Intestine-specific gene expression is determined by unique interactions among tissue-restricted transcriptional modulators. In this application, the PI reveals novel physical and functional interactions between members of the zinc finger subfamily, GATA-4, -5, and -6, and the tissue-restricted homeodomain transcription factor, hepatocyte nuclear factor-1alpha (HNF-1alpha), that result in synergistic activation of the promoter of the intestine specific lactase-phlorizin hydrolase (LPH) gene. This critical finding supports a paradigm whereby the overlapping expression of members of the GATA-4, -5, and -6 subfamily and HNF-1alpha regulates intestine specific gene expression in vivo. Intestine-specific gene expression may be further regulated by individual GATA factors, which reveal unique, independent functions not previously known, and by friend of GATA-2 (FOG-2), a member of a recently described multi-zinc finger family of cofactors whose expression and function in the intestine have not yet been determined. GATA factors, HNF-1alpha, and FOG-2 are all coexpressed in the intestinal epithelium indicating that interactions among these proteins is likely to occur in vivo. Based on these preliminary data, it is hypothesized that independent and overlapping expression among GATA factors, HNF-1alpha and FOG-2 are required for the tissue- and cell-type-specific expression of the LPH gene along complex crypt-villus, proximal-distal, and developmental gradients.
The specific aims of the proposed studies are (I) to define the mechanism that establishes independent functions for individual GATA factors in the activation of the LPH promoter, (II) to delineate the mechanisms by which GATA-4, -5, -6 and HNF-1alpha regulate LPH gene expression in vivo, and (III) to define the significance of FOG-2 as a repressor of GATA-activated LPH gene transcription. These studies will provide a fundamental understanding of the role that evolutionarily conserved zinc finger and homeodomain proteins play in the regulation of intestine specific gene expression. Characterizing specific interactions among GATA, HNF-1, and FOG proteins will also elucidate some of the mechanisms governing the complex processes of cell-specific gene expression, cellular differentiation, and intestinal development.
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