There goes the neighborhood: Assembly of transcriptional complexes during the regulation of metabolism and inflammation by the glucocorticoid receptor

Abstract

Glucocorticoids (GCs), as ligands for the glucocorticoid receptor (GR), represent one of the most effective and frequently used classes of drugs for anti-inflammatory and immunosuppressive therapy. In addition, its role in physiological and pathophysiological processes makes the GR an important research target. The past decades have yielded a wealth of insight into the physiological and pharmacological effects of GCs. Today’s era of next generation sequencing techniques is now beginning to elucidate the molecular and genomic circuits underlying GR’s cell type-specific actions. This review focuses on the concepts and insights gained from recent studies in two of the most important tissues for GC action: the liver (mediating GR’s metabolic effects) and macrophages (as the main target of anti-inflammatory GC therapy). We summarize results obtained from transgenic mouse models, molecular and genome-wide studies to illustrate GR’s complex interactions with DNA, chromatin, co-regulators and other transcription factors. Characterizing the cell type-specific transcriptional complexes assembled around GR will pave the road for the development of new anti-inflammatory and metabolic therapies in the future.

Multifaceted Control of GR Signaling and Its Impact on Hepatic Transcriptional Networks and Metabolism

“…Glucocorticoids have immunosuppressant and anti-inflammatory properties, making them an effective treatment for allergies, inflammatory and autoimmune diseases. The anti-inflammatory effects mediated by GR are conducted by the immune cells, with the macrophages having a particularly important role in the repression of inflammatory genes [reviewed in ( 157 )]. However, by administering GCs systemically, there is a risk of eliciting undesirable side effects on other tissues and cellular processes, such as hepatic metabolism, which is highly impacted by GR regulation.…”

Nuclear Receptor Function through Genomics: Lessons from the Glucocorticoid Receptor

“…It binds as a homodimer, and possibly as a homotetramer [35], to a palindromic DNA sequence roughly approximated as g/aGnACAnnnTGTnCt/c. GR binding in vivo has been dramatically informed by the advent of genome-wide approaches [36,37]. Early chromatin immunoprecipitation with deep sequencing ( ChIP-seq ) studies set the stage for new and surprising determinants for GR binding in diverse cell types and tissues obtained from mice and humans [10,38–44].…”

A naturally hypersensitive glucocorticoid receptor elicits a compensatory reduction of hypothalamus–pituitary–adrenal axis activity early in ontogeny

“…Hence, the effect of GR Ala610Val on transcriptional response appears to be context-dependent. Recent research suggests that contextual ability of GR to elicit specific transcriptional responses is conferred by the interaction between GR, co-regulators such as GRIP1, and the chromatin landscape [ 40 , 41 ]. There is evidence from the structural analysis of the LBD of the human GR that GR Ala610Val probably influences architecture of the GR-LBD and its interaction with ligands [ 42 , 43 ].…”