NF-κB-Dependent Assembly of an Enhanceosome-Like Complex on the Promoter Region of Apoptosis Inhibitor Bfl-1/A1

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Abstract
Expression of the prosurvival Bcl-2 homologue Bfl-1/A1 is induced by NF-κB-activating stimuli, while B and T cells from c-rel knockout mice show an absolute defect in bfl-1/a1 gene activation. Here, we demonstrate NF-κB-dependent assembly of an enhanceosome-like complex on the promoter region of bfl-1. Binding of NF-κB subunit c-Rel to DNA nucleated the concerted binding of transcription factors AP-1 and C/EBPβ to the 5′-regulatory region of bfl-1. Optimal stability of the complex was dependent on proper orientation and phasing of the NF-κB site. Chromatin immunoprecipitation analyses demonstrated that T-cell activation triggers in vivo binding of endogenous c-Rel, c-Jun, C/EBPβ, and HMG-IC to the bfl-1 regulatory region, coincident with selective recruitment of coactivators TAFII250 and p300, SWI/SNF chromatin remodeling factor component BRG-1, and basal transcription factors TATA-binding protein (TBP) and TFIIB, as well as hyperacetylation of histones H3 and H4. These results highlight a critical role for NF-κB in bfl-1 transcription and point to the need for a complex and precise regulatory network to control bfl-1 expression. To our knowledge, this is the first demonstration of enhanceosome-mediated regulation of a cell death inhibitor.