The changing paradigm: estrogen receptor α recognition on DNA and within the dynamic nature of nucleosomes

Estrogen receptor alpha (ERα) plays a major role in the expression of estrogen-responsive genes. Although its conventional binding characteristics have been considered coincident with & exclusively in the class of steroid hormone receptors, increasing evidence challenges this paradigm. ERα was shown to bind to consensus estrogen response element half-sites (cHERE) in DNA in the presence of the ubiquitous, abundant & conserved architectural protein, high mobility group protein 1 (HMGB1). It also binds to direct repeats with various spacers, in addition to everted repeats. These in vitro binding sites have been shown to be active in vivo, with both the binding affinity and transcriptional activity increased in the presence of HMGB1. Surprisingly, ERα does not bind to the optimally oriented cERE at the dyad in rotationally phased and translationally positioned nucleosomes. However, the presence of HMGB1 restructures the nucleosome to facilitate increased ERα accessibility, resulting in sequence-specific estrogen receptor binding. The finding that HMGB1 interacts with unbound ERα provides a unique avenue for enhanced ERα activity and possibly an increase in the extent of targeting at estrogen-responsive genes. The findings are consistent with ERα 1) targeting a much wider selection of genomic response elements (half-sites and inverted, direct and everted repeats) and 2) exhibiting characteristics of both steroid and non steroid nuclear receptors. Growing evidence already shows a competition occurs at the DNA level between ERα and the non steroid nuclear hormone receptor, thyroid receptor (TR). Collectively, these reports suggest a less restrictive cataloging for estrogen receptor and a broader paradigm for understanding its role in the regulation of estrogen-responsive genes and influence on non steroid hormone receptor activities.