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.
Bochkis
Irina M
IM
Department of Genetics and Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Schug
Jonathan
J
Rubins
Nir E
NE
Chopra
Atul R
AR
O'Malley
Bert W
BW
Kaestner
Klaus H
KH
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