Research

Overview

We use the whole gamut of biological techniques -- molecular, cellular, biochemical, proteomic and genomic -- 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 also a highly conserved member of the nuclear receptor super family of ligand-dependent transcription factors.

Figure 1.
Hepatocyte nuclear factor (HNF)4a and human disease.The relationship between HNF4a, select target genes and human diseases is shown. Shaded box, direct connection to diseases indicated; open box, possible connection.


Figure 2. Nuclear Receptor Subfamilies.
Since HNF4 forms exclusively homodimers, is located only in the nucleus and binds DNA elements consisting of direct repeats, it defines a unique subfamily of nuclear receptors. This suggests that the mechanism of action of HNF4 is distinct from that of other receptors, which definitely appears to be the case. Adapted from Jiang et al., 1995, MCB 15: 5131-5143.

Current Projects

(for more details on these topics, see Publications and HNF4 Information)



• DNA binding
• characterization of oligomeric structure of HNF4 and DNA binding; role of the F domain
• Protein-Protein Interactions
• characterization of interactions between HNF4 and known co-regulatory proteins - e.g., co-activators (GRIP1, p300, DRIP members); co-repressors (SMRT); other transcription factors (p53, C/EBPa)
• identification of novel HNF4 interacting proteins using mass spec technology followed by functional characterization
• Post-translational modifications
• identification of HNF4 phosphorylation sites by mass spec
• characterization of function of those sites by site-directed mutagenesis and a variety of functional assays
• Genome-wide analysis of HNF4 target genes
• use the latest tools in bioinformatics and DNA arrays to identify all HNF4 target genes in the human genome
• develop a system to use DNA arrays as an assay to look at the function of HNF4 under a variety of different conditions