Glucocorticoid Response Research Articles

Genetic and Epigenetic Cis-Regulatory Disruptions Impacting the Canonical Wnt Signaling Repressor TLE1 Gene Promote Glucocorticoid Resistance in Childhood Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is the most prevalent childhood cancer and despite improved survival rates, more children die of ALL than any other cancer. Glucocorticoids (GCs) are a mainstay of contemporary, multi-drug chemotherapy in the treatment of childhood ALL. Resistance to GCs is predictive of ALL relapse and poor clinical outcomes, and therefore represents a major hurdle limiting further improvements in survival rates. While advances have been made in identifying genes implicated in GC resistance, there remains an insufficient understanding of the impact of cis-regulatory disruptions in GC resistance. This is particularly relevant for GCs, which function through the activation of the glucocorticoid receptor (GR) nuclear receptor transcription factor. To better understand the role of cis-regulatory disruptions in GC resistance we comprehensively mapped the dynamic gene regulatory response to GCs in two human ALL cell lines using functional genomic (RNA-seq, ChIP-seq, ATAC-seq and HiChIP) and massively parallel reporter (ATAC-STARR-seq) assays at multiple time points within a 24-hour window. In total, over 100 independent datasets were generated and integrated. We identified thousands of GR binding sites and GC-responsive changes to chromatin state, including the formation of over 250 GC-responsive super-enhancers and depletion of AP-1 bound cis-regulatory elements implicated in cell proliferation and anti-apoptotic processes. Our results further show that GR mediates gene regulatory effects in ALL cells at GC-responsive chromatin sites through long-range looping interactions with GC-responsive gene promoters. Notably, GC-responsive chromatin sites were also enriched for functionally active cis-regulatory elements. By integrating our GC response maps with inherited DNA sequence variants and differentially accessible chromatin sites associated with GC resistance in primary ALL cells from patients enrolled on St. Jude clinical trials, we identified two GR-bound cis-regulatory elements at the canonical Wnt signaling repressor TLE1 gene locus that were genetically or epigenetically disrupted in GC-resistant patient samples. Functional evaluation of these two GR binding sites using CRISPR genome or CRISPR interference epigenome editing validated their impact on GC resistance and TLE1 gene expression. To better understand the relationship between GC signaling and canonical Wnt signaling, we further performed TOP-flash luciferase reporter assays, cellular drug viability assays and transcriptomic drug response profiling which identified mutual antagonism between these two signaling pathways. Collectively, these data uncovered genetic and epigenetic cis-regulatory disruptions of canonical Wnt signaling as a novel mechanism impacting GC resistance in childhood ALL and further suggest that therapeutic inhibition of canonical Wnt signaling could improve GC sensitivity in patients with resistant disease.

Targeting PLZF Enhances Glucocorticoid Sensitivity in Acute Myeloid Leukemia

Glucocorticoids (GCs) are Glucocorticoid Receptor (GR) agonists that are extensively used in clinic, from management of autoimmune and inflammatory disorders to being the corner stone in treatment of adult and childhood lymphoid cancers. Unlike lymphoblastic leukemias, acute myeloid leukemia (AML) cells are generally resistant to glucocorticoids and the mechanisms underlying this resistance are yet to be elucidated. Recent efforts by our group and others suggest that certain genetic alterations, such as RUNX1 loss of function mutations, or therapy-induced stress by chemo-agents such as cytarabine or small molecules like FLT3-inhibitors could sensitize AML cells to GCs, most probably via up-regulation of glucocorticoid receptor (GR) expression. To better characterize GC-response in AML, we compared gene expression landscape of GC-resistant versus GC-sensitive AML cell lines exposed to dexamethasone (Dex) for different time points. Interestingly, we found that the number of down-regulated genes upon GC treatment is similar in both cell lines. However, GC-sensitive cell line showed 3 to 6 times more up-regulated genes following GC treatment compared to the resistant cell line. A significant portion of up-regulated genes in the sensitive cells were targets of GR transcription factor. Gene set enrichment analysis revealed up-regulation of genes associated with macrophage differentiation, inflammation, and apoptosis pathways only in the sensitive cells. To identify modulators of the GC response in AML, we conducted a genome-wide CRISPR/Cas9-based genetic screen on resistant cell lines in the presence or absence of Dex. We identified the promyelocytic leukemia zinc factor (PLZF) as a critical transcription factor that determines GC-response in AML cells. In line with this, we showed that PLZF knockdown conferred sensitivity to GC-resistant AML cells, whereas PLZF over-expression conferred resistance to the sensitive cells. Transcriptome analysis showed an overlap of up-regulated pathways between PLZF-depleted cells and GC-sensitive cells in presence of Dex including inflammation and apoptosis pathways, suggesting that PLZF depletion primes AML cells to GC-response. Furthermore, Dex treatment induced expression of a subset of GR target genes in PLZF depleted cells. Importantly, this effect was not associated with significant changes in GR global protein levels or sub-cellular distribution. PLZF has been recently shown to be a neosubstrate for Cereblon-mediated protein degradation. To define potential therapeutic strategies that target PLZF in AML, we selected two cereblon modulating molecules including Lenalidomide, which is commonly used in the clinic for treatment of hematological malignancies, and CC-3060 compound that is more potent in PLZF degradation. Combination of Dex with PLZF-degrading compounds increased cell death in a significant portion of 95 primary AML samples tested, and as expected, a broader synergistic effect was obtained with CC-3060 compound. Combination of Dex and Lenalidomide appeared more effective in samples harboring NPM1 mutation, independently of recurrent additional mutations of FLT3 or DNMT3A. Importantly, these combinations had no cytotoxicity effect on normal CD34+ cordblood cells in vitro. Current efforts are ongoing to assess efficacy of this newly identified combinatorial therapy in vivo. All together our study shows that GR trans-activating capacity is diminished in resistant AML cells leading to a failure in activating pro-differentiation and anti-leukemic genes upon Dex treatment. PLZF interferes with GC-induced cell death in AML cells at least in part via suppressing 100 of genes involved in GC-response. PLZF suppression induces inflammatory response and sensitizes AML cells to anti-inflammatory effects of glucocorticoids. Based on our results, potent PLZF degrading compounds hold promises to potentiate GC-response in AML.

High salt intake activates the hypothalamic-pituitary-adrenal axis, amplifies the stress response, and alters tissue glucocorticoid exposure in mice.

High salt intake is common and contributes to poor cardiovascular health. Urinary sodium excretion correlates directly with glucocorticoid excretion in humans and experimental animals. We hypothesized that high salt intake activates the hypothalamic-pituitary-adrenal axis activation and leads to sustained glucocorticoid excess. In male C57BL/6 mice, high salt intake for 2-8 weeks caused an increase in diurnal peak levels of plasma corticosterone. After 2 weeks, high salt increased Crh and Pomc mRNA abundance in the hypothalamus and anterior pituitary, consistent with basal hypothalamic-pituitary-adrenal axis activation. Additionally, high salt intake amplified glucocorticoid response to restraint stress, indicative of enhanced axis sensitivity. The binding capacity of Corticosteroid-Binding Globulin was reduced and its encoding mRNA downregulated in the liver. In the hippocampus and anterior pituitary, Fkbp5 mRNA levels were increased, indicating increased glucocorticoid exposure. The mRNA expression of the glucocorticoid-regenerating enzyme, 11β-hydroxysteroid dehydrogenase Type 1, was increased in these brain areas and in the liver. Sustained high salt intake activated a water conservation response by the kidney, increasing plasma levels of the vasopressin surrogate, copeptin. Increased mRNA abundance of Tonebp and Avpr1b in the anterior pituitary suggested that vasopressin signalling contributes to hypothalamic-pituitary-adrenal axis activation by high salt diet. Chronic high salt intake amplifies basal and stress-induced glucocorticoid levels and resets glucocorticoid biology centrally, peripherally and within cells.

Great tits differ in glucocorticoid plasticity in response to spring temperature.

Fluctuations in environmental temperature affect energy metabolism and stimulate the expression of reversible phenotypic plasticity in vertebrate behavioural and physiological traits. Changes in circulating concentrations of glucocorticoid hormones often underpin environmentally induced phenotypic plasticity. Ongoing climate change is predicted to increase fluctuations in environmental temperature globally, making it imperative to determine the standing phenotypic variation in glucocorticoid responses of free-living populations to evaluate their potential for coping via plastic or evolutionary changes. Using a reaction norm approach, we repeatedly sampled wild great tit (<i>Parus major</i>) individuals for circulating glucocorticoid concentrations during reproduction across five years to quantify individual variation in glucocorticoid plasticity along an environmental temperature gradient. As expected, baseline and stress-induced glucocorticoid concentrations increased with lower environmental temperatures at the population and within-individual level. Moreover, we provide unique evidence that individuals differ significantly in their plastic responses to the temperature gradient for both glucocorticoid traits, with some displaying greater plasticity than others. Average concentrations and degree of plasticity covaried for baseline glucocorticoids, indicating that these two reaction norm components are linked. Hence, individual variation in glucocorticoid plasticity in response to a key environmental factor exists in a wild vertebrate population, representing a crucial step to assess their potential to endure temperature fluctuations.

Macrophage migration inhibitory factor promotes glucocorticoid resistance of neutrophilic inflammation in a murine model of severe asthma

BackgroundSevere neutrophilic asthma is resistant to treatment with glucocorticoids. The immunomodulatory protein macrophage migration inhibitory factor (MIF) promotes neutrophil recruitment to the lung and antagonises responses to glucocorticoids. We hypothesised...

Evaluation of cross-platform compatibility of a DNA methylation-based glucocorticoid response biomarker

BackgroundIdentifying blood-based DNA methylation patterns is a minimally invasive way to detect biomarkers in predicting age, characteristics of certain diseases and conditions, as well as responses to immunotherapies. As microarray platforms continue to evolve and increase the scope of CpGs measured, new discoveries based on the most recent platform version and how they compare to available data from the previous versions of the platform are unknown. The neutrophil dexamethasone methylation index (NDMI 850) is a blood-based DNA methylation biomarker built on the Illumina MethylationEPIC (850K) array that measures epigenetic responses to dexamethasone (DEX), a synthetic glucocorticoid often administered for inflammation. Here, we compare the NDMI 850 to one we built using data from the Illumina Methylation 450K (NDMI 450).ResultsThe NDMI 450 consisted of 22 loci, 15 of which were present on the NDMI 850. In adult whole blood samples, the linear composite scores from NDMI 450 and NDMI 850 were highly correlated and had equivalent predictive accuracy for detecting DEX exposure among adult glioma patients and non-glioma adult controls. However, the NDMI 450 scores of newborn cord blood were significantly lower than NDMI 850 in samples measured with both assays.ConclusionsWe developed an algorithm that reproduces the DNA methylation glucocorticoid response score using 450K data, increasing the accessibility for researchers to assess this biomarker in archived or publicly available datasets that use the 450K version of the Illumina BeadChip array. However, the NDMI850 and NDMI450 do not give similar results in cord blood, and due to data availability limitations, results from sample types of newborn cord blood should be interpreted with care.

Modeling gene × environment interactions in PTSD using human neurons reveals diagnosis-specific glucocorticoid-induced gene expression

Post-traumatic stress disorder (PTSD) can develop following severe trauma, but the extent to which genetic and environmental risk factors contribute to individual clinical outcomes is unknown. Here, we compared transcriptional responses to hydrocortisone exposure in human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons and peripheral blood mononuclear cells (PBMCs) from combat veterans with PTSD (n = 19 hiPSC and n = 20 PBMC donors) and controls (n = 20 hiPSC and n = 20 PBMC donors). In neurons only, we observed diagnosis-specific glucocorticoid-induced changes in gene expression corresponding with PTSD-specific transcriptomic patterns found in human postmortem brains. We observed glucocorticoid hypersensitivity in PTSD neurons, and identified genes that contribute to this PTSD-dependent glucocorticoid response. We find evidence of a coregulated network of transcription factors that mediates glucocorticoid hyper-responsivity in PTSD. These findings suggest that induced neurons represent a platform for examining the molecular mechanisms underlying PTSD, identifying biomarkers of stress response, and conducting drug screening to identify new therapeutics.

DiffBrainNet: Differential analyses add new insights into the response to glucocorticoids at the level of genes, networks and brain regions

Genome-wide gene expression analyses are invaluable tools for studying biological and disease processes, allowing a hypothesis-free comparison of expression profiles. Traditionally, transcriptomic analysis has focused on gene-level effects found by differential expression. In recent years, network analysis has emerged as an important additional level of investigation, providing information on molecular connectivity, especially for diseases associated with a large number of linked effects of smaller magnitude, like neuropsychiatric disorders. Here, we describe how combined differential expression and prior-knowledge-based differential network analysis can be used to explore complex datasets. As an example, we analyze the transcriptional responses following administration of the glucocorticoid/stress receptor agonist dexamethasone in 8 mouse brain regions important for stress processing. By applying a combination of differential network- and expression-analyses, we find that these explain distinct but complementary biological mechanisms of the glucocorticoid responses. Additionally, network analysis identifies new differentially connected partners of risk genes and can be used to generate hypotheses on molecular pathways affected. With DiffBrainNet (http://diffbrainnet.psych.mpg.de), we provide an analysis framework and a publicly available resource for the study of the transcriptional landscape of the mouse brain which can identify molecular pathways important for basic functioning and response to glucocorticoids in a brain-region specific manner.

A plant-derived glucocorticoid receptor modulator with potency to attenuate the side effects of glucocorticoid therapy.

Continuous efforts have been made to move towards maintaining the beneficial anti-inflammatory functions of glucocorticoids (GCs) while minimizing side effects. Here, we investigated the selective glucocorticoid receptor (GR) modulator-like properties of a plant-derived compound caesaldekarin e (CA-e). The therapeutic efficacy of CA-e was evaluated in several mouse models, including dextran sulfate sodium-induced colitis, ovalbumin-induced lung allergic inflammation, imiquimod-induced psoriasis-like skin inflammation and skin atrophy. The action of CA-e targeting the GR was analysed using molecular docking, cellular thermal shift assays and microscale thermophoresis. Other methods included DNA-protein pull-down assays and mass spectrometry. CA-e selectively inhibited positive GC response element ((+) GRE)-mediated direct transactivation while maintaining and even enhancing the anti-inflammatory effects of treatment with dexamethasone. CA-e, alone and in combination with dexamethasone, efficiently alleviated inflammation in several mouse models with milder side effects compared with dexamethasone alone. Mechanistically, CA-e inhibited the formation of dimers by binding to the dimerization interface located in the ligand-binding domain of GR and facilitated embryonic ectoderm development that is involved in the regulation of transcriptional repression to compete for binding to (+) GRE, eventually leading to the repression of (+) GRE-regulated genes. In addition, CA-e repressed NF-κB-dependent genes by enhancing the interaction between GR and p65. Our results reveal that CA-e is a novel GR modulator with strong potency to attenuate the side effects of GC therapy and can be used as a potential molecular tool for deciphering GR signalling.

The glucocorticoid response to environmental change is not specific to agents of natural selection in wild red squirrels

Evolutionary endocrinology aims to understand how natural selection shapes endocrine systems and the degree to which endocrine systems themselves can induce phenotypic responses to environmental changes. Such responses may be specialized in that they reflect past selection for responsiveness only to those ecological factors that ultimately influence natural selection. Alternatively, endocrine responses may be broad and generalized, allowing organisms to cope with a variety of environmental changes simultaneously. Here, we empirically tested whether the endocrine response of female North American red squirrels (Tamiasciurus hudsonicus) was specialized or generalized. We first quantified the direction and magnitude of natural selection acting on three female life history traits (parturition date, litter size, offspring postnatal growth rate) during 32 years of fluctuations in four potential ecological agents of selection (food availability, conspecific density, predator abundance, and temperature). Only three of the four variables (food, density, and predators) affected patterns of natural selection on female life history traits. We then quantified fecal glucocorticoid metabolites (FGMs) across 7 years and found that all four environmental variables, regardless of their effects on patterns of selection, were associated with glucocorticoid production. Our results provide support for a generalized, rather than specific, glucocorticoid response to environmental change that can integrate across multiple co-occurring environmental stressors.

MiR-642a-5p increases glucocorticoid sensitivity by suppressing the TLR4 signalling pathway in THP-1 cells

The incidence rate of ulcerative colitis (UC) is increasing annually, and glucocorticoid (GC) resistance (GCR) is a common cause of UC-induced remission failure. Our previous studies have shown that the expression of miR-642a-5p is downregulated in UC with GCR, suggesting that miR-642a-5p may be related to the GC response. Therefore, we investigated the mechanism by which miR-642a-5p regulates the GC response in THP-1 cells.We found that after treatment with miR-642a-5p mimics and DEX, the expression levels of glucocorticoid receptor (GR) in the nucleus and NF-κB p65 and p50 in the cytoplasm were increased (P < 0.05). miR-642a-5p mimics transfected into THP-1 cells could synergize with dexamethasone (DEX) to reduce lipopolysaccharide (LPS)-induced inflammatory factor levels such as TNF-α, IL-1β, IL-6 and IL-12 (P < 0.05). Bioinformatics analysis and luciferase reporter assays confirmed that TLR4 is a target gene of miR-642a-5p. miR-642a-5p mimic pretreatment enhanced the inhibitory effect of DEX on TLR4 induced by LPS and inhibited the expression of TLR4 on the cell surface (P < 0.05). Additionally, miR-642a-5p further prevented the nuclear import of NF-κB P65 and inhibited the phosphorylation of ERK, p38 and JNK.These results suggest that miR-642a-5p can inhibit the inflammation by suppressing the TLR4 signalling pathway in THP-1 cells. It also highlights the TLR4 signalling pathway as a potential therapeutic target in anti-inflammation.

Narrative Review: Glucocorticoids in Alcoholic Hepatitis-Benefits, Side Effects, and Mechanisms.

Alcoholic hepatitis is a major health and economic burden worldwide. Glucocorticoids (GCs) are the only first-line drugs recommended to treat severe alcoholic hepatitis (sAH), with limited short-term efficacy and significant side effects. In this review, I summarize the major benefits and side effects of GC therapy in sAH and the potential underlying mechanisms. The review of the literature and data mining clearly indicate that the hepatic signaling of glucocorticoid receptor (GR) is markedly impaired in sAH patients. The impaired GR signaling causes hepatic down-regulation of genes essential for gluconeogenesis, lipid catabolism, cytoprotection, and anti-inflammation in sAH patients. The efficacy of GCs in sAH may be compromised by GC resistance and/or GC’s extrahepatic side effects, particularly the side effects of intestinal epithelial GR on gut permeability and inflammation in AH. Prednisolone, a major GC used for sAH, activates both the GR and mineralocorticoid receptor (MR). When GC non-responsiveness occurs in sAH patients, the activation of MR by prednisolone might increase the risk of alcohol abuse, liver fibrosis, and acute kidney injury. To improve the GC therapy of sAH, the effort should be focused on developing the biomarker(s) for GC responsiveness, liver-targeting GR agonists, and strategies to overcome GC non-responsiveness and prevent alcohol relapse in sAH patients.

DNA methylation as a pharmacodynamic marker of glucocorticoid response and glioma survival

Assessing individual responses to glucocorticoid drug therapies that compromise immune status and affect survival outcomes in neuro-oncology is a great challenge. Here we introduce a blood-based neutrophil dexamethasone methylation index (NDMI) that provides a measure of the epigenetic response of subjects to dexamethasone. This marker outperforms conventional approaches based on leukocyte composition as a marker of glucocorticoid response. The NDMI is associated with low CD4 T cells and the accumulation of monocytic myeloid-derived suppressor cells and also serves as prognostic factor in glioma survival. In a non-glioma population, the NDMI increases with a history of prednisone use. Therefore, it may also be informative in other conditions where glucocorticoids are employed. We conclude that DNA methylation remodeling within the peripheral immune compartment is a rich source of clinically relevant markers of glucocorticoid response.

Simulating physiological flexibility in the acute glucocorticoid response to stressors reveals limitations of current empirical approaches.

Wild animals often experience unpredictable challenges that demand rapid and flexible responses. The glucocorticoid mediated stress response is one of the major systems that allows vertebrates to rapidly adjust their physiology and behavior. Given its role in responding to challenges, evolutionary physiologists have focused on the consequences of between-individual and, more recently, within-individual variation in the acute glucocorticoid response. However, empirical studies of physiological flexibility are severely limited by the logistical challenges of measuring the same animal multiple times. Data simulation is a powerful approach when empirical data are limited, but has not been adopted to date in studies of physiological flexibility. In this article, I develop a simulation that can generate realistic acute glucocorticoid response data with user specified characteristics. Simulated animals can be sampled continuously through an acute response and across as many separate responses as desired, while varying key parameters. Using the simulation, I develop several scenarios that address key questions in physiological flexibility. These scenarios demonstrate the conditions under which a single glucocorticoid trait can be accurately assessed with typical experimental designs, the consequences of covariation between different components of the acute stress response, and the way that context specific differences in variability of acute responses can influence the power to detect relationships between the strength of the acute stress response and fitness. I also describe how to use the simulation tools to aid in the design and evaluation of empirical studies of physiological flexibility.

Stress and Stress-Induced Glucocorticoids Facilitate Empathic Accuracy in Men but Have No Effects for Women

Empathy, the ability to understand the feelings of other people, is critical for navigating our social world and maintaining social connections. Given that acute stress, and resulting increased glucocorticoids, triggers a shift in two large-scale brain networks, prioritizing salience over executive control, we predicted that acute psychosocial stress would facilitate empathic accuracy. We also investigated the moderating role of gender, given that men typically show a more robust glucocorticoid response to acute stress than women. As predicted, results from two independent experiments (N = 267 college-age participants; 2,256 observations) showed that acute psychosocial stress facilitated empathic accuracy for men, an effect related to their glucocorticoid response in the stress condition. Conversely, psychosocial stress had no effect on empathic accuracy for women, who also showed a smaller cortisol response to stress than men. Exploratory analyses further revealed that women taking oral contraceptives performed worse on the empathic-accuracy task than regularly cycling women. This research highlights the important, but complex, role of stress in cognitive empathy.

Suppression of Glucocorticoid Response in Stressed Mice Using 50 Hz Electric Field According to Immobilization Degree and Posture.

Simple SummaryWith an increasing demand for electricity and electrical equipment, humans are routinely and unintentionally exposed to electric fields (EFs); no significant adverse effects have been identified from exposure to EFs, but slight physiological effects are known to occur. There are, however, methods and devices that expose subjects to EFs for medical purposes. The effects of such methods are not strong and primarily involve the physical properties of EFs, which are invisible and easily disturbed, yet the mechanisms of the biological effects of such EFs have not been identified. We have developed a simple experimental system that allows us to reproducibly observe the inhibitory properties of EFs on the glucocorticoid response to added stress. Using this system, we have revealed the biological effects of EFs. This study has shown that human body posture may affect action of the EF and that it is important to adjust the degree of immobilization in order to capture the effect of the EF. The results of this study provide useful information not only for medical applications of EFs but also for the assessment of risks to health.Various studies on immobilized BALB/c mice to evaluate changes in hormone levels associated with stress responses have advanced the characterization of multiple aspects of the biological actions of extremely low-frequency (ELF) electric fields (EFs). In this study, we aimed to investigate the effect of mouse posture on its stress responses and evaluate the importance of adjusting the stress degree in the model. Mice were immobilized inside centrifuge tubes and exposed to an ELF EF generated between parallel plate electrodes. Blood was collected under anesthesia immediately after EF exposure, and plasma glucocorticoids were assayed. The inhibitory effects of EFs on glucocorticoid elevation by immobilization were reproduced regardless whether mice were in the abdominal or lateral recumbent position, for the EF vector delivered to mice through the sagittal or frontal plane. The effect of ELF EF was reproduced in moderately and mildly stressed mice but not in severely immobilized mice. Hence, adjusting the stress degree is critical to the reproducibility of the results for this model. We characterized the effects of ELF EF on homeostasis, including the stress response, and provided valuable information for the scientific evaluation of the biological risks and medical applications of ELF EF.

Individual variation, personality, and the ability of animals to cope with climate change

The Sixth Assessment of the Intergovernmental Panel on Climate Change describes negative effects of climate change on animals occurring on a larger scale than previously appreciated. Animal species are increasingly experiencing more frequent and extreme weather in comparison with conditions in which the species evolved. Individual variation in behavioural and physiological responses of animals to stimuli from the environment is ubiquitous across all species. Populations with relatively high levels of individual variation are more likely to be able to survive in a range of environmental conditions and cope with climate change than populations with low levels of variation. Behavioural and physiological responses are linked in animals, and personality can be defined as consistent individual behavioural and physiological responses of animals to changes in their immediate environment. Glucocorticoids (cortisol and corticosterone) are hormones that, in addition to metabolic roles, are released when the neuroendocrine stress system is activated in response to stimuli from the environment perceived to be threatening. The size of a glucocorticoid response of an animal is an indication of the animal’s personality. Animals with reactive personalities have relatively high glucocorticoid responses, are relatively slow and thorough to explore new situations, and are more flexible and able to cope with changing or unpredictable conditions than animals with proactive personalities. Animals with reactive personalities are likely to be better able to cope with environmental changes due to climate change than animals with proactive personalities. A reaction norm shows the relationship between phenotype and environmental conditions, with the slope of a reaction norm for an individual animal a measure of phenotypic plasticity. If reaction norm slopes are not parallel, there is individual variation in plasticity. Populations with relatively high individual variation in plasticity of reaction norms will have more animals that can adjust to a new situation than populations with little variation in plasticity, so are more likely to persist as environments change due to climate change. Future studies of individual variation in plasticity of responses to changing environments will help understanding of how populations of animals may be able to cope with climate change.

Epigenomic profiling of glucocorticoid responses identifies cis-regulatory disruptions impacting steroid resistance in childhood acute lymphoblastic leukemia

Glucocorticoids (GCs) are a mainstay of contemporary, multidrug chemotherapy in the treatment of childhood acute lymphoblastic leukemia (ALL), and resistance to GCs remains a major clinical concern. Resistance to GCs is predictive of ALL relapse and poor clinical outcome, and therefore represents a major hurdle limiting further improvements in survival rates. While advances have been made in identifying genes implicated in GC resistance, there remains an insufficient understanding of the impact of cis-regulatory disruptions in resistance. To address this, we mapped the gene regulatory response to GCs in two ALL cell lines using functional genomics and high-throughput reporter assays and identified thousands of GC-responsive changes to chromatin state, including the formation of over 250 GC-responsive super-enhancers and a depletion of AP-1 bound cis-regulatory elements implicated in cell proliferation and anti-apoptotic processes. By integrating our GC response maps with genetic and epigenetic datasets in primary ALL cells from patients, we further uncovered cis-regulatory disruptions at GC-responsive genes that impact GC resistance in childhood ALL. Overall, these data indicate that GCs initiate pervasive effects on the leukemia epigenome, and that alterations to the GC gene regulatory network contribute to GC resistance.

Endocrine flexibility.

Endocrine flexibility.

Glucocorticoid receptor expression as an integrative measure to assess glucocorticoid plasticity and efficiency in evolutionary endocrinology: A perspective

Organisms have to cope with the changes that take place in their environment in order to keep their physical and psychological stability. In vertebrates, the hypothalamic-pituitary-adrenal (HPA) axis plays a key role in mediating phenotypic adjustments to environmental changes, primarily by regulating glucocorticoids (GCs). Although circulating GCs have widely been used as proxy for individual health and fitness, our understanding of HPA regulation is still very limited, especially in free-living animals. Circulating GCs only exert their actions when they are bound to receptors, and therefore, GC receptors play a pivotal role mediating HPA regulation and GC downstream phenotypic changes. Because under challenging conditions GC actions (as well as negative feedback activation) occur mainly through binding to low-affinity glucocorticoid receptors (GR), we propose that GR activity, and in particular GR expression, may play a crucial role in GC regulation and dynamics, and be ultimately related to organismal capacity to appropriately respond to environmental changes. Thus, we suggest that GR expression will provide more comprehensive information of GC variation and function. To support this idea, we compile previous evidence demonstrating the fundamental role of GR on GC responses and the fine-tuning of circulating GCs. We also make predictions about the phenotypic differences in GC responsiveness - and ultimately HPA regulation capacity - associated with differences in GR expression, focusing on GC plasticity and efficiency. Finally, we discuss current priorities and limitations of integrating measures of GR expression into evolutionary endocrinology and ecology studies, and propose further research directions towards the use of GR expression and the study of the mechanisms regulating GR activity to gather information on coping strategies and stress resilience. Our goals are to provide an integrative perspective that will prompt reconsideration on the ecological and physiological interpretation of current GC measurements, and motivate further research on the role of GR in tuning individual responses to dynamic environments.