Mechanisms of Glucocorticoid-Regulated Gene Transcription

One fascinating aspect of glucocorticoid signaling is their broad range of physiological and pharmacological effects. These effects are at least in part a consequence of transcriptional regulation by the glucocorticoid receptor (GR). Activation of GR by glucocorticoids results in tissue-specific changes in gene expression levels with some genes being activated whereas others are repressed. This raises two questions: First, how does GR regulate different subsets of target genes in different tissues? And second, how can GR both activate and repress the expression of genes?To answer these questions, this chapter will describe the function of the various "components" and how they cooperate to mediate the transcriptional responses to glucocorticoids. The first "component" is GR itself. The second "component" is the chromatin and its role in specifying where in the genome GR binds. Binding to the genome however is just the first step in regulating the expression of genes and transcriptional regulation by GR depends on the recruitment of coregulator proteins that either directly or indirectly influence the recruitment and or activity of RNA polymerase II. Ultimately, the integration of inputs including GR isoform, DNA sequence, chromatin and cooperation with coregulators determines which genes are regulated and the direction of their regulation.