Modelling negative feedback networks for activating transcription factor 3 predicts a dominant role for miRNAs in immediate early gene regulation

Activating transcription factor 3 (Atf3) is rapidly and transiently upregulated in numerous systems, and is associated with various disease states. Atf3 is required for negative feedback regulation of other genes, but is itself subject to negative feedback regulation possibly by autorepression. In cardiomyocytes, Atf3 and Egr1 mRNAs are upregulated via ERK1/2 signalling and Atf3 suppresses Egr1 expression. We previously developed a mathematical model for the Atf3-Egr1 system. Here, we adjusted and extended the model to explore mechanisms of Atf3 feedback regulation. Introduction of an autorepressive loop for Atf3 tuned down its expression and inhibition of Egr1 was lost, demonstrating that negative feedback regulation of Atf3 by Atf3 itself is implausible in this context. Experimentally, signals downstream from ERK1/2 suppress Atf3 expression. Mathematical modelling indicated that this cannot occur by phosphorylation of pre-existing inhibitory transcriptional regulators because the time delay is too short. De novo synthesis of an inhibitory transcription factor (ITF) with a high affinity for the Atf3 promoter could suppress Atf3 expression, but (as with the Atf3 autorepression loop) inhibition of Egr1 was lost. Developing the model to include newly-synthesised miRNAs very efficiently terminated Atf3 protein expression and, with a 4-fold increase in the rate of degradation of mRNA from the mRNA/miRNA complex, profiles for Atf3 mRNA, Atf3 protein and Egr1 mRNA approximated to the experimental data. Combining the ITF model with that of the miRNA did not improve the profiles suggesting that miRNAs are likely to play a dominant role in switching off Atf3 expression post-induction.

Comments on 'Current GCMs' Unrealistic Negative Feedback in the Arctic'

In contrast to prior studies showing a positive lapse-rate feedback associated with the Arctic inversion, Boé et al. reported that strong present-day Arctic temperature inversions are associated with stronger negative longwave feedbacks and thus reduced Arctic amplification in the model ensemble from phase 3 of the Coupled Model Intercomparison Project (CMIP3). A permutation test reveals that the relation between longwave feedbacks and inversion strength is an artifact of statistical self-correlation and that shortwave feedbacks have a stronger correlation with intermodel spread. The present comment concludes that the conventional understanding of a positive lapse-rate feedback associated with the Arctic inversion is consistent with the CMIP3 model ensemble.

A new feedback on climate change from the hydrological cycle

An intensification of the hydrological cycle is a likely consequence of global warming. But changes in the hydrological cycle could affect sea-surface temperature by modifying diffusive ocean heat transports. We investigate this mechanism by studying a coupled general circulation model sensitivity experiment in which the hydrological cycle is artificially amplified. We find that the amplified hydrological cycle depresses sea-surface temperature by enhancing ocean heat uptake in low latitudes. We estimate that a 10% increase in the hydrological cycle will contribute a basin-scale sea-surface temperature decrease of around 0.1°C away from high latitudes, with larger decreases locally. We conclude that an intensified hydrological cycle is likely to contribute a weak negative feedback to anthropogenic climate change.

Plant species and functional group effects on abiotic and microbial soil properties and plant-soil feedback responses in two grasslands

1 Plant species differ in their capacity to influence soil organic matter, soil nutrient availability and the composition of soil microbial communities. Their influences on soil properties result in net positive or negative feedback effects, which influence plant performance and plant community composition. 2 For two grassland systems, one on a sandy soil in the Netherlands and one on a chalk soil in the United Kingdom, we investigated how individual plant species grown in monocultures changed abiotic and biotic soil conditions. Then, we determined feedback effects of these soils to plants of the same or different species. Feedback effects were analysed at the level of plant species and plant taxonomic groups (grasses vs. forbs). 3 In the sandy soils, plant species differed in their effects on soil chemical properties, in particular potassium levels, but PLFA (phospholipid fatty acid) signatures of the soil microbial community did not differ between plant species. The effects of soil chemical properties were even greater when grasses and forbs were compared, especially because potassium levels were lower in grass monocultures. 4 In the chalk soil, there were no effects of plant species on soil chemical properties, but PLFA profiles differed significantly between soils from different monocultures. PLFA profiles differed between species, rather than between grasses and forbs. 5 In the feedback experiment, all plant species in sandy soils grew less vigorously in soils conditioned by grasses than in soils conditioned by forbs. These effects correlated significantly with soil chemical properties. None of the seven plant species showed significant differences between performance in soil conditioned by the same vs. other plant species. 6 In the chalk soil, Sanguisorba minor and in particular Briza media performed best in soil collected from conspecifics, while Bromus erectus performed best in soil from heterospecifics. There was no distinctive pattern between soils collected from forb and grass monocultures, and plant performance could not be related to soil chemical properties or PLFA signatures. 7 Our study shows that mechanisms of plant-soil feedback can depend on plant species, plant taxonomic (or functional) groups and site-specific differences in abiotic and biotic soil properties. Understanding how plant species can influence their rhizosphere, and how other plant species respond to these changes, will greatly enhance our understanding of the functioning and stability of ecosystems.

The role of atmosphere feedbacks during ENSO in the CMIP3 models. Part II: using AMIP runs to understand the heat flux feedback mechanisms

Several studies using ocean–atmosphere general circulation models (GCMs) suggest that the atmospheric component plays a dominant role in the modelled El Niño-Southern Oscillation (ENSO). To help elucidate these findings, the two main atmosphere feedbacks relevant to ENSO, the Bjerknes positive feedback (μ) and the heat flux negative feedback (α), are here analysed in nine AMIP runs of the CMIP3 multimodel dataset. We find that these models generally have improved feedbacks compared to the coupled runs which were analysed in part I of this study. The Bjerknes feedback, μ, is increased in most AMIP runs compared to the coupled run counterparts, and exhibits both positive and negative biases with respect to ERA40. As in the coupled runs, the shortwave and latent heat flux feedbacks are the two dominant components of α in the AMIP runs. We investigate the mechanisms behind these two important feedbacks, in particular focusing on the strong 1997–1998 El Niño. Biases in the shortwave flux feedback, α SW, are the main source of model uncertainty in α. Most models do not successfully represent the negative αSW in the East Pacific, primarily due to an overly strong low-cloud positive feedback in the far eastern Pacific. Biases in the cloud response to dynamical changes dominate the modelled α SW biases, though errors in the large-scale circulation response to sea surface temperature (SST) forcing also play a role. Analysis of the cloud radiative forcing in the East Pacific reveals model biases in low cloud amount and optical thickness which may affect α SW. We further show that the negative latent heat flux feedback, α LH, exhibits less diversity than α SW and is primarily driven by variations in the near-surface specific humidity difference. However, biases in both the near-surface wind speed and humidity response to SST forcing can explain the inter-model αLH differences.

Feedback regulation by Atf3 in the endothelin-1-responsive transcriptome of cardiomyocytes: Egr1 is a principal Atf3 target

Endothelin-1 promotes cardiomyocyte hypertrophy by inducing changes in gene expression. Immediate early genes including activating transcription factor 3 (Atf3), Egr1 and Ptgs2 are rapidly and transiently upregulated by endothelin-1 in cardiomyocytes. Atf3 regulates expression of downstream genes and is implicated in negative feedback regulation of other immediate early genes. To identify Atf3-regulated genes, we knocked down Atf3 expression in cardiomyocytes exposed to endothelin-1 and used microarrays to interrogate the transcriptomic effects. Of upregulated mRNAs, expression of 23 (including Egr1, Ptgs2) was enhanced and expression of 25 was inhibited by Atf3 knockdown. Using quantitative PCR, we determined that knockdown of Atf3 had little effect on upregulation of Egr1 mRNA over 30 min, but abolished the subsequent decline, causing sustained Egr1 mRNA expression and enhanced protein expression. This resulted from direct binding of Atf3 to the Egr1 promoter. Mathematical modelling established that Atf3 can suffice to suppress Egr1 expression. Given the widespread co-regulation of Atf3 with Egr1, we suggest that the Atf3-Egr1 negative feedback loop is of general significance. Loss of Atf3 caused abnormal cardiomyocyte growth, presumably resulting from dysregulation of target genes. Our data therefore identify Atf3 as a nexus in cardiomyocyte hypertrophy required to facilitate the full and proper growth response.

Atmosphere feedbacks during ENSO in a coupled GCM with a modified atmospheric convection scheme

The too diverse representation of ENSO in a coupled GCM limits one’s ability to describe future change of its properties. Several studies pointed to the key role of atmosphere feedbacks in contributing to this diversity. These feedbacks are analyzed here in two simulations of a coupled GCM that differ only by the parameterization of deep atmospheric convection and the associated clouds. Using the Kerry–Emanuel (KE) scheme in the L’Institut Pierre-Simon Laplace Coupled Model, version 4 (IPSL CM4; KE simulation), ENSO has about the right amplitude, whereas it is almost suppressed when using the Tiedke (TI) scheme. Quantifying both the dynamical Bjerknes feedback and the heat flux feedback in KE, TI, and the corresponding Atmospheric Model Intercomparison Project (AMIP) atmosphere-only simulations, it is shown that the suppression of ENSO in TI is due to a doubling of the damping via heat flux feedback. Because the Bjerknes positive feedback is weak in both simulations, the KE simulation exhibits the right ENSO amplitude owing to an error compensation between a too weak heat flux feedback and a too weak Bjerknes feedback. In TI, the heat flux feedback strength is closer to estimates from observations and reanalysis, leading to ENSO suppression. The shortwave heat flux and, to a lesser extent, the latent heat flux feedbacks are the dominant contributors to the change between TI and KE. The shortwave heat flux feedback differences are traced back to a modified distribution of the large-scale regimes of deep convection (negative feedback) and subsidence (positive feedback) in the east Pacific. These are further associated with the model systematic errors. It is argued that a systematic and detailed evaluation of atmosphere feedbacks during ENSO is a necessary step to fully understand its simulation in coupled GCMs.

The role of atmosphere feedbacks during ENSO in the CMIP3 models

Several studies using ocean-atmosphere GCMs suggest that the atmospheric component plays a dominant role in the modelled ENSO. To help elucidate these findings, the two main atmosphere feedbacks relevant to ENSO, the Bjerknes positive feedback (µ) and the heat flux negative feedback (), are analysed here in 12 coupled GCMs. We find that the models generally underestimate both feedbacks, leading to an error compensation. The strength of is inversely related to the ENSO amplitude in the models and the latent heat and shortwave flux components of this feedback dominate. Furthermore, the shortwave component could help explain the model diversity in both overall and ENSO amplitude.

Developmental programming: Deficits in reproductive hormone dynamics and ovulatory outcomes in prenatal, testosterone-treated sheep

Prenatal testosterone excess leads to neuroendocrine, ovarian, and metabolic disruptions, culminating in reproductive phenotypes mimicking that of women with polycystic ovary syndrome (PCOS). The objective of this study was to determine the consequences of prenatal testosterone treatment on periovulatory hormonal dynamics and ovulatory outcomes. To generate prenatal testosterone-treated females, pregnant sheep were injected intramuscularly (days 30-90 of gestation, term = 147 days) with 100 mg of testosterone-propionate in cottonseed oil semi-weekly. Female offspring born to untreated control females and prenatal testosterone-treated females were then studied during their first two breeding seasons. Sheep were given two injections of prostaglandin F-2alpha 11 days apart, and blood samples were collected at 2-h intervals for 120 h, 10-min intervals for 8 h during the luteal phase (first breeding season only), and daily for an additional 15 days to characterize changes in reproductive hormonal dynamics. During the first breeding season, prenatal testosterone-treated females manifested disruptions in the timing and magnitude of primary gonadotropin surges, luteal defects, and reduced responsiveness to progesterone negative feedback. Disruptions in the periovulatory sequence of events during the second breeding season included: 1) delayed but increased preovulatory estradiol rise, 2) delayed and severely reduced primary gonadotropin surge in prenatal testosterone-treated females having an LH surge, 3) tendency for an amplified secondary FSH surge and a shift in the relative balance of FSH regulatory proteins, and 4) luteal responses that ranged from normal to anovulatory. These outcomes are likely to be of relevance to developmental origin of infertility disorders and suggest that differences in fetal exposure or fetal susceptibility to testosterone may account for the variability in reproductive phenotypes.

Identification of stimulatory and inhibitory inputs to the hypothalamic-pituitary-adrenal axis during hypoglycaemia or transport in ewes

This study used the novel approach of statistical modelling to investigate the control of hypothalamic-pituitary-adrenal (HPA) axis and quantify temporal relationships between hormones. Two experimental paradigms were chosen, insulin-induced hypoglycaemia and 2 h transport, to assess differences in control between noncognitive and cognitive stimuli. Vasopressin and corticotropin-releasing hormone (CRH) were measured in hypophysial portal plasma, and adrenocorticotropin hormone (ACTH) and cortisol in jugular plasma of conscious sheep, and deconvolution analysis was used to calculate secretory rates, before modelling. During hypoglycaemia, the relationship between plasma glucose and vasopressin or CRH was best described by log(10) transforming variables (i.e. a positive power-curve relationship). A negative-feedback relationship with log(10) cortisol concentration 2 h previously was detected. Analysis of the 'transport' stimulus suggested that the strength of the perceived stimulus decreased over time after accounting for cortisol facilitation and negative-feedback. The time course of vasopressin and CRH responses to each stimulus were different However, at the pituitary level, the data suggested that log(10) ACTH secretion rate was related to log(10) vasopressin and CRH concentrations with very similar regression coefficients and an identical ratio of actions (2.3 : 1) for both stimuli. Similar magnitude negative-feedback effects of log(10) cortisol at -110 min (hypoglycaemia) or -40 min (transport) were detected, and both models contained a stimulatory relationship with cortisol at 0 min (facilitation). At adrenal gland level, cortisol secretory rates were related to simultaneously measured untransformed ACTH concentration but the regression coefficient for the hypoglycaemia model was 2.5-fold greater than for transport. No individual sustained maximum cortisol secretion for longer than 20 min during hypoglycaemia and 40 min during transport. These unique models demonstrate that corticosteroid negative-feedback is a significant control mechanism at both the pituitary and hypothalamus. The amplitude of HPA response may be related to stimulus intensity and corticosteroid negative-feedback, while duration depended on feedback alone.

Effects of trauma exposure on the cortisol response to dexamethasone administration in PTSD and major depressive disorder

Objective: To evaluate cortisol suppression following 0.5 mg of dexamethasone (DEX) in trauma survivors (N = 52),with posttraumatic stress disorder (PTSD), major depressive disorder (MDD), both, or neither disorder, and in subjects never exposed to trauma (N = 10), in order to examine interactions between diagnosis and trauma history on cortisol negative feedback inhibition. Method: Lifetime trauma exposure and psychiatric diagnoses were assessed and blood samples were obtained at 8:00 a.m. for the determination of baseline cortisol. Participants ingested 0.5 mg of DEX at 11:00 p.m. and blood samples for determination of cortisol and DEX were obtained at 8:00 a.m. the following day. Results: PTSD was associated with enhanced cortisol suppression in response to DEX Among trauma survivors, the presence of a traumatic event prior to the "focal" trauma had a substantial impact on cortisol suppression in subjects with MDD. Such subjects were more likely to show cortisol alterations similar to those associated with PTSD, whereas subjects with MDD with no prior trauma were more likely to show alterations in the opposite direction, i.e. relative non-suppression. Conclusions: Cortisol hypersuppression in PTSD appears not to be dependent on the presence of traumatic events prior to the focal trauma. However, prior trauma exposure may affect cortisol suppression in MDD. This finding may have implications for understanding why only some depressed patients show non-suppression on the DST. Published by Elsevier Ltd.

The ACTH response to dexamethasone in PTSD

Objective: Enhanced negative feedback and reduced adrenal output are two different models that have been put forth to explain the paradoxical observations of increased release of corticotropin-releasing factor in the face of low cortisol levels in posttraumatic stress disorder (PTSID). To discriminate between these models, the authors measured levels of adrenocorticopic hormone (ACTH) and cortisol at baseline and in response to dexamethasone in medically healthy subjects with and without PTSID. Under conditions of enhanced negative feedback inhibition, ACTH levels would not be altered relative to cortisol levels, but the ACTH response to dexamethasone would be augmented, in concert with the enhanced cortisol response to dexamethasone. In contrast, under conditions of reduced adrenal output, ACTH levels would be expected to be higher at baseline relative to cortisol levels, but the ACTH response to dexamethasone would be unchanged in PTSID relative to healthy comparison subjects. Method: The ACTH and cortisol responses to 0.50 mg of dexamethasone were assessed in 19 subjects (15 men and four women) with PTSID and 19 subjects (14 men and five women) without psychiatric disorder. Results: The ACTH-to-cortisol ratio did not differ between groups before or after dexamethasone, but the subjects with PTSD showed greater suppression of ACTH (as well as cortisol) in response to dexamethasone. Conclusions: The data support the hypothesis of enhanced cortisol negative feedback inhibition of ACTH secretion at the level of the pituitary in PTSD. Pituitary glucocorticoid receptor binding, rather than low adrenal output, is implicated as a likely mechanism for this effect.

Intra-ovarian roles of activins and inhibins

Granulosa cells are the main ovarian source of inhibins, activins and activin-binding protein (follistatin) while germ (oogonia, oocytes) and somatic (theca, granulosa, luteal) cells express activin receptors, signaling components and inhibin co-receptor (betaglycan). Activins are implicated in various intra-ovarian roles including germ cell survival and primordial follicle assembly; follicle growth from preantral to mid-antral stages; suppression of thecal androgen production; promotion of granulosa cell proliferation, FSHR and CYP19A1 expression; enhancement of oocyte developmental competence; retardation of follicle luteinization and/or atresia and involvement in luteolysis. Inhibins (primarily inhibin A) are produced in greatest amounts by preovulatory follicles (and corpus luteum in primates) and suppress FSH secretion through endocrine negative feedback. Together with follistatin, inhibins act locally to oppose auto-/paracrine activin (and BMP) signaling thus modulating many of the above processes. The balance between activin-inhibin shifts during follicle development with activin signalling prevailing at earlier stages but declining as inhibin and betaglycan expression rise.

The impact of resolution on the adjustment and decadal variability of the Atlantic Meridional Overturning Circulation in a coupled climate model

Variations in the Atlantic Meridional Overturning Circulation (MOC) exert an important influence on climate, particularly on decadal time scales. Simulation of the MOC in coupled climate models is compromised, to a degree that is unknown, by their lack of fidelity in resolving some of the key processes involved. There is an overarching need to increase the resolution and fidelity of climate models, but also to assess how increases in resolution influence the simulation of key phenomena such as the MOC. In this study we investigate the impact of significantly increasing the (ocean and atmosphere) resolution of a coupled climate model on the simulation of MOC variability by comparing high and low resolution versions of the same model. In both versions, decadal variability of the MOC is closely linked to density anomalies that propagate from the Labrador Sea southward along the deep western boundary. We demonstrate that the MOC adjustment proceeds more rapidly in the higher resolution model due the increased speed of western boundary waves. However, the response of the Atlantic Sea Surface Temperatures (SSTs) to MOC variations is relatively robust - in pattern if not in magnitude - across the two resolutions. The MOC also excites a coupled ocean-atmosphere response in the tropical Atlantic in both model versions. In the higher resolution model, but not the lower resolution model, there is evidence of a significant response in the extratropical atmosphere over the North Atlantic 6 years after a maximum in the MOC. In both models there is evidence of a weak negative feedback on deep density anomalies in the Labrador Sea, and hence on the MOC (with a time scale of approximately ten years). Our results highlight the need for further work to understand the decadal variability of the MOC and its simulation in climate models.