We use molecular, cellular and biochemical techniques to decipher the molecular mechanism by which a certain liver-enriched transcription factor, hepatocyte nuclear factor 4 (HNF4), controls the expression of a variety of genes, including those involved in cholesterol, fatty acid and glucose metabolism as well as detoxification processes. HNF4 is essential for the development of a wide variety of organisms and has been directly linked to several human diseases, including diabetes, hemophilia and hepatitis B infections. HNF4 is a member of the nuclear receptor super family of ligand-dependent transcription factors.
My lab studies molecular mechanisms of differentiation using the mammalian liver and the transcription factor HNF4 as tools. One of the most fundamental issues in all of development is the dichotomy between cell proliferation and differentiation and how those two states are maintained in a mutually exclusive fashion. My lab studies this issue using as a tool the liver-enriched transcription factor HNF4a. HNF4a is a highly conserved member of the nuclear receptor superfamily of ligand-dependent transcription factors that regulate nearly every aspect of development and physiology and play a major role in many human diseases. HNF4a in the adult is known to play a role in maintaining the phenotype of adult hepatocytes and pancreatic beta cells. It is genetically linked to an inherited form of diabetes (MODY1) as well as hemophilia B (Leyden) and may play an important role in atherosclerosis and hepatitis B viral infections. HNF4a also plays an important role in early development. At embryonic day 4.25 in the mouse HNF4a RNA and protein are found in the primitive endoderm of the blastocyst. There are as many as 9 naturally occurring splice variants encoded by the HNF4a gene from two different promoters, P1 and P2. There is some evidence that the mouse HNF4a7 isoform expressed from the P2 promoter is expressed in the embryo and adult beta cells and stomach, whereas it is known that the HNF4a1 and HNF4a2 isoforms expressed from the P1 promoter are present primarily in the adult liver and kidney. However, it has not been determined which HNF4a isoform(s) are expressed at the earliest stages of development, such as in the preimplantation blastocyst, and no one has looked at the human embryo. Therefore, we propose to determine which HNF4a isoforms are expressed at different stages of the early human embryo and investigate the possibility that one or more of those isoforms may play a role in the developmental switch between a proliferating cell to a differentiated cell. We have generated a number of highly specific antibodies that recognize various isoforms of human HNF4a that will be useful for these studies.
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