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Research Description:
We use multidisciplinary approaches to understand stem/progenitor cell function, blood cell development, and vascular biology. Such approaches include genomics, proteomics, chemical genetics, embryonic stem cell differentiation, computational analysis, and traditional methodologies.
In addition to elucidating biological principles, we aim to develop innovative therapeutic strategies based on targeting novel mechanisms.
Projects relevant to stem cell biology/regenerative medicine include:
Mechanisms of hematopoiesis:
We are analyzing the function/regulation of GATA factors that control hematopoietic stem cells (HSCs) and hematopoiesis. Transcriptional profiling and ChIPchip analysis have identified a 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, human adult stem/progenitors, and embryonic stem cell systems to discover new modes of controlling stem/progenitor cell function and to devise novel applications towards translational medicine. Defining novel hematopoietic mechanisms has enormous importance, as deviations from physiological programs yield leukemias, lymphomas, myelodysplasia, and additional blood disorders.
Vascular mechanisms and engineering::
We have developed a novel murine model characterized by severe hematopoietic stem/progenitor cell depletion and a severe vascular integrity defect. We are dissecting mechanisms underlying the establishment and maintenance of vascular integrity in normal and disease states. Understanding such mechanisms is essential for developing efficient approaches to promote the vascularization of engineered tissues, a limiting factor in regenerative medicine
Selected References:
- Johnson K.D., Hsu A.P., Ryu, M.-J., Wang J., Gao X., Boyer M.E., Keles S., Lee Y., Calvo K.R., Zhang J., Holland S.M., and Bresnick E.H. (2012) Cis-element mutated in GATA2-dependent immunodeficiency governs hematopoiesis and vascular integrity. J. Clin. Invest., In Press
- Linnemann AK, O'Geen H, Keles S, Farnham PJ, Bresnick EH. Genetic framework for GATA factor function in vascular biology. Proc Natl Acad Sci U S A. 2011 Aug 16;108(33):13641-6. Epub 2011 Aug 1. (http://www.ncbi.nlm.nih.gov/pubmed/21808000)
- Lee HY, Johnson KD, Boyer ME, Bresnick EH. Relocalizing genetic loci into specific subnuclear neighborhoods .J Biol Chem. 2011 May 27;286(21):18834-44. Epub 2011 Mar 11. (http://www.ncbi.nlm.nih.gov/pubmed/21398517)
- Snow JW, Trowbridge JJ, Fujiwara T, Emambokus NE, Grass JA, Orkin SH, Bresnick EH. A single cis element maintains repression of the key developmental regulator Gata2. . PLoS Genet. 2010 Sep 9;6(9). pii: e1001103. (http://www.ncbi.nlm.nih.gov/pubmed/20838598)
- Lee HY, Johnson KD, Fujiwara T, Boyer ME, Kim SI, Bresnick EH. Controlling hematopoiesis through sumoylation-dependent regulation of a GATA factor. Mol Cell. 2009 Dec 25;36(6):984-95. .(http://www.ncbi.nlm.nih.gov/pubmed/20064464)