TY - JOUR T1 - ROLE OF EPIGENETIC MECHANISMS IN DIFFERENTIAL REGULATION OF THE DIOXIN-INDUCIBLE HUMAN <em>CYP1A1</em> AND <em>CYP1B1</em> GENES. JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.110.064899 SP - mol.110.064899 AU - Sudheer R. Beedanagari AU - Robert T. Taylor AU - Peter Bui AU - Feng Wang AU - Derek W. Nickerson AU - Oliver Hankinson Y1 - 2010/07/14 UR - http://molpharm.aspetjournals.org/content/early/2010/07/14/mol.110.064899.abstract N2 - The Aryl Hydrocarbon Receptor (Ahr) mediates induction of CYP1A1 and CYP1B1 by 2,3,7,8-tetrachlorodibenzo-ρ-dioxin (dioxin) via binding to Xenobiotic Responsive Elements (XREs) in their enhancer regions. CYP1A1 and CYPIB1 were both inducible by dioxin in human MCF-7 cells. However, only CYP1A1 was inducible in human HepG2 cells. Further experiments focused on providing an explanation for this last observation. Dioxin induced recruitment of AHR and the transcriptional coactivators p300 and PCAF to the CYP1B1 enhancer in HepG2 cells, but failed to induce recruitment of RNA polymerase II (polII) or the TATA binding protein (TBP) and acetylations of histones 3 and 4 or methylation of histone 3 at the promoter. Since p300 was required for dioxin induction of the aforementioned histone modifications at the CYP1B1 promoter and for induction of CYP1B1 transcription (in MCF-7 cells), the recruitments of p300 and AhR, although necessary, are not sufficient for eliciting the above responses to dioxin. Cytosine residues within CpG dinucleotides at the enhancer, including those within the XREs, were partially methylated, whereas those at the promoter were fully methylated. Treatment of HepG2 cells with 5-aza-2′-deoxycytidine led to partial demethylation of the promoter, and restored polII and TBP binding, and CYP1B1 inducibility. Thus the deficiency of CYP1B1 induction in HepG2 cells is ascribable to cytosine methylation at the promoter which prevents recruitment of TBP and polII. Importantly, our data indicate that stable recruitment of p300 and PCAF to the CYP1B1 gene does not require their tethering to the promoter as well as to the enhancer. ER -