title: Hepatocyte nuclear factor 4 alpha and farnesoid X receptor co-regulates gene transcription in mouse livers on a genome-wide scale.
abstract: OBJECTIVE
  Farnesoid X receptor (Fxr) is a ligand-activated nuclear receptor critical for liver function. Reports indicate that the functions of Fxr in the liver may overlap with those of hepatocyte nuclear factor 4α (Hnf4α), but studies of their precise genome-wide interaction to regulate gene transcription in the liver are lacking. Thus, we compared the genome-wide binding of Fxr and Hnf4α in the liver of mice and characterized their cooperative activity on binding to and activating target gene transcription.
  
  
  METHODS
  Genome-wide ChIP-Seq data of Fxr and Hnf4α in mouse liver were analyzed by MACS, BEDTools, and DAVID. Co-immunoprecipitation, ChIP-qPCR, and luciferase assays were done to test for protein-protein interaction and cooperative binding.
  
  
  RESULTS
  ChIP-seq analysis showed nearly 50% binding sites of Fxr and Hnf4α in mouse liver overlap and Hnf4α bound to shared target sites upstream and in close proximity to Fxr. Moreover, genes co-bound by Fxr and Hnf4α are enriched in complement and coagulation cascades and drug metabolism. A direct Fxr-Hnf4α protein interaction dependent on Fxr activity was detected and transcriptional assays suggest that Hnf4α can increase Fxr transcriptional activity. Conversely, binding assays showed Hnf4α can be either Fxr-dependent or -independent at different shared binding sites.
  
  
  CONCLUSIONS
  Our results showed that Fxr cooperates with Hnf4α in the liver to modulate gene transcription. This study provides the first evidence on a genome-wide scale of both cooperative and independent interactions between Fxr and Hnf4α in regulating gene transcription in the liver.
authors: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, 66160, USA.
authors: Ann M
authors: AM
authors: Thomas
authors: Steve N
authors: SN
authors: Hart
authors: Guodong
authors: G
authors: Li
authors: Hong
authors: H
authors: Lu
authors: Yaping
authors: Y
authors: Fang
authors: Jianwen
authors: J
authors: Fang
authors: Xiao-Bo
authors: XB
authors: Zhong
authors: Grace L
authors: GL
authors: Guo
mesh_terms: D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D003412:Cricetulus; D016678:Genome; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015533:Transcriptional Activation; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D051557:Hepatocyte Nuclear Factor 4; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated