Binding of Retinoic Acid Receptor Heterodimers to DNA

Abstract

The retinoic acid signaling pathway is controlled essentially through two types of nuclear receptors, RARs and RXRs. Ligand dependent activation or repression of retinoid-regulated genes is dependent on the binding of retinoic acid receptor (RAR)/9-cis-retinoic acid receptor (RXR) heterodimers to retinoic acid response element (RARE). Although unliganded RXR/RAR heterodimers bind constitutively to DNA , a clear ligand-dependent occupancy of the RARE present in the RARβ2 gene promoter has been reported (Dey, A., Minucci, S., and Ozato, K. (1994) 14, 8191–8201). Nucleosomes are viewed as general repressors of the transcriptional machinery, in part by preventing the access of transcription factors to DNA. The ability of hRXRα/hRARα heterodimers to bind to a nucleosomal template has therefore been examined. The assembly of a fragment from the RARβ2 gene promoter, which contains a canonical DR5 RARE, into a nucleosome core prevented hRXRα/hRARα binding to this DNA, in conditions where a strong interaction is observed with a linear DNA template. However, histone tails removal by limited proteolysis and histone hyperacetylation yielded nucleosomal RAREs able to bind to hRXRα/hRARα heterodimers. These data establish therefore the role of histones NHtermini as a major impediment to retinoid receptors access to DNA, and identify histone hyperacetylation as a potential physiological regulator of retinoid-induced transcription.