Glucocorticoid receptor binds half sites as a monomer and regulates specific target genes

Schiller, Benjamin J.; Chodankar, Rajas; Watson, Lisa; Stallcup, Michael R.

doi:10.1186/preaccept-2066059439130185

Cited by 25 publications

(35 citation statements)

References 36 publications

(52 reference statements)

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“…However, the discovery of monomeric occupancy near transcriptionally active genes, and the ability of monomeric-binding sites to drive transcription in vitro, indicate an expanded transactivation mechanism incorporating GR monomers. In support of this, similar monomeric function has recently been described in vitro for human U2OS osteosarcoma cell lines carrying stably integrated GR alleles (Schiller et al 2014). Revision of the transrepression mechanism may also be in order to include binding of GR monomers to half sites.…”

Section: Discussionsupporting

confidence: 60%

Genomic redistribution of GR monomers and dimers mediates transcriptional response to exogenous glucocorticoid in vivo

et al. 2015

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Glucocorticoids (GCs) are commonly prescribed drugs, but their anti-inflammatory benefits are mitigated by metabolic side effects. Their transcriptional effects, including tissue-specific gene activation and repression, are mediated by the glucocorticoid receptor (GR), which is known to bind as a homodimer to a palindromic DNA sequence. Using ChIP-exo in mouse liver under endogenous corticosterone exposure, we report here that monomeric GR interaction with a half-site motif is more prevalent than homodimer binding. Monomers colocalize with lineage-determining transcription factors in both liver and primary macrophages, and the GR half-site motif drives transcription, suggesting that monomeric binding is fundamental to GR's tissue-specific functions. In response to exogenous GC in vivo, GR dimers assemble on chromatin near ligand-activated genes, concomitant with monomer evacuation of sites near repressed genes. Thus, pharmacological GCs mediate gene expression by favoring GR homodimer occupancy at classic palindromic sites at the expense of monomeric binding. The findings have important implications for improving therapies that target GR.

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Section: Discussionsupporting

confidence: 60%

Genomic redistribution of GR monomers and dimers mediates transcriptional response to exogenous glucocorticoid in vivo

et al. 2015

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“…However, two 5Ј-AGAACA half-sites were identified in the XIRP1 promoter (at Ϫ560 and Ϫ64). HRE half-sites bound by GR monomers have also been implicated in GR trans-repression but not trans-activation (66). Therefore, the presence of these sites in the XIRP1 promoter seems like an unlikely explanation for the MR-dependent induction of XIRP1 as observed here.…”

Section: Discussionmentioning

confidence: 56%

Mineralocorticoid Receptor (MR) trans-Activation of Inflammatory AP-1 Signaling

Dougherty

Elinoff

Ferreyra

et al. 2016

Journal of Biological Chemistry

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Glucocorticoids are commonly used to treat inflammatory disorders. The glucocorticoid receptor (GR) can tether to inflammatory transcription factor complexes, such as NFB and AP-1, and trans-repress the transcription of cytokines, chemokines, and adhesion molecules. In contrast, aldosterone and the mineralocorticoid receptor (MR) primarily promote cardiovascular inflammation by incompletely understood mechanisms. Although MR has been shown to weakly repress NFB, its role in modulating AP-1 has not been established. Here, the effects of GR and MR on NFB and AP-1 signaling were directly compared using a variety of ligands, two different AP-1 consensus sequences, GR and MR DNA-binding domain mutants, and siRNA knockdown or overexpression of core AP-1 family members. Both GR and MR repressed an NFB reporter without influencing p65 or p50 binding to DNA. Likewise, neither GR nor MR affected AP-1 binding, but repression or activation of AP-1 reporters occurred in a ligand-, AP-1 consensus sequence-, and AP-1 family member-specific manner. Notably, aldosterone interactions with both GR and MR demonstrated a potential to activate AP-1. DNA-binding domain mutations that eliminated the ability of GR and MR to cis-activate a hormone response element-driven reporter variably affected the strength and polarity of these responses. Importantly, MR modulation of NFB and AP-1 signaling was consistent with a trans-mechanism, and AP-1 effects were confirmed for specific gene targets in primary human cells. Steroid nuclear receptor trans-effects on inflammatory signaling are context-dependent and influenced by nuclear receptor conformation, DNA sequence, and the expression of heterologous binding partners. Aldosterone activation of AP-1 may contribute to its proinflammatory effects in the vasculature.

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“…Recent genome-wide ChIP-Seq analysis and ChIP exo Seq analysis demonstrated that the GR monomer binds to half GRE-like sites (Schiller et al, 2014;Lim et al, 2015;Starick et al, 2015). The half site motifs are in vicinity of binding to motifs of lineage-specific TFs observed in distinct cell lines and in liver and macrophages (Lim et al, 2015;Starick et al, 2015) ( Figure 1A).…”

Section: Transactivation and Transrepression Of Gene Regulation By Thmentioning

confidence: 95%

The glucocorticoid receptor in inflammatory processes: transrepression is not enough

Hübner¹,

Dejager²,

Libert³

et al. 2015

Biological Chemistry

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Glucocorticoids (GCs) are the most commonly used anti-inflammatory agents to treat inflammatory and immune diseases. However, steroid therapies are accompanied by severe side-effects during long-term treatment. The dogma that transrepression of genes, by tethering of the glucocorticoid receptor (GR) to DNAbound pro-inflammatory transcription factors, is the main anti-inflammatory mechanism, is now challenged. Recent discoveries using conditional GR mutant mice and genomic approaches reveal that transactivation of antiinflammatory acting genes is essential to suppress many inflammatory disease models. This novel view radically changes the concept to design selective acting GR ligands with a reduced side-effect profile.

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Glucocorticoid receptor binds half sites as a monomer and regulates specific target genes

Cited by 25 publications

References 36 publications

Genomic redistribution of GR monomers and dimers mediates transcriptional response to exogenous glucocorticoid in vivo

Genomic redistribution of GR monomers and dimers mediates transcriptional response to exogenous glucocorticoid in vivo

Mineralocorticoid Receptor (MR) trans-Activation of Inflammatory AP-1 Signaling

The glucocorticoid receptor in inflammatory processes: transrepression is not enough

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