Combinatorial gene regulation by modulation of relative pulse timing
Ontology highlight
ABSTRACT:
ORGANISM(S): Saccharomyces cerevisiae
PROVIDER: GSE71712 | GEO | 2015/10/15
SECONDARY ACCESSION(S): PRJNA291871
REPOSITORIES: GEO
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Project description:Gene-expression measurements were made over a 60 minute time course as steady state E. coli cells were subjected to a pulse of glucose.
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Project description:Studies of individual living cells have revealed that many transcription factors activate in dynamic, and often stochastic, pulses within the same cell. However, it has remained unclear whether cells might exploit the dynamic interaction of these pulses to control gene expression. Here, using quantitative single-cell time-lapse imaging of Saccharomyces cerevisiae, we show that the pulsatile transcription factors Msn2 and Mig1 combinatorially regulate their target genes through modulation of their relative pulse timing. The activator Msn2 and repressor Mig1 showed pulsed activation in either a temporally overlapping or non-overlapping manner during their transient response to different inputs, with only the non-overlapping dynamics efficiently activating target gene expression. Similarly, under constant environmental conditions, where Msn2 and Mig1 exhibit sporadic pulsing, glucose concentration modulated the temporal overlap between pulses of the two factors. Together, these results reveal a time-based mode of combinatorial gene regulation. Regulation through relative signal timing is common in engineering and neurobiology, and these results suggest that it could also function broadly within the signalling and regulatory systems of the cell.
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Project description:The Saccharomyces cerevisiae SFP1 is required for proper regulation of ribosome biogenesis and cell size in response to nutrients. A mutant deleted for SFP1 shows specific traits among which a slow growth phenotype, which is particularly evident during growth on glucose. To assess the effects of nutrients on the activity of Sfp1 independent by growth rate related feedback we grew an sfp1Πmutant and its isogenic reference strain in chemostat cultures, at the same specific growth rate, under glucose/ethanol-limitation. Our data show that Sfp1 is involved in the modulation of cell size and RiBi gene expression and that these two functions are differently influenced by nutrients. The continuous cultures were then pulsed with a glucose excess generating a situation of batch growth similar to shake flask cultures. The dynamic analysis of the metabolic and transcriptional response following the glucose addition suggested that Sfp1 plays a role at the crossroads of ribosome biogenesis and central carbon metabolism regulation. Finally, we show that the down-regulation of RP genes, which was observed in an sfp1Πstrain during shake flask growth, cannot be directly ascribed to the absence of Sfp1 but is most probably a secondary effect due to the low growth potential of the mutant strain. Experiment Overall Design: After ten volume changes, few seconds after the samples for the steady state analysis were collected, the anaerobic glucose pulse experiments were started by sparging the medium reservoir and the fermenter with pure nitrogen gas (airflow of 0.5 L min-1, Hoek-Loos, Schiedam, <5 ppm O2). NorpreneTM tubing and butyl septa were used to minimize oxygen diffusion into the anaerobic culture. Two minutes after nitrogen sparging and just before the addition of glucose, the medium and the effluent pumps were switched off. At this time point (which we will refer to as time T=0) the 200 mM glucose pulse was injected aseptically through a rubber septum. Experiment Overall Design: Sampling from chemostats, total RNA extraction, probe preparation and hybridization to Affymetrix Genechip® microarrays were performed as previously described (1). Samples were collected at steady state and then at 5, 10, 30, 60 and 120 minutes after the pulse. The results relative to steady state samples were derived from three independent cultures, those relative to the time course analysis were derived from two independent cultures. Experiment Overall Design: 1) Cipollina C., van den Brink J., Daran-Lapujade P., Pronk J.T., Vai M. and de Winde J.H. (2007) Revisiting the role of yeast Sfp1 in ribosome biogenesis and cell size control: A chemostat study. Microbiology. In press.
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Project description:Reproduction requires pulsatile release of hypothalamic GnRH, which regulates expression of the pituitary gonadotropins FSH and luteinizing hormone (LH). Fshb expression shows an inverted U-shaped response to GnRH pulse frequency. Increasing GnRH pulse frequency beyond ~one pulse/2 hours, despite increasing the average GnRH concentration, induces progressively less Fshb. To clarify regulatory mechanisms underlying Fshb gene control, we developed three biologically inspired and topologically distinct mathematical models. The models represent: 1) parallel activation of Fshb inhibitory and stimulatory factors (e.g. inhibin α, VGF), 2) activation of a signaling component with a refractory period (e.g. G protein), and 3) inactivation of a factor needed for Fshb induction (e.g. GDF9). Simulations with all three models recapitulated the Fshb expression levels obtained in standard perifusion experiments at different GnRH pulse frequencies. Notably, simulations altering average concentration, pulse duration and frequency showed that the apparent frequency-dependent pattern of Fshb expression obtained with model 1 actually resulted from variations in average GnRH concentration. In contrast, models 2 and 3 showed “true” frequency sensing. To resolve which components of this GnRH signal induce Fshb, a massively parallel experimental system was developed. Analysis of over 4000 samples in ~40 experiments indicated that, while early genes Egr1 and Fos respond only to variations in GnRH concentration, Fshb induction is sensitive to GnRH pulse frequency changes, whilst maintaining the same average concentration. These results provide a framework for understanding the role of different regulatory factors in modulating the responses of the Fshb gene.
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Project description:Reproduction requires pulsatile release of hypothalamic gonadotropin-releasing hormone (GnRH), which regulates expression of the pituitary gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Fshb expression shows an inverted U-shaped response to GnRH pulse frequency. Increasing GnRH pulse frequency beyond ~one pulse/2 hours, despite increasing the average GnRH concentration, induces progressively less Fshb. To clarify regulatory mechanisms underlying Fshb gene control, we developed three biologically inspired and topologically distinct mathematical models. The models represent: 1) parallel activation of Fshb inhibitory and stimulatory factors (e.g. inhibin α, VGF), 2) activation of a signaling component with a refractory period (e.g. G protein), and 3) inactivation of a factor needed for Fshb induction (e.g. GDF9). Simulations with all three models recapitulated the Fshb expression levels obtained in standard perifusion experiments at different GnRH pulse frequencies. Notably, simulations altering average concentration, pulse duration and frequency showed that the apparent frequency-dependent pattern of Fshb expression obtained with model 1 actually resulted from variations in average GnRH concentration. In contrast, models 2 and 3 showed “true” frequency sensing. To resolve which components of this GnRH signal induce Fshb, a massively parallel experimental system was developed. Analysis of over 4000 samples in ~40 experiments indicated that, while early genes Egr1 and Fos respond only to variations in GnRH concentration, Fshb induction is sensitive to GnRH pulse frequency changes, whilst maintaining the same average concentration. These results provide a framework for understanding the role of different regulatory factors in modulating the responses of the Fshb gene.
2017-04-07 | GSE85869 | GEO
Project description:Reproduction requires pulsatile release of hypothalamic gonadotropin-releasing hormone (GnRH), which regulates expression of the pituitary gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Fshb expression shows an inverted U-shaped response to GnRH pulse frequency. Increasing GnRH pulse frequency beyond ~one pulse/2 hours, despite increasing the average GnRH concentration, induces progressively less Fshb. To clarify regulatory mechanisms underlying Fshb gene control, we developed three biologically inspired and topologically distinct mathematical models. The models represent: 1) parallel activation of Fshb inhibitory and stimulatory factors (e.g. inhibin α, VGF), 2) activation of a signaling component with a refractory period (e.g. G protein), and 3) inactivation of a factor needed for Fshb induction (e.g. GDF9). Simulations with all three models recapitulated the Fshb expression levels obtained in standard perifusion experiments at different GnRH pulse frequencies. Notably, simulations altering average concentration, pulse duration and frequency showed that the apparent frequency-dependent pattern of Fshb expression obtained with model 1 actually resulted from variations in average GnRH concentration. In contrast, models 2 and 3 showed “true” frequency sensing. To resolve which components of this GnRH signal induce Fshb, a massively parallel experimental system was developed. Analysis of over 4000 samples in ~40 experiments indicated that, while early genes Egr1 and Fos respond only to variations in GnRH concentration, Fshb induction is sensitive to GnRH pulse frequency changes, whilst maintaining the same average concentration. These results provide a framework for understanding the role of different regulatory factors in modulating the responses of the Fshb gene.
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Project description:Reproduction requires pulsatile release of hypothalamic gonadotropin-releasing hormone (GnRH), which regulates expression of the pituitary gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Fshb expression shows an inverted U-shaped response to GnRH pulse frequency. Increasing GnRH pulse frequency beyond ~one pulse/2 hours, despite increasing the average GnRH concentration, induces progressively less Fshb. To clarify regulatory mechanisms underlying Fshb gene control, we developed three biologically inspired and topologically distinct mathematical models. The models represent: 1) parallel activation of Fshb inhibitory and stimulatory factors (e.g. inhibin α, VGF), 2) activation of a signaling component with a refractory period (e.g. G protein), and 3) inactivation of a factor needed for Fshb induction (e.g. GDF9). Simulations with all three models recapitulated the Fshb expression levels obtained in standard perifusion experiments at different GnRH pulse frequencies. Notably, simulations altering average concentration, pulse duration and frequency showed that the apparent frequency-dependent pattern of Fshb expression obtained with model 1 actually resulted from variations in average GnRH concentration. In contrast, models 2 and 3 showed “true” frequency sensing. To resolve which components of this GnRH signal induce Fshb, a massively parallel experimental system was developed. Analysis of over 4000 samples in ~40 experiments indicated that, while early genes Egr1 and Fos respond only to variations in GnRH concentration, Fshb induction is sensitive to GnRH pulse frequency changes, whilst maintaining the same average concentration. These results provide a framework for understanding the role of different regulatory factors in modulating the responses of the Fshb gene.
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Project description:Reproduction requires pulsatile release of hypothalamic gonadotropin-releasing hormone (GnRH), which regulates expression of the pituitary gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Fshb expression shows an inverted U-shaped response to GnRH pulse frequency. Increasing GnRH pulse frequency beyond ~one pulse/2 hours, despite increasing the average GnRH concentration, induces progressively less Fshb. To clarify regulatory mechanisms underlying Fshb gene control, we developed three biologically inspired and topologically distinct mathematical models. The models represent: 1) parallel activation of Fshb inhibitory and stimulatory factors (e.g. inhibin α, VGF), 2) activation of a signaling component with a refractory period (e.g. G protein), and 3) inactivation of a factor needed for Fshb induction (e.g. GDF9). Simulations with all three models recapitulated the Fshb expression levels obtained in standard perifusion experiments at different GnRH pulse frequencies. Notably, simulations altering average concentration, pulse duration and frequency showed that the apparent frequency-dependent pattern of Fshb expression obtained with model 1 actually resulted from variations in average GnRH concentration. In contrast, models 2 and 3 showed “true” frequency sensing. To resolve which components of this GnRH signal induce Fshb, a massively parallel experimental system was developed. Analysis of over 4000 samples in ~40 experiments indicated that, while early genes Egr1 and Fos respond only to variations in GnRH concentration, Fshb induction is sensitive to GnRH pulse frequency changes, whilst maintaining the same average concentration. These results provide a framework for understanding the role of different regulatory factors in modulating the responses of the Fshb gene.
2017-04-07 | GSE85669 | GEO
Project description:Reproduction requires pulsatile release of hypothalamic gonadotropin-releasing hormone (GnRH), which regulates expression of the pituitary gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Fshb expression shows an inverted U-shaped response to GnRH pulse frequency. Increasing GnRH pulse frequency beyond ~one pulse/2 hours, despite increasing the average GnRH concentration, induces progressively less Fshb. To clarify regulatory mechanisms underlying Fshb gene control, we developed three biologically inspired and topologically distinct mathematical models. The models represent: 1) parallel activation of Fshb inhibitory and stimulatory factors (e.g. inhibin α, VGF), 2) activation of a signaling component with a refractory period (e.g. G protein), and 3) inactivation of a factor needed for Fshb induction (e.g. GDF9). Simulations with all three models recapitulated the Fshb expression levels obtained in standard perifusion experiments at different GnRH pulse frequencies. Notably, simulations altering average concentration, pulse duration and frequency showed that the apparent frequency-dependent pattern of Fshb expression obtained with model 1 actually resulted from variations in average GnRH concentration. In contrast, models 2 and 3 showed “true” frequency sensing. To resolve which components of this GnRH signal induce Fshb, a massively parallel experimental system was developed. Analysis of over 4000 samples in ~40 experiments indicated that, while early genes Egr1 and Fos respond only to variations in GnRH concentration, Fshb induction is sensitive to GnRH pulse frequency changes, whilst maintaining the same average concentration. These results provide a framework for understanding the role of different regulatory factors in modulating the responses of the Fshb gene.
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