Distinct genome-wide gene-specific selectivity patterns of fourglucocorticoid receptor coregulators

摘要

Glucocorticoids are a class of steroid hormones that bind to and activate the glucocorticoid receptor (GR), which then positively or negatively regulates transcription of many genes that govern multiple important physiological pathways such as inflammation and metabolism of glucose, fat and bone. The remodeling of chromatin and regulated assembly or disassembly of active transcription complexes by GR and other DNA-binding transcription factors is mediated and modulated by several hundred transcriptional coregulator proteins. Previous studies focusing on single coregulators demonstrated that each coregulator is required for regulation of only a subset of all the genes regulated by a steroid hormone. We hypothesized that the gene-specific patterns of coregulators may correspond to specific physiological pathways such that different coregulators modulate the pathway-specificity of hormone action, thereby providing a mechanism for fine tuning of the hormone response. We tested this by direct comparison of multiple coregulators, using siRNA to deplete the products of four steroid hormone receptor coregulator genes (CCAR1, CCAR2, CALCOCO1 and ZNF282). Global analysis of glucocorticoid-regulated geneexpression after siRNA mediated depletion of coregulators confirmed that eachcoregulator acted in a selective and gene-specific manner and demonstrated bothpositive and negative effects on glucocorticoid-regulated expression ofdifferent genes. We identified several classes of hormone-regulated genes basedon the effects of coregulator depletion. Each coregulator supported hormonalregulation of some genes and opposed hormonal regulation of other genes(coregulator-modulated genes), blocked hormonal regulation of a second class ofgenes (coregulator-blocked genes), and had no effect on hormonal regulation of athird gene class (coregulator-independent genes). In spite of previouslydemonstrated physical and functional interactions among these four coregulators,the majority of the several hundred modulated and blocked genes for each of thefour coregulators tested were unique to that coregulator. Finally, pathwayanalysis on coregulator-modulated genes supported the hypothesis that individualcoregulators may regulate only a subset of the many physiological pathwayscontrolled by glucocorticoids. We conclude that gene-specific actions ofcoregulators correspond to specific physiological pathways, suggesting thatcoregulators provide a potential mechanism for physiological fine tuning in vivoand may thus represent attractive targets for therapeutic intervention.