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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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The combinatorial code governing cellular responses to complex stimuli

ABSTRACT: Integration of multiple signals shapes cell adaptation to their microenvironment through synergistic and antagonistic interactions. The combinatorial complexity governing signal integration for multiple cellular output responses has not been resolved. For outputs measured in the conditions 0 (control), signals X, Y, X+Y, combinatorial analysis revealed 82 possible interaction profiles, which we biologically assimilated to 5 positive, and 5 negative interaction modes. To experimentally validate their use in living cells, we designed an original computational workflow, and applied it to transcriptomics data of innate immune cells integrating physiopathological signal combinations. Up to 9 of the 10 defined modes coexisted in context-dependent proportions. Each integration mode was enriched in specific molecular pathways, suggesting a coupling between genes involved in particular functions, and the corresponding mode of integration. We propose that multimodality and functional coupling are general principles underlying the systems level integration of physiopathological and pharmacological stimuli by mammalian cells. The general experiment design : No stimulus (Medium), stimulus X, stimulus Y and combination treatment X+Y was applied for 6 or 24 hours, with different stimuli combinations. Every experimental condition was carried out in 3 independent biological replicates.

ORGANISM(S): Homo sapiens

SUBMITTER: Raphael Zollinger

PROVIDER: E-GEOD-57915 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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The combinatorial code governing cellular responses to complex stimuli

Project description:Integration of multiple signals shapes cell adaptation to their microenvironment through synergistic and antagonistic interactions. The combinatorial complexity governing signal integration for multiple cellular output responses has not been resolved. For outputs measured in the conditions 0 (control), signals X, Y, X+Y, combinatorial analysis revealed 82 possible interaction profiles, which we biologically assimilated to 5 positive, and 5 negative interaction modes. To experimentally validate their use in living cells, we designed an original computational workflow, and applied it to transcriptomics data of innate immune cells integrating physiopathological signal combinations. Up to 9 of the 10 defined modes coexisted in context-dependent proportions. Each integration mode was enriched in specific molecular pathways, suggesting a coupling between genes involved in particular functions, and the corresponding mode of integration. We propose that multimodality and functional coupling are general principles underlying the systems level integration of physiopathological and pharmacological stimuli by mammalian cells.

2015-03-06 | GSE57915 | GEO

Identification and Characterization of Enhancers Controlling the Inflammatory Gene Expression Program in Macrophages

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Molecular encoding of stimulus features in a single sensory neuron type enables neuronal and behavioral plasticity

Project description:Neurons modify their molecular profiles in response to an animal’s experience. How specific experiences are transduced to modulate gene expression and precisely tune neuronal functions are not fully defined. Here, we describe the molecular profile of a thermosensory neuron pair in C. elegans experiencing different temperature stimuli. We find that distinct salient features of the temperature stimulus including its duration, magnitude of change, and absolute value are encoded in the gene expression program in this single neuron, and identify a novel transmembrane protein and a transcription factor whose specific transcriptional dynamics are essential to drive neuronal, behavioral, and developmental plasticity. Expression changes are driven by broadly expressed activity-dependent transcription factors and corresponding cis-regulatory elements that nevertheless direct neuron- and stimulus-specific gene expression programs. Our results indicate that coupling of defined stimulus characteristics to the gene regulatory logic in individual specialized neuron types can customize neuronal properties to drive precise behavioral adaptation.

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Identification and Characterization of Enhancers Controlling the Inflammatory Gene Expression Program in Macrophages

2010-03-05 | E-GEOD-19553 | biostudies-arrayexpress

Homo sapiens

Project description:The combinatorial code governing cellular responses to complex stimuli

| PRJNA253209 | ENA

Environmental interactions and epistasis are revealed in the proteomic responses to complex stimuli

Project description:Ultimately, the genotype of a cell and its interaction with the environment determine the cell’s biochemical state. While the cell’s response to a single stimulus has been studied extensively, a conceptual framework to model the effect of multiple environmental stimuli applied concurrently is not as well developed. In this study, we developed the concepts of environmental interactions and epistasis to explain the responses of the S. cerevisiae proteome to simultaneous environmental stimuli. We hypothesize that, as an abstraction, environmental stimuli can be treated as analogous to genetic elements. This would allow modeling of the effects of multiple stimuli using the concepts and tools developed for studying gene interactions. Mirroring gene interactions, our results show that environmental interactions play a critical role in determining the state of the proteome. We show that individual and complex environmental stimuli behave similarly to genetic elements in regulating the cellular responses to stimuli, including the phenomena of dominance and suppression. Interestingly, we observed that the effect of a stimulus on a protein is dominant over other stimuli if the response to the stimulus involves the protein. Using publicly available transcriptomic data, we find that environmental interactions and epistasis regulate transcriptomic responses as well.

2015-07-20 | PXD002371 | Pride

Escherichia coli treated with 13 antibiotics, 3 synergistic combinations, and IPTG

Project description:Microarrays allow us to monitor the change in transcription of every gene in the genome in response to a change in cellular state. We use cDNA microarrays to measure the response of E. coli to 13 different antibiotics and 3 synergistic combinations. Hierarchichal clustering reveals 4 distinct classes of antibiotics distinguished by their modes of action, and allows us to predict the mechanism for promethazine, a drug whose mode of action has not previously been established. The expression profiles of the synergistic combinations exhibit a complex relationship between the two component antibiotics, with similarity to one of the two drugs, as well as a surprising number of new gene responses exhibited by E. coli in response to neither drug alone. The subset of drugs which act in synergy with each other suggests that only very specific combination of mechanisms give rise to synergistic behavior. Keywords: stress response, antibiotic response, synergy

2008-02-12 | GSE10440 | GEO

Genomic architecture of biomass heterosis in Arabidopsis

Project description:Heterosis is most frequently manifested by the substantially increased vigorous growth of hybrids compared with their parents. Investigating genomic variations in natural populations is essential to understand the initial molecular mechanisms underlying heterosis in plants. Here, we characterized the genomic architecture associated with biomass heterosis in 200 Arabidopsis hybrids. The genome-wide heterozygosity of hybrids makes a limited contribution to biomass heterosis, and no locus shows an obvious overdominance effect in hybrids. However, the accumulation of significant genetic loci identified in genome wide association studies (GWAS) in hybrids strongly correlates with better-parent heterosis (BPH). Candidate genes for biomass BPH fall into diverse biological functions, including cellular, metabolic, and developmental processes and stimulus-responsive pathways. Important heterosis candidates include WUSCHEL, ARGOS, and some genes that encode key factors involved in cell cycle regulation. Interestingly, transcriptomic analyses in representative Arabidopsis hybrid combinations reveal that heterosis candidate genes are functionally enriched in stimulus-responsive pathways, including responses to biotic and abiotic stimuli and immune responses. In addition, stimulus-responsive genes are repressed to low-parent levels in hybrids with high BPH, whereas middle-parent expression patterns are exhibited in hybrids with no BPH. Our study reveals a genomic architecture for understanding the molecular mechanisms of biomass heterosis in Arabidopsis, in which the accumulation of the superior alleles of genes involved in metabolic and cellular processes improve the development and growth of hybrids, whereas the overall repressed expression of stimulus responsive genes prioritizes growth over responding to environmental stimuli in hybrids under normal conditions.

2017-08-03 | GSE100595 | GEO

Genomic architecture of biomass heterosis in Arabidopsis

2017-08-03 | GSE85759 | GEO

Cross-regulation between the response regulators PhoB and TctD allows for the integration of diverse environmental signals in Pseudomonas aeruginosa

Project description:Two-component systems (TCS) serve as basic stimulus-response coupling mechanisms to allow organisms to sense and respond to a large variety of environmental conditions. In the opportunistic pathogen Pseudomonas aeruginosa, more than 100 genes encode TCS components. To avoid unwanted cross-talk between TCSs, the signaling cascades are usually very specific, with one sensor talking to its cognate response regulator. However, cross-regulation may provide effective means to integrate different environmental stimuli into a harmonized output response and thus to coordinate gene expression in response to complex and challenging habitats. Here, we applied a protein-fragment complementation assay (PCA) and identified a direct interaction of two response regulators of the OmpR/PhoB subfamily, namely PhoB and TctD in P. aeruginosa in vivo. Transcriptional profiling and ChIP-seq analysis uncovered adjacent bipartite binding motifs of the two response regulators in 8 promoter regions, of which 6 showed a common PhoB-TctD binding motif with a fixed spacing between the two motifs. We further demonstrate that phosphate limitation exhibits a PhoB-dependent activating activity on the expression of those genes, whereas the presence of a preferred carbon source inhibits gene expression in a TctD-dependent manner. Thus, the perception and the integration of two important environmental signals are achieved by a titration of the relative amounts of two phosphorylated response regulators that inversely regulate a common subset of genes. In conclusion, our results shed light on the general principles underlying two-component signal transduction pathways and the exploitation of cross-regulation to adapt bacterial behavior to complex environments. Transcriptome profiling of the UCBP-PA14 phoB and tctD mutants complemented by phoB ChIP-seq experiments.

2015-06-08 | E-GEOD-64056 | biostudies-arrayexpress

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