HREs resemble enhancer elements in that they are not strictly dependent on position and location or orientation. They generally are found within a few hundred nucleotides upstream (5′) of the transcription initiation site, but they may be located within the coding region of the gene, in introns. heterologous reporter systems coupled with genome-wide chromatin immunoprecipitation and bioinformatic analyses. Although these simple HREs bind the hormone-receptor complex more avidly than surrounding DNA—or DNA from an unrelated source—and confer hormone responsiveness to a reporter gene, it soon became apparent that the regulatory circuitry of natural genes must be much more complicated. Glucocorticoids, progestins, mineralocorticoids, and androgens have vastly different physiologic actions. How could the specificity required for these effects be achieved through regulation of gene expression by the same HRE ? Questions like this have led to experiments which have allowed for elaboration of a more complex model of transcription regulation by the steroid hormone receptor family of proteins. For example, in the vast majority of cellular genes, the HRE is found associated with other specific regulatory DNA elements (and associated binding proteins); these associations are mandatory for optimal function. The extensive sequence similarity noted between steroid hormone receptors, particularly in their DNA-binding domains (DBD), led to discovery of the nuclear receptor superfamily of proteins. These—and a large number of coregulator proteins—allow for a wide variety of DNA–protein and protein–protein interactions and the specificity necessary for highly regulated physiologic control. A schematic of such an assembly is illustrated in Figure 1.

Fig1. The hormone response transcriptional activation unit. The hormone response transcription unit is an assembly of DNA elements and complementary, cognate DNA-bound proteins that interact, through protein–protein interactions, with a number of coactivator or corepressor molecules. An essential component is the hormone response element that is bound by the ligand (▴)-bound receptor (R). Also important are the accessory factor elements (AFEs) with bound transcription factors. More than two dozen of these accessory factors (AFs), which are often members of the nuclear receptor superfamily, have been linked to hormone effects on transcription. The AFs can interact with each other, with the liganded nuclear receptors, or with coregulators. These components communicate with the basal transcription machinery, forming the polymerase II PIC (ie, RNAP II and GTFs; through a coregulator complex that can consist of one or more members of the p160, corepressor, mediator-related, or CBP/p300 families. Recall that many of the transcription coregulators carry intrinsic enzymatic activities that covalently modify the DNA, transcription proteins, and the histones present in the nucleosomes (not shown here) in and around the enhancer (HRE, AFE) and promoter. Collectively the hormone, hormone receptor, chromatin, DNA and transcription machinery integrate and process hormone signals to regulate transcription in a physiologic fashion.

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