Submitted on November 14, 2008
Revised on April 3, 2009
Accepted on May 1, 2009
Foxa2-Dependent Hepatic Gene Regulatory Networks Depend on Physiological State
Irina M Bochkis1, Jonathan Schug1, Nir E Rubins1, Atul R Chopra2, Bert W. O'Malley2, and Klaus H Kaestner1*
1 University of Pennsylvania
2 Baylor College of Medicine
* To whom correspondence should be addressed. E-mail: kaestner{at}mail.med.upenn.edu.
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.
