Nuclear Receptor Function through Genomics: Lessons from the Glucocorticoid Receptor

Abstract

Unlocking the therapeutic potential of the glucocorticoid receptor (GR) has motivated a search for small molecules that selectively modulate its ability to activate or repress gene transcription. Recently, breakthrough studies in the field of genomics have reinvigorated debate over longstanding transcriptional models explaining how GR controls tissue-specific gene expression. Here, we highlight these genomic studies with the dual goals of advancing understanding of nuclear receptor-mediated transcription and stimulating thought on the development of anti-inflammatory and immunosuppressive ligands for GR that have reduced harmful effects on metabolism.

Keywords: cistromics; functional genomics; glucocorticoid receptor; nuclear receptor; transcription.

Copyright © 2017 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Tissue-specific functions of GC signaling to GR

GCs mediate distinct biological effects in different tissues and cell types to systemically influence metabolism, cardiovascular function, cognition and inflammation. They impact energy homeostasis by increasing glucose production (GP) in the liver and promoting catabolic processes in muscle, adipose and bone. Their immunosuppressive effects are conferred by the repression of pro-inflammatory genes and activation of anti-inflammatory genes in white blood cells.

Figure 2. Genomic occupancy of GR monomers and dimers regulates gene transcription

(A) Under normal physiological settings, cortisol enables GR to activate transcription through monomeric and dimeric interaction with half-site and palindromic motifs scattered throughout the genome. Neither monomers nor dimers can efficiently access motifs buried in repressive chromatin. Thus, most of their binding sites reside in open chromatin established by lineage determining TFs. Genomic occupancy is tilted toward monomers given that monomeric sites outnumber dimeric by 5:1 in liver. (B) In response to GC drugs, induced gene expression is associated with increased GR occupancy at dimeric sites, whereas down-regulated and unchanged genes correlate with a concomitant loss of GR at monomeric sites. While the genome-wide balance remains tilted toward monomers, gain of occupancy at one set of sites at the expense of another suggests a squelching mechanism for GC-mediated repression of gene expression. Indirect repression can also result from the primary induction by dimeric GR of genes whose products repress transcription. Genomic data do not support a mechanism for direct GC-mediated repression.