Transcriptional regulation involves transcription factor (TF) binding to specific enhancer/silencer elements and recruitment of many coregulator proteins, which remodel chromatin and regulate assembly of an active transcription complex. TF binding to genomic sites and coregulator actions are selective; i.e. not every appropriate motif and available TF binding site is occupied, and the coregulators required for transcriptional regulation by a specific TF varies in a gene-specific manner. Gene-specific actions of coregulators represent unexplored physiological regulatory mechanisms. To facilitate future studies on coregulator physiological roles, we examine here the mechanisms by which coregulator Hic-5 modulates transcriptional regulation by the glucocorticoid receptor (GR) using gene-specific mechanisms. GR is activated by binding of glucocorticoid (GC) hormones and synthetic ligands; among many other physiological pathways, GR regulates inflammation and metabolism of glucose, fat, and protein. Regulation of some genes by GC and GR requires Hic-5 (Hic-5 modulated or mod genes), while regulation of other genes by GC/GR is not affected by Hic-5 depletion (Hic-5 independent or ind genes). We identified a third class of genes that are not regulated by GC/GR until Hic-5 is depleted from cells (Hic-5 blocked or block genes). Hic-5 strongly inhibits GC-induced binding of GR and chromatin remodeling on block genes; but on mod genes Hic-5 facilitates recruitment of the Mediator complex and RNA polymerase II. Thus regulation of Hic-5 expression or activity could modulate the set of genes regulated by GC, and thus the biological response, within a given cell type and between different cell types. The proposed project focuses on block genes, which provide a unique opportunity to explore novel mechanisms that control TF binding site selection. We will define specific characteristics of ind, mod, and block genes and their chromatin environment that determine gene-specific actions of Hic-5 (Aim 1). In addition, our preliminary data indicate that block genes require different chromatin remodeling complexes than ind and mod genes; we will therefore explore the hypothesis that Hic-5 selectively interferes with the chromatin remodelers required for GC regulation of the block genes (Aim 2). Finally, functional genomic analyses of GR and Hic-5 mutants will test the roles of the GR-Hic-5 interaction and of Hic-5 protein domains in differentia regulation of Hic-5 modulated and Hic-5 blocked genes (Aim 3). Our results will define novel molecular mechanisms and potentiate future exploration of Hic-5 roles in the physiology of GC and in binding site selection by TFs.
Glucocorticoid (GC) hormones are released by the adrenal glands in response to many types of stress (hunger, cold, fear, illness, inflammation, etc) and regulate many physiological programs, including inflammation and metabolism of carbohydrate, fat, and protein. GC action is elevated in obesity and diabetes to deal with the associated inflammation, but the increased GC also exacerbate the disease by contributing to hyperglycemia, hyperlipidemia, and insulin resistance. GC actions are carried out by the GC receptor (GR), which regulates gene expression with the help of many coregulator proteins. The proposed project will define mechanisms by which coregulators modulate the set of genes that is regulated by GC, thus altering the physiological actions of GC. The results will provide novel information about coregulators as possible therapeutic targets for treating diabetes as well as inflammatory diseases.
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