BINDING OF RETINOIC ACID RECEPTOR HETERODIMERS TO DNA - A ROLE FOR HISTONES NH2 TERMINI

The retinoic acid signaling pathway is controlled essentially through two types of nuclear receptors, RARs and RXRs. Ligand dependent activa tion or repression of retinoid-regulated genes is dependent on the bin ding of retinoic acid receptor (RAR)/9-cis-retinoic acid receptor (RXR ) heterodimers to retinoic acid response element (RARE). Although unli ganded RXR/RAR heterodimers bind constitutively to DNA in vitro, a cle ar in vivo ligand-dependent occupancy of the RARE present in the RAR b eta 2 gene promoter has been reported (Dey, A., Minucci, S., and Ozato , K. (1994) Mol. Cell. Biol. 14, 8191-8201). Nucleosomes are viewed as general repressors of the transcriptional machinery, in part by preve nting the access of transcription factors to DNA. The ability of hRXR alpha/hRAR alpha heterodimers to bind to a nucleosomal template in vit ro has therefore been examined. The assembly of a fragment from the RA R beta 2 gene promoter, which contains a canonical DR5 RARE, into a nu cleosome core prevented hRXR alpha/hRAR alpha binding to this DNA, in conditions where a strong interaction is observed with a linear DNA te mplate. However, histone tails removal by limited proteolysis and hist one hyperacetylation yielded nucleosomal RAREs able to bind to hRXR al pha/hRAR alpha heterodimers. These data establish therefore the role o f histones NH2 termini as a major impediment to retinoid receptors acc ess to DNA, and identify histone hyperacetylation as a potential physi ological regulator of retinoid-induced transcription.