Emery H. Bresnick, PhD
Position title: Professor of Cell & Regenerative Biology; Director of UW Madison Blood Research Program
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.