Genomic effects of glucocorticoids

Abstract

Glucocorticoids and their receptor (GR) have been an important area of research because of their pleiotropic physiological functions and extensive use in the clinic. In addition, the association between GR and glucocorticoids, which is highly specific, leads to rapid nuclear translocation where GR associates with chromatin to regulate gene transcription. This simplified model system has been instrumental for studying the complexity of transcription regulation processes occurring at chromatin. In this review we discuss our current understanding of GR action that has been enhanced by recent developments in genome wide measurements of chromatin accessibility, histone marks, chromatin remodeling and 3D chromatin structure in various cell types responding to glucocorticoids.

Gene activation and repression by the glucocorticoid receptor are mediated by sequestering Ep300 and two modes of chromatin binding

“…4f). Previous studies have shown that GR sites are overall accessible prior to GR activation and that this accessibility increases in a subset of loci following GR binding (2,5,10,32,(51)(52)(53). Our results here show that hormone treatment elevates chromatin accessibility specifically at GR sites associated with GR-activated genes.…”

“…While significant progress has been made in understanding how these regulatory sites are initiated and maintained, less is known about the mechanisms that determine the specific function of GR sites in activating or repressing transcription. Gene activation is thought to be primarily controlled by direct binding of GR to its recognition element (GRE) and subsequent recruitment of co-activators such as SRC-1, GRIP1 and CBP/EP300 (7)(8)(9)(10). Models for transcriptional repression include direct and indirect GR binding to DNA.…”

“…One of the proposed mechanisms, trans-repression, stems from the indirect binding of GR to regulatory loci lacking GR recognition elements (GREs). In this case, tethering of GR to DNA-bound transcription factors like AP-1 and nuclear factor-kB (NF-κB) disrupts their association with coactivators and thereby antagonizes their activity (10)(11)(12)(13). However genome-wide analyses indicate that the association of AP-1 and NF-κB on GR binding sites is common to both upand downregulated genes, and thus cannot explain the opposite transcriptional responses (1,6,14).…”

Quantifying transcription factor binding dynamics at the single-molecule level in live cells

“…Subsequently, the cells were treated with the synthetic ligand dexamethasone (Dex) prior to imaging. Dex binds to the ligand-binding pocket of the GR which induces the nuclear translocation of the receptor, and results in chromatin binding and subsequent regulation of transcription [30]. Using a custom made tracking software (see section 2.3), individual localizations of single molecules are classified as belonging to a bound track segment (i.e.…”

Hierarchical role for transcription factors and chromatin structure in genome organization along adipogenesis

“…These results reflect the complex relationship between gene regulation and genome architecture, as evident for other regulatory layers of gene transcription. For example, TF binding may promote, inhibit, or potentiate gene transcription [41,42]. Thus, to define the molecular basis of genome architecture during adipogenesis, we searched for coordinated dynamics between genome reorganization and other chromatin processes (e.g., histone modifications and TF binding).…”