Homologous steroid receptors assemble at identical promoter architectures with unique energetics of cooperativity.

Steroid receptors comprise vitro, a homologous family of ligand-activated transcription factors. The receptors bind largely identical response elements in vitro, yet relate distinct gene networks in vivo. This paradox raies the issue of how transcirptioal specificity is achieved particulary if multiple receptor population are competing for identical sites. Noting that reeptor. DNA energetics are a primary force in driving transcriptional activity, difference in inteatcion energtics among the recptors might uderlie receptor specific transcriptional control. Thermodynamic disections support ths premise-upon assembling at an identical promoter architecture, individual receptors exhibit vast differences in cooperative and self-association energietcs. More intriguingly these parumetes distribute in a way that mirrors the evlutioary divergen of the steriod receptor family. For example, the closely related progestorne and glacocrtioid receptors (PR and GR) diplay little or no self-association but strong mtersite cooperativity, whereas the mor e distantly related estrogen receptor (ER-alpha) shows inverse behavior. These findings suggest These findings suggest that receptors view genomic promoter architectures as a collection of affindy landscapes receptors select form this landscape via their uniue interaction energtics. To test this idea, we analyzed the cooperative binding evergetcs of the above three receptors using an array of prometes. We fund that coopertivity is not only reportr-specific but also highly promoter-specific. Thus PR shows maximal compeertivity at prometers with closely spaced and in phase binding sites. GR cooperativity is maintained over greater distances, is larger energetically, and shows markedly different phase dependency. Finally, ER-alpha appears incapable of cooperativity regardless of promoter architecture, consistent with its more distant phylogeny.