A guide to changing paradigms of glucocorticoid receptor function—a model system for genome regulation and physiology

Background: Most work in endocrinology focus on the action of a single hormone, and very little on the cross-talks between two hormones. Here we characterize the nature of interactions between thyroid hormone and glucocorticoid signaling during Xenopus tropicalis metamorphosis. Methods: We used functional genomics to derive genome wide profiles of methylated DNA and measured changes of gene expression after hormonal treatments of a highly responsive tissue, tailfin. Clustering classified the data into four types of biological responses, and biological networks were modeled by system biology. Results: We found that gene expression is mostly regulated by either T3 or CORT, or their additive effect when they both regulate the same genes. A small but non-negligible fraction of genes (12%) displayed non-trivial regulations indicative of complex interactions between the signaling pathways. Strikingly, DNA methylation changes display the opposite and are dominated by cross-talks. Conclusion: Cross-talks between thyroid hormones and glucocorticoids are more complex than initially envisioned and are not limited to the simple addition of their individual effects, a statement that can be summarized with the pseudo-equation: TH ∙ GC > TH + GC. DNA methylation changes are highly dynamic and buffered from genome expression.

Section: X-talks: An Unexpected Large Impact On Dna Methylationmentioning

confidence: 99%

Transcriptome and Methylome Analysis Reveal Complex Cross-Talks between Thyroid Hormone and Glucocorticoid Signaling at Xenopus Metamorphosis

Buisine

Grimaldi

Jonchère

et al. 2021

“…However, GCs also directly influence the biological functions of the neoplastic cell. Cancer cells, like normal cells, respond to GCs according to the number and type of GR isoforms expressed and GR affinities for specific GCs [79][80][81]. Studies have associated GR genetic changes to the development of various tumors.…”

Section: Glucocorticoids and Cancermentioning

confidence: 99%

Glucocorticoid and PD-1 Cross-Talk: Does the Immune System Become Confused?

Adorisio

Cannarile

Delfino

et al. 2021

Programmed cell death protein 1 (PD-1) and its ligands, PD-L1/2, control T cell activation and tolerance. While PD-1 expression is induced upon T cell receptor (TCR) activation or cytokine signaling, PD-L1 is expressed on B cells, antigen presenting cells, and on non-immune tissues, including cancer cells. Importantly, PD-L1 binding inhibits T cell activation. Therefore, the modulation of PD-1/PD-L1 expression on immune cells, both circulating or in a tumor microenvironment and/or on the tumor cell surface, is one mechanism of cancer immune evasion. Therapies that target PD-1/PD-L1, blocking the T cell-cancer cell interaction, have been successful in patients with various types of cancer. Glucocorticoids (GCs) are often administered to manage the side effects of chemo- or immuno-therapy, exerting a wide range of immunosuppressive and anti-inflammatory effects. However, GCs may also have tumor-promoting effects, interfering with therapy. In this review, we examine GC signaling and how it intersects with PD-1/PD-L1 pathways, including a discussion on the potential for GC- and PD-1/PD-L1-targeted therapies to “confuse” the immune system, leading to a cancer cell advantage that counteracts anti-cancer immunotherapy. Therefore, combination therapies should be utilized with an awareness of the potential for opposing effects on the immune system.

“…The ligand-bound GR as a transcription factor impacts gene expression of anti- and pro-inflammatory genes in different multimerization states. GR homodimer binds glucocorticoid-response elements (GRE) while monomeric GR either binds DNA half-sites (half GRE) or tethers transcription factors [ 2 ]. GR dimerization was shown to be responsible for the GC dependent induction of anti-inflammatory genes [ 3 ] such as Tsc22d3 (GILZ) [ 4 ] and Dusp1 (MKP-1, DUSP1) [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…However, this mouse model was performed under non-intensive care conditions while patients usually receive intensive care management during systemic inflammation. Using a mouse model with affecting complete GR dimerization capacity induced by a point mutation in the DNA-binding domain (DBD) of the GR (GR dim/dim mice [ 2 , 9 ]), we recently showed that impaired GR aggravates pulmonary dysfunction during endotoxemia under intensive care management [ 10 ]. Furthermore, in a large-animal model of arteriosclerotic swine undergoing hemorrhagic shock (HS) followed by resuscitation in an intensive care unit (ICU) setting, we found that sodium thiosulfate dependent attenuation of lung damage coincided with increased GR expression in the lungs [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Impaired Glucocorticoid Receptor Signaling Aggravates Lung Injury after Hemorrhagic Shock

Preuss

Burret

Gröger

et al. 2021

Self Cite

We previously showed that attenuated lung injury after hemorrhagic shock (HS) coincided with enhanced levels of the glucocorticoid (GC) receptor (GR) in lung tissue of swine. Here, we investigated the effects of impaired GR signaling on the lung during resuscitated HS using a dysfunctional GR mouse model (GRdim/dim). In a mouse intensive care unit, HS led to impaired lung mechanics and aggravated lung inflammation in GRdim/dim mice compared to wildtype mice (GR+/+). After HS, high levels of the pro-inflammatory and pro-apoptotic transcription factor STAT1/pSTAT1 were found in lung samples from GRdim/dim mice. Lungs of GRdim/dim mice revealed apoptosis, most likely as consequence of reduced expression of the lung-protective Angpt1 compared to GR+/+ after HS. RNA-sequencing revealed increased expression of pro-apoptotic and cytokine-signaling associated genes in lung tissue of GRdim/dim mice. Furthermore, high levels of pro-inflammatory cytokines and iNOS were found in lungs of GRdim/dim mice. Our results indicate impaired repression of STAT1/pSTAT1 due to dysfunctional GR signaling in GRdim/dim mice, which leads to increased inflammation and apoptosis in the lungs. These data highlight the crucial role of functional GR signaling to attenuate HS-induced lung damage.