Functional Involvement of the Brahma/SWI2-related Gene 1 Protein in Cytochrome P4501A1 Transcription Mediated by the Aryl Hydrocarbon Receptor Complex

Abstract

Chromatin remodeling is a key step in overcoming the nucleosomal repression of active transcription in eukaryotes. The mammalian SWI/SNF ATP-dependent chromatin-remodeling complexes contain multiple subunits. The ATPase activities in these complexes are attributable to either BRG-1 or the related Brahma protein. The aryl hydrocarbon receptor (AHR), after binding xenobiotic ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), associates with the AHR nuclear translocator (ARNT), and the dimer so formed activates transcription of several genes, including the cytochrome P4501A1 (CYP1A1) gene. We show that BRG-1 potentiates AHR/ARNT-mediated reporter gene activity in a TCDD-dependent fashion in Hepa1c1c7 cells. Introduction of BRG-1 into the BRG-1- and hBrm-deficient SW13 and C33A human cell lines also enhances expression from a transiently transfected AHR/ARNT-dependent reporter gene. Replenishment of BRG-1 to SW13 cells also restores endogenous cytochrome P4501A1 (CYP1A1) gene expression, whereas an ATPase-deficient mutant of BRG-1 is unable to do so. Chromatin immunoprecipitation analysis demonstrated that BRG-1 associates with the enhancer region of the mouse CYP1A1 gene in vivo in a TCDD- and ARNT-dependent fashion, suggesting the specific recruitment of BRG-1 by AHR/ARNT. Finally, we demonstrate that the glutamine-rich subdomain of the transcriptional activation domain of AHR can interact with BRG-1. Together these studies reveal a functional involvement of BRG-1 in activating CYP1A1 gene transcription and implicate the importance of ATP-dependent chromatin remodeling activity on inducible gene expression mediated by AHR/ARNT.