How to tame your genes: mechanisms of inflammatory gene repression by glucocorticoids

Abstract

Glucocorticoids (GCs) are widely used therapeutic agents to treat a broad range of inflammatory conditions. Their functional effects are elicited by binding to the glucocorticoid receptor (GR), which regulates transcription of distinct gene networks in response to ligand. However, the mechanisms governing various aspects of undesired side effects versus beneficial immunomodulation upon GR activation remain complex and incompletely understood. In this review, we discuss emerging models of inflammatory gene regulation by GR, highlighting GR's regulatory specificity conferred by context‐dependent changes in chromatin architecture and transcription factor or co‐regulator dynamics. GR controls both gene activation and repression, with the repression mechanism being central to favourable clinical outcomes. We describe current knowledge about 3D genome organisation and its role in spatiotemporal transcriptional control by GR. Looking beyond, we summarise the evidence for dynamics in gene regulation by GR through cooperative convergence of epigenetic modifications, transcription factor crosstalk, molecular condensate formation and chromatin looping. Further characterising these genomic events will reframe our understanding of mechanisms of transcriptional repression by GR.

Integrative analysis of macrophage ribo-Seq and RNA-Seq data define glucocorticoid receptor regulated inflammatory response genes into distinct regulatory classes

“…Importantly, gene enrichment and STRING protein network analysis revealed a vast array of Dex-GR target genes in the intensified regulatory class that are involved in macrophage inflammation modulation. In this regard, however, much remains to be learned about mechanisms of translational control [10] , [118] , [119] , [120] , [121] , [122] , [123] . Nevertheless, an important step toward this goal is to characterize the post-transcriptional regulation of early GR responsive genes (e.g.…”

“…GR classically exerts its transcriptional regulation, following GC binding, by interacting with evolutionarily conserved 15 bp palindromic consensus DNA sequences (AGAACANNNTGTTCT) designated as glucocorticoid response elements (GREs). GREs are primarily present in the enhancer and promoter regions of GR target genes and drive, predominantly through protein–protein interactions with co-activators and histone acetyl transferases (HATs), the transcription of anti-inflammatory factors [7] , [8] , [9] , [10] . Transcriptional inhibition by GR is, on the other hand, exerted via recruitment of co-repressors such as Glucocorticoid receptor interacting protein 1 (GRIP1) and histone deacetylases (HDACs), disrupting pro-inflammatory NF-κB/interferon response factor3 (IRF3) complexes, and interaction with classical palindromes or with cryptic GREs within NF-κB and AP-1 motifs [11] , [12] , [13] , [14] ( Fig.…”

Regulation of Cyclooxygenase-2 Expression in Human T Cells by Glucocorticoid Receptor-Mediated Transrepression of Nuclear Factor of Activated T Cells

“…GCs mediate these biological effects through binding to an intracellular glucocorticoid receptor (GR). Upon ligand binding, the GR translocates to the nucleus, where it participates in the regulation of gene expression, both positively (transactivation) or negatively (transrepression) [ 22 , 23 , 24 ]. The transcriptional induction of gene expression by GCs depends on ligand-activated GR binding to glucocorticoid response elements (GRE) in the promoter region of target genes, as in the case of genes involved in glucose and fat metabolism [ 25 , 26 ].…”

“…The transcriptional induction of gene expression by GCs depends on ligand-activated GR binding to glucocorticoid response elements (GRE) in the promoter region of target genes, as in the case of genes involved in glucose and fat metabolism [ 25 , 26 ]. On the other hand, several mechanisms have been suggested for the negative regulation of gene expression by GCs, such as the activation of GR-dependent inhibitory genes; binding to negative GREs; or, most commonly, by transcriptional interference involving competition with coactivators, as well as by GR interaction with transcription factors [ 22 , 27 , 28 ]. GR-mediated transcriptional repression (transrepression) is the main mechanism by which GCs inhibit the activity of several transcription factors, including NFκB, activator protein (AP)-1, CREB, signal transducers, and activators of transcription (STATs) or interferon-regulatory factors (IRFs), among others.…”

“…The tethering of ligand-activated GR to these regulatory transcription factors involved in the upregulation of inflammatory genes is the main mechanism described to explain the anti-inflammatory and immunomodulatory properties of GCs. Therefore, GCs inhibit the synthesis, release, and/or action of cytokines and other mediators that promote inflammatory and immune responses [ 20 , 22 , 29 ]. In this regard, it is well known that COX-2 expression is negatively regulated by GCs such as dexamethasone (Dex) in numerous types of cells, both at the transcriptional and post-transcriptional level [ 30 , 31 , 32 , 33 , 34 , 35 ].…”