Sequence-selective interactions of transcription factor elements with tandem glucocorticoid-responsive elements at physiological steroid concentrations.

Synergism in transcription is said to occur when the combined response from two DNA elements for the binding of trans-acting factors is greater than the sum of the responses from each element in isolation. The synergism of steroid receptors with themselves or with other trans-acting factors at saturating concentrations of steroid has proved to be an important component of steroid-regulated gene transcription. We have recently described a glucocorticoid modulatory element (GME) of the rat tyrosine aminotransferase gene that, in conjunction with a trans-acting factor, modulates the transcriptional activity of receptor-glucocorticoid and -antiglucocorticoid complexes with homologous and heterologous genes and promoters (Oshima, H., and Simons, S. S., Jr. (1992) Mol. Endocrinol. 6, 416-428). We now report that, under certain circumstances, the GME displays synergistic activity with a glucocorticoid-responsive element (GRE). However, several properties of GME action are different from those previously observed for synergism. The effects of the GME were marked at subsaturating or physiological concentrations of glucocorticoids but insignificant at saturating concentrations, which are the established conditions for synergism. The GME was found to increase the agonist activity of partial antiglucocorticoids, while synergism involving antisteroids has yet to be reported. Furthermore, the GRE was active in conjunction with two tandem repeats of a GRE, which was a combination that did not support conventional synergism. Most importantly, the effects of the GME were greater than with any other trans-acting factor binding element tested, indicative of a sequence-selective activity. The efficacy of the GME was also insensitive to the spacing between elements. Thus, the GME provides a mechanism for selective transcriptional modulation by physiological concentrations of steroid, and by antisteroids, of a common class of genes that are under the control of two or more GREs.