| First Author | Thomas AM | Year | 2013 |
| Journal | Pharm Res | Volume | 30 |
| Issue | 9 | Pages | 2188-98 |
| PubMed ID | 23462932 | Mgi Jnum | J:329802 |
| Mgi Id | MGI:6879858 | Doi | 10.1007/s11095-013-1006-7 |
| Citation | Thomas AM, et al. (2013) Hepatocyte nuclear factor 4 alpha and farnesoid X receptor co-regulates gene transcription in mouse livers on a genome-wide scale. Pharm Res 30(9):2188-98 |
| abstractText | PURPOSE: 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 4alpha (Hnf4alpha), 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 Hnf4alpha 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 Hnf4alpha 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 Hnf4alpha in mouse liver overlap and Hnf4alpha bound to shared target sites upstream and in close proximity to Fxr. Moreover, genes co-bound by Fxr and Hnf4alpha are enriched in complement and coagulation cascades and drug metabolism. A direct Fxr-Hnf4alpha protein interaction dependent on Fxr activity was detected and transcriptional assays suggest that Hnf4alpha can increase Fxr transcriptional activity. Conversely, binding assays showed Hnf4alpha can be either Fxr-dependent or -independent at different shared binding sites. CONCLUSION: Our results showed that Fxr cooperates with Hnf4alpha 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 Hnf4alpha in regulating gene transcription in the liver. |
