HDAC1 bound to the Cyp1a1 promoter blocks histone acetylation associated with Ah receptor-mediated trans-activation

Metabolic bioactivation of polycyclic aromatic hydrocarbons, such as the environmental procarcinogen benzo[a]pyrene, is catalyzed by a cytochrome P450 monooxygenase encoded by the substrate-inducible Cyplal gene. Cyplal induction requires trans-activation by the heterodimeric transcriptional complex formed by the liganded Ah receptor (AHR) and its partner, ARNT. Previously, we showed that constitutively bound HDAC1 dissociates from Cyplal promoter chromatin after ligand-mediated induction, concomitantly with the recruitment of AHR/ARNT complexes and p300. Here, we investigated the hypothesis that HDAC1 binding maintains the Cyplal gene in a silenced state in uninduced cells. We find that Cyplal induction by the AHR/ARNT is associated with modification of specific chromatin marks, including hyperacetylation of historic H3K14 and F14K16, trimethylation of historic H3K4, and phosphorylation of H3S10. HDAC1 and DNMT1 form complexes on the Cyplal promoter of uninduced cells but HDAC1 inhibition alone is not sufficient to induce Cyplal expression, although it allows for the hyperacetylation of H3K14 and H4K16 to levels similar to those found in B[a]P-induced cells. These results show that by blocking the modification of histone marks, HDAC1 plays a central role in Cyplal expression and that its removal is a necessary but not sufficient condition for Cyplal induction, underscoring the requirement for a concerted series of chromatin-remodeling events to complete the initial steps of gene trans-activation by the Ah receptor. (c) 2007 Elsevier B.V All rights reserved.