Foxa2-dependent hepatic gene regulatory networks depend on physiological state.
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.
Department of Genetics and Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Irina M
IM
Bochkis
Jonathan
J
Schug
Nir E
NE
Rubins
Atul R
AR
Chopra
Bert W
BW
O'Malley
Klaus H
KH
Kaestner
D000818:Animals; D001483:Base Sequence; D019826:Cholic Acid / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D053263:Gene Regulatory Networks / Q000235:genetics / Q000502:physiology*; D023281:Genomics / Q000379:methods; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D051958:Nuclear Receptor Coactivator 2 / Q000235:genetics; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism
C496503:Foxa2 protein, mouse; C498002:Ncoa2 protein, mouse; D051958:Nuclear Receptor Coactivator 2; D014157:Transcription Factors; D051542:Hepatocyte Nuclear Factor 3-beta; D019826:Cholic Acid