Transcriptional coactivator complexes.

The last two decades have witnessed a tremendous expansion in our knowledge of the mechanisms employed by eukaryotic cells to control gene activity. A critical insight to transcriptional control mechanisms was provided by the discovery of coactivators, a diverse array of cellular factors that connect sequence-specific DNA binding activators to the general transcriptional machinery, or that help activators and the transcriptional apparatus to navigate through the constraints of chromatin. A number of coactivators have been isolated as large multifunctional complexes, and biochemical, genetic, molecular, and cellular strategies have all contributed to uncovering many of their components, activities, and modes of action. Coactivator functions can be broadly divide into two classes: (a) adaptors that direct activator recruitment of the transcriptional apparatus, (b) chromatin-remodeling or -modifying enzymes. Strikingly, several distinct coactivator complexes nonetheless share many subunits and appear to be assembled in a modular fashion. Such structural and functional modularity could provide the cell with building blocks from which to construct a versatile array of coactivator complexes according to its needs. The extent of functional interplay between these different activities in gene-specific transcriptional regulation is only now becoming apparent, and will remain an active area of research for years to come.

Transcriptional regulation by the nuclear receptor superfamily.

In the past year, additional experimental data have expanded our understanding of the molecular mechanisms that underlie nuclear receptor control of regulatory programs. It is increasingly clear that steroid members (e.g. glucocorticoid and estrogen) and non-steroid members (e.g. retinoic acid, thyroid hormone, and vitamin D) of the nuclear receptor superfamily may utilize distinct strategies in achieving their complex control of gene regulation.

The orientation and spacing of core DNA-binding motifs dictate selective transcriptional responses to three nuclear receptors.

Characterization of several thyroid hormone (T3), retinoic acid, and estrogen response elements has led to the identification of conserved DNA half-sites (core binding motifs). We present evidence that differences in both the relative orientation and spacing of these motifs within hormone response elements determine the distinct transcriptional responses of three members of the nuclear receptor superfamily. When separated by 3 bp, direct repeat, palindromic, and inverted palindromic arrangements of these motifs impart selective transcriptional responses to retinoic acid, estrogen, and T3 receptors, respectively. Varying the spacing between core motifs alters the specificity. Without spacing, a direct repeat of the core motif paradoxically configures the T3 receptor to confer transactivation in the absence of T3 and repression in its presence. Such an element occurs naturally in the mouse beta-thyrotropin promoter, physiologically under negative regulation by T3. The orientation and spacing of core binding motifs may thus function in concert as a code that accounts for the selective patterns of transcriptional responses of hormonally regulated promoters.