After completing my doctoral studies in Dr. John Lough’s lab at the Medical College of Wisconsin I decided to join the laboratory of Dr. Stephen Duncan. Research in the Duncan lab includes investigation into the underlying mechanisms that guide liver development and hepatocyte differentiation, as well as cardiomyocyte development. Projects include the directed differentiation of induced pluripotent human stem cells (hiPSCs) down the hepatic and cardiac lineages. The ultimate goal of the laboratory is the development of cell-based therapies for treatment of patients with chronic liver disease, and repairing cardiac tissue following myocardial infarction. Understanding the molecular mechanisms that guide proper hepatic and cardiac development is of great clinical importance.
My contribution to the lab is investigation into the role of 2 pioneer transcription factors GATA4 and GATA6 whose functions are known to include hepatic- and cardiac-specific gene regulation. Dual ablation of both GATA4 and GATA6 results in animals that lack both hearts and livers, whereas sole ablation of either GATA4 or GATA6 results in a failure of liver bud expansion, disruption of hepatic-specific gene promoters. Additionally sole GATA4 ablation results in cardiac morphological defects that are secondary to disruption of proepicardial organ (PEO) development, and various point mutations in GATA4 have been identified that result in various cardiac developmental abnormalities. The molecular mechanisms that cause the phenotypes observed following disruption of GATA4 and/or GATA6 remain largely unknown; therefore, the hypothesis of my work is that GATA4 and GATA6 perform partially redundant roles of modifying chromatin surrounding hepatic- and cardiac-specific promoters such that they are in an epigenetic state compatible with the onset of gene transcription. I am currently investigating this hypothesis using hiPSC lines expressing shRNAs that specifically target GATA4 and/or GATA6 in combination with Chromatin Immunoprecipitation Assays (ChIP).
Fisher JB, Kim M-S, Blinka S, Ge Z-D, Wan T, et al. (2012) Stress-Induced Cell-Cycle Activation in Tip60 Haploinsufficient Adult Cardiomyocytes. PloS ONE 7(2): e31569. doi:10.1371/journal.pone.0031569
Jun Cai, Ann DeLaForest, Joseph Fisher, Amanda Urick, Thomas Wagner, Kirk Twaroski, Max Cayo, Masato Nagaoka, and Stephen A. Duncan. (2012) Protocol for Directed Differentiation of Human Pluripotent Stem Cells Toward a Hepatic Fate. Harvard Stem Cell Institute. Stembook Node: 721
Yaofei Hu*, Joseph B. Fisher*, Stacy Koprowski, Donna McAllister, Min-Su Kim, John Lough. Homozygous disruption of the tip60 gene causes early embryonic lethality. (2009) Developmental Dynamics 238:2912-2921. *Co-first authors