[Frontiers in Bioscience 13, 6276-6288, May 1, 2008]
Bile acids and gene regulation: from nuclear receptors to chromatin
Nico Mitro, Federica Gilardi, Cristina Godio, Elena Scotti, Emma De Fabiani, Donatella Caruso, Maurizio Crestani
Department of Pharmacological Sciences, University of Milan, via Balzaretti 9, 20133 Milan, Italy
FIGURES
Figure 1. General mechanism of FXR-mediated transcriptional regulation. Under basal conditions (A) (i.e., low bile acid concentration) FXR is not activated and the transcription rate of target genes is low. Upon activation by bile acids (B) FXR undergoes conformational change and recruits coactivators such as steroid receptor coactivator-1 (SRC-1), PPAR gamma coactivator-1 (PGC-1), Baf60c (BRG1/Brm-associated factor of 60 kDa, subunit c) and DRIP205 a subunit of the vitamin D receptor interacting protein (DRIP)/thyroid hormone receptor associated protein (TRAP) coactivator complex. DRIP205 can contact proteins of the preinitiation complex (PIC). RXR: 9-cis retinoic acid receptor; FXRE: FXR responsive element; TATA: TATA box.
Figure 2. Multistep regulation of CYP7A1 gene by bile acids. (A) When intrahepatic concentrations of bile acids are low HDAC7 is mainly localized in the cytoplasm and CYP7A1 gene transcription is activated by HNF-4 and LRH-1 bound to the bile acid responsive element (BARE). These nuclear receptors recruit the coactivators PGC-1, CBP and SRC-1. General transcription factors (GTFs) are recruited to the CYP7A1 promoter and RNA polymerase II (RPII) C-terminal domain (CTD) repeat is phosphorylated. (B) Upon increase of intrahepatic bile acid concentrations, HDAC7 translocates into the nucleus and assembles a corepressor complex containing HDAC7, HDAC3 and SMRT on HNF-4 bound to the BARE of CYP7A1 promoter. At the same time, coactivators dissociate from the CYP7A1 promoter and the CTD of RPII is dephosphorylated, causing the arrest of transcriptional elongation. (C) At a later stage, RPII dissociates from the promoter, the nuclear receptor SHP associates with LRH-1 and keeps the corepressor complex on CYP7A1 promoter. HDAC1, the ATP-dependent chromatin remodeling complex including mSin3A, Brm and BAFs also are assembled and remodel nucleosomes of the CYP7A1 promoter. The histone methyltransferase, G9a, methylates lysine 9 of histone H3, thus marking chromatin in the transcriptional inactive state.