loci in a cell type-specific manner.
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 established novel epigenetic mechanisms involved in chromatin activation and repression.
We are also dissecting the molecular underpinnings of hemoglobinopathies,
which result from dysregulation of transcriptional mechanisms, and devising strategies to treat such diseases.
Based on our work that has elucidated novel regulatory mechanisms in endothelial cells,
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.
As GATA-2 is linked to the control of angiogenesis and the development of coronary artery disease,
we are using genomic and molecular approaches to define how GATA-2 functions in the vascular
system in normal and pathophysiological states.
- Gao, X., Johnson, K.D., Chang, Y.-I., Boyer, M.E., Dewey, C., Zhang, J., and Bresnick, E.H. (2013) Gata2 cis-element requirement for hematopoietic stem cell generation in the mammalian embryo. J. Exp. Med., (In press)
- Kirby D. Johnson, Amy P. Hsu, Myung-Jeom Ryu, Jinyong Wang, Xin Gao, Meghan E. Boyer,
Yangang Liu, Youngsook Lee, Katherine R. Calvo, Sunduz Keles, Jing Zhang,
Steven M. Holland, and Emery H. Bresnick (2012) Cis-element mutated in GATA2-dependent
immunodeficiency governs hematopoiesis
and vascular integrity. Journal of Clinical Investigation, Oct. 2012, Vol 122, No. 10
- 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. 2012 Jan;32(1):226-39. Epub 2011 Oct 24. [Link]
- Linnemann, A., O'Geen, H., Keles, S., Farnham, P.J., and Bresnick, E.H. (2011) Genetic framework for GATA factor function in vascular biology. Proc. Natl. Acad. Sci. USA, 2011 Aug 16;108(33):13641-6. Epub 2011 Aug 1. [Link]
- Lee HY, Johnson KD, Boyer ME, Bresnick EH. (2011) Relocalizing genetic loci into specific subnuclear neighborhoods.
J Biol Chem. 2011 May 27;286(21):18834-44. Epub 2011 Mar 11
- Snow JW, Trowbridge JJ, Johnson KD, Fujiwara T, Emambokus NE, Grass JA, Orkin SH, Bresnick EH. (2011) Context-dependent function of "GATA switch" sites in vivo.
Blood. 2011 May 5;117(18):4769-72. Epub 2011 Mar 11.
- Li L, Jothi R, Cui K, Lee JY, Cohen T, Gorivodsky M, Tzchori I, Zhao Y, Hayes SM, Bresnick EH, Zhao K, Westphal H, Love PE. (2011) Nuclear adaptor Ldb1 regulates a transcriptional program essential for the maintenance of hematopoietic stem cells.
Nat Immunol. 2011 Feb;12(2):129-36. Epub 2010 Dec 26
- 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, 107:20429-20434
- 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
- Wu J. and Bresnick, E.H. (2007). Bare rudiments of Notch signaling: how receptor levels are regulated. Trends Biochem. Sci.10, 477-485.