Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Recurrent design patterns in the feedback regulation of the mammalian signalling network.

ABSTRACT: Biochemical networks are characterized by recurrent patterns and motifs, but the design principles underlying the dynamics of the mammalian intracellular signalling network remain unclear. We systematically analysed decay rates of 134 signalling proteins and investigated their gene expression profiles in response to stimulation to get insights into transcriptional feedback regulation. We found a clear separation of the signalling pathways into flexible and static parts: for each pathway a subgroup of unstable signal inhibitors is transcriptionally induced upon stimulation, while the other constitutively expressed signalling proteins are long-lived. Kinetic modelling suggests that this design principle allows for swift feedback regulation and establishes latency phases after signalling, and that it might be an optimal design due to a trade-off between energy efficiency and flexibility.

SUBMITTER: Legewie S

PROVIDER: S-EPMC2424294 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Recurrent design patterns in the feedback regulation of the mammalian signalling network.

Legewie Stefan S Herzel Hanspeter H Westerhoff Hans V HV Blüthgen Nils N

Molecular systems biology 20080506

Biochemical networks are characterized by recurrent patterns and motifs, but the design principles underlying the dynamics of the mammalian intracellular signalling network remain unclear. We systematically analysed decay rates of 134 signalling proteins and investigated their gene expression profiles in response to stimulation to get insights into transcriptional feedback regulation. We found a clear separation of the signalling pathways into flexible and static parts: for each pathway a subgro ...[more]

PMID: 18463614

Similar Datasets

Regulation of root patterns in mammalian teeth.

Project description:Mammalian teeth have diverse pattern of the crown and root. The patterning mechanism of the root position and number is relatively unknown compared to that of the crown. The root number does not always match to the cusp number, which has prevented the complete understanding of root patterning. In the present study, to elucidate the mechanism of root pattern formation, we examined (1) the pattern of cervical tongues, which are tongue-like epithelial processes extending from cervical loops, (2) factors influencing the cervical tongue pattern and (3) the relationship among patterns of cusp, cervical tongue and root in multi-rooted teeth. We found a simple mechanism of cervical tongue formation in which the lateral growth of dental mesenchyme in the cuspal region pushes the cervical loop outward, and the cervical tongue appears in the intercuspal region subsequently. In contrast, when lateral growth was physically inhibited, cervical tongue formation was suppressed. Furthermore, by building simple formulas to predict the maximum number of cervical tongues and roots based on the cusp pattern, we demonstrated a positive relationship among cusp, cervical tongue and root numbers. These results suggest that the cusp pattern and the lateral growth of cusps are important in the regulation of the root pattern.

| S-EPMC5629201 | biostudies-literature

MicroRNA-mediated feedback and feedforward loops are recurrent network motifs in mammals.

Project description:MicroRNAs (miRNAs) are regulatory molecules that participate in diverse biological processes in animals and plants. While thousands of mammalian genes are potentially targeted by miRNAs, the functions of miRNAs in the context of gene networks are not well understood. Specifically, it is unknown whether miRNA-containing networks have recurrent circuit motifs, as has been observed in regulatory networks of bacteria and yeast. Here we develop a computational method that utilizes gene expression data to show that two classes of circuits-corresponding to positive and negative transcriptional coregulation of a miRNA and its targets-are prevalent in the human and mouse genomes. Additionally, we find that neuronal-enriched miRNAs tend to be coexpressed with their target genes, suggesting that these miRNAs could be involved in neuronal homeostasis. Our results strongly suggest that coordinated transcriptional and miRNA-mediated regulation is a recurrent motif to enhance the robustness of gene regulation in mammalian genomes.

| S-EPMC2072999 | biostudies-literature

Pervasive translational regulation of the cell signalling circuitry underlies mammalian development.

Project description:The degree and dynamics of translational control during mammalian development remain poorly understood. Here we monitored translation of the mammalian genome as cells become specified and organize into tissues in vivo. This identified unexpected and pervasive translational regulation of most of the core signalling circuitry including Shh, Wnt, Hippo, PI3K and MAPK pathways. We further identify and functionally characterize a complex landscape of upstream open reading frames (uORFs) across 5'-untranslated regions (UTRs) of key signalling components. Focusing on the Shh pathway, we demonstrate the importance of uORFs within the major SHH receptor, Ptch1, in control of cell signalling and neuronal differentiation. Finally, we show that the expression of hundreds of mRNAs underlying critical tissue-specific developmental processes is largely regulated at the translation but not transcript levels. Altogether, this work reveals a new layer of translational control to major signalling components and gene regulatory networks that diversifies gene expression spatially across developing tissues.

| S-EPMC5316868 | biostudies-literature

sfrp1 promotes cardiomyocyte differentiation in Xenopus via negative-feedback regulation of Wnt signalling.

Project description:Wnt signalling is a key regulator of vertebrate heart development, yet it is unclear which specific Wnt signalling components are required to regulate which aspect of cardiogenesis. Previously, we identified Wnt6 as an endogenous Wnt ligand required for controlling heart muscle differentiation via canonical Wnt/?-catenin signalling. Here we show for the first time a requirement for an endogenous Wnt signalling inhibitor for normal heart muscle differentiation. Expression of sfrp1 is strongly induced in differentiating heart muscle. We show that sfrp1 is not only able to promote heart muscle differentiation but is also required for the formation of normal size heart muscle in the embryo. sfrp1 is functionally able to inhibit Wnt6 signalling and its requirement during heart development relates to relieving the cardiogenesis-restricting function of endogenous wnt6. In turn, we discover that sfrp1 expression in the heart is regulated by Wnt6 signalling, which for the first time indicates that sfrp genes can function as part of a Wnt negative-feedback regulatory loop. Our experiments indicate that sfrp1 controls the size of the differentiating heart muscle primarily by regulating cell fate within the cardiac mesoderm between muscular and non-muscular cell lineages. The cardiac mesoderm is therefore not passively patterned by signals from the surrounding tissue, but regulates its differentiation into muscular and non-muscular tissue using positional information from the surrounding tissue. This regulatory network might ensure that Wnt activation enables expansion and migration of cardiac progenitors, followed by Wnt inhibition permitting cardiomyocyte differentiation.

| S-EPMC4074298 | biostudies-literature

Stochastic signalling rewires the interaction map of a multiple feedback network during yeast evolution.

Project description:During evolution, genetic networks are rewired through strengthening or weakening their interactions to develop new regulatory schemes. In the galactose network, the GAL1/GAL3 paralogues and the GAL2 gene enhance their own expression mediated by the Gal4p transcriptional activator. The wiring strength in these feedback loops is set by the number of Gal4p binding sites. Here we show using synthetic circuits that multiplying the binding sites increases the expression of a gene under the direct control of an activator, but this enhancement is not fed back in the circuit. The feedback loops are rather activated by genes that have frequent stochastic bursts and fast RNA decay rates. In this way, rapid adaptation to galactose can be triggered even by weakly expressed genes. Our results indicate that nonlinear stochastic transcriptional responses enable feedback loops to function autonomously, or contrary to what is dictated by the strength of interactions enclosing the circuit.

| S-EPMC3293423 | biostudies-literature

Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma.

Project description:Osteosarcoma is a primary malignancy of bone that affects children and adults. Here, we present the largest sequencing study of osteosarcoma to date, comprising 112 childhood and adult tumours encompassing all major histological subtypes. A key finding of our study is the identification of mutations in insulin-like growth factor (IGF) signalling genes in 8/112 (7%) of cases. We validate this observation using fluorescence in situ hybridization (FISH) in an additional 87 osteosarcomas, with IGF1 receptor (IGF1R) amplification observed in 14% of tumours. These findings may inform patient selection in future trials of IGF1R inhibitors in osteosarcoma. Analysing patterns of mutation, we identify distinct rearrangement profiles including a process characterized by chromothripsis and amplification. This process operates recurrently at discrete genomic regions and generates driver mutations. It may represent an age-independent mutational mechanism that contributes to the development of osteosarcoma in children and adults alike.

| S-EPMC5490007 | biostudies-literature

Feedback regulation of apical progenitor fate by immature neurons through Wnt7-Celsr3-Fzd3 signalling.

Project description:Sequential generation of neurons and glial cells during development is critical for the wiring and function of the cerebral cortex. This process requires accurate coordination of neural progenitor cell (NPC) fate decisions, by NPC-autonomous mechanisms as well as by negative feedback from neurons. Here, we show that neurogenesis is protracted and gliogenesis decreased in mice with mutations of genes Celsr3 and Fzd3. This phenotype is not due to gene inactivation in progenitors, but rather in immature cortical neurons. Mutant neurons are unable to upregulate expression of Jag1 in response to cortical Wnt7, resulting in blunted activation of Notch signalling in NPC. Thus, Celsr3 and Fzd3 enable immature neurons to respond to Wnt7, upregulate Jag1 and thereby facilitate feedback signals that tune the timing of NPC fate decisions via Notch activation.

| S-EPMC4786577 | biostudies-literature

A genetic mammalian proportional-integral feedback control circuit for robust and precise gene regulation.

Project description:The processes that keep a cell alive are constantly challenged by unpredictable changes in its environment. Cells manage to counteract these changes by employing sophisticated regulatory strategies that maintain a steady internal milieu. Recently, the antithetic integral feedback motif has been demonstrated to be a minimal and universal biological regulatory strategy that can guarantee robust perfect adaptation for noisy gene regulatory networks in Escherichia coli. Here, we present a realization of the antithetic integral feedback motif in a synthetic gene circuit in mammalian cells. We show that the motif robustly maintains the expression of a synthetic transcription factor at tunable levels even when it is perturbed by increased degradation or its interaction network structure is perturbed by a negative feedback loop with an RNA-binding protein. We further demonstrate an improved regulatory strategy by augmenting the antithetic integral motif with additional negative feedback to realize antithetic proportional-integral control. We show that this motif produces robust perfect adaptation while also reducing the variance of the regulated synthetic transcription factor. We demonstrate that the integral and proportional-integral feedback motifs can mitigate the impact of gene expression burden, and we computationally explore their use in cell therapy. We believe that the engineering of precise and robust perfect adaptation will enable substantial advances in industrial biotechnology and cell-based therapeutics.

| S-EPMC9214505 | biostudies-literature

Multiple feedback loop design in the tryptophan regulatory network of Escherichia coli suggests a paradigm for robust regulation of processes in series.

Project description:Biological networks have evolved through adaptation in uncertain environments. Of the different possible design paradigms, some may offer functional advantages over others. These designs can be quantified by the structure of the network resulting from molecular interactions and the parameter values. One may, therefore, like to identify the design motif present in the evolved network that makes it preferable over other alternatives. In this work, we focus on the regulatory networks characterized by serially arranged processes, which are regulated by multiple feedback loops. Specifically, we consider the tryptophan system present in Escherichia coli, which may be conceptualized as three processes in series, namely transcription, translation and tryptophan synthesis. The multiple feedback loop motif results from three distinct negative feedback loops, namely genetic repression, mRNA attenuation and enzyme inhibition. A framework is introduced to identify the key design components of this network responsible for its physiological performance. We demonstrate that the multiple feedback loop motif, as seen in the tryptophan system, enables robust performance to variations in system parameters while maintaining a rapid response to achieve homeostasis. Superior performance, if arising from a design principle, is intrinsic and, therefore, inherent to any similarly designed system, either natural or engineered. An experimental engineering implementation of the multiple feedback loop design on a two-tank system supports the generality of the robust attributes offered by the design.

| S-EPMC1578758 | biostudies-literature

Feedback, Crosstalk and Competition: Ingredients for Emergent Non-Linear Behaviour in the PI3K/mTOR Signalling Network.

Project description:The PI3K/mTOR signalling pathway plays a central role in the governing of cell growth, survival and metabolism. As such, it must integrate and decode information from both external and internal sources to guide efficient decision-making by the cell. To facilitate this, the pathway has evolved an intricate web of complex regulatory mechanisms and elaborate crosstalk with neighbouring signalling pathways, making it a highly non-linear system. Here, we describe the mechanistic biological details that underpin these regulatory mechanisms, covering a multitude of negative and positive feedback loops, feed-forward loops, competing protein interactions, and crosstalk with major signalling pathways. Further, we highlight the non-linear and dynamic network behaviours that arise from these regulations, uncovered through computational and experimental studies. Given the pivotal role of the PI3K/mTOR network in cellular homeostasis and its frequent dysregulation in pathologies including cancer and diabetes, a coherent and systems-level understanding of the complex regulation and consequential dynamic signalling behaviours within this network is imperative for advancing biology and development of new therapeutic approaches.

| S-EPMC8267830 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data