Zebrafish are an excellent model for studying embryonic development and we are using the power of zebrafish genetics to define genes required for liver growth as well as to identify new models of liver diseases. Fatty liver disease is emerging as an important liver pathology and is typically associated with obesity and type II diabetes and together these comprise Metabolic Syndrome, which affects nearly 5% of the American population. We have found a zebrafish mutant that develops fatty liver disease in the embryo, and have named it foie gras (fgr). The foie gras gene is well conserved in animals, but has no assigned sequence or motif that suggest its function. The primary focus of the Sadler Edepli lab is to understand the cellular function of foie gras, and to use the fgr mutant embryo as a model for studying fatty liver disease.
The second focus of our lab is to determine the epigenetic basis for liver growth in the embryo and during hepatocarcinogenesis. We focus on the uhrf1 gene which is a major epigenetic regulator, and has been best studied for its role in DNA methylation. We demonstrated that a loss of function mutant in this gene prevents liver outgrowth in embryos and liver regeneration in adults. UHRF1 is overexpressed in many types of cancer and we have shown that UHRF1 is a bone fide oncogene in liver cancer and its widespread overexpression in cancer types across tissues may point to its role in driving the global hypomethylation of the cancer genome. We are now working to dissect the mechanism by which UHRF1 drives oncogenesis and understanding how senescence as a tumor suppressive mechanism gets bypassed in cancers caused by UHRF1 overexpression.