Foxa2-dependent hepatic gene regulatory networks depend on physiological state

Department of Genetics and Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Physiological Genomics (Impact Factor: 2.37). 06/2009; 38(2):186-95. DOI: 10.1152/physiolgenomics.90376.2008
Source: PubMed


Bile acids are powerful detergents produced by the liver to aid in the absorption of dietary lipids. We recently reported a novel role for Foxa2 in bile acid metabolism. The winged helix transcription factor Foxa2 is required to prevent intrahepatic cholestasis and liver injury in mice fed a cholic acid-enriched diet. Here, we use functional genomics to study how Foxa2 regulates its targets in a cholic acid-dependent manner. We found that multiple signaling pathways essential for the hepatic response to acute liver injury are impaired in livers of Foxa2-deficient mice, suggesting that the deletion of Foxa2 in the hepatocyte affects the liver on a large scale. We also discovered distinct feed-forward regulatory loops controlling Foxa2-dependent targets in a cholic acid-dependent or -independent manner. We show that Foxa2 interacts with different transcription factors to achieve gene expression responses appropriate for each physiologic state.

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Available from: Irina M Bochkis
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    • "Next, we sought experimental evidence of binding of tissue-specific transcriptional regulators near microRNA TSSs. Foxa2 is an important transcriptional regulator of liver development and function (11,24–29) so we checked previously published experimental data for Foxa2 binding (13) and found that indeed seven of the putative liver-enriched microRNAs TSSs (associated with 10 microRNAs) were within 2KB of experimentally defined Foxa2 sites (Table 5). A further eight miRNA had a Foxa2 site within 15 kb of the TSS. "
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    • "This evidence suggests one hypothetical model in which FoxA2 could be involved in regulating the expression of PXR, which in turn regulates CYP3A4 transcription . Indeed, FoxA2 has been shown to bind to the proximal mouse PXR promoter (Kyrmizi et al., 2006), to regulate mouse liver PXR expression (Bochkis et al., 2008), and to amplify this biological network by directly regulating the PXR coregulator Ncoa2 (SRC-2) (Bochkis et al., 2009). However , whether FoxA2 is an equally important regulator of human CYP3A4 and PXR was not known, in particular, because Odom et al. (2007) previously determined that Foxa2 binding regions within target genes in mouse and human genomes have diverged substantially. "
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