Farnesoid X Receptor and Hepatocyte Nuclear Factor 4 alpha Interact to Regulate Gene Transcription in the Liver

Abstract

Farnesoid X receptor (FXR) is a ligand‐activated nuclear receptor critical for liver function. Studies show mice deficient in FXR develop cholestasis, hyperlipidemia and liver tumors. Hepatocyte nuclear factor 4α (HNF4α) is also a nuclear receptor critical for regulating liver development, differentiation and function. The old paradigm suggested linear activation of target gene transcription following direct binding of FXR to gene regulatory regions. However, we show that FXR activates gene transcription by cooperating with HNF4α to regulate gene transcriptional activation in the liver. Data obtained from chromatin immunoprecipitation followed by massive parallel sequencing (ChIP‐seq) of mouse liver, shows that about 40% of FXR binding sites in liver overlapped with HNF4α binding sites. Genes that are bound by both FXR and HNF4α showed more active transcription, revealed by higher levels of H3K4 mono‐methylation and mRNA expression, than for genes that were bound by either factor alone. In addition, the majority of FXR and HNF4α binding sites are close in proximity, about 25–30 base pairs apart. Luciferase assays suggest that HNF4α may have an additive effect on FXR transcriptional activation. Co‐immunoprecipitation assays imply FXR may directly interact with HNF4α. In conclusion, this study shows evidence of a cooperative interaction between FXR and HNF4α in regulating liver gene transcription.