Negative feedback that improves information transmission in yeast signalling

Yu, Richard; Pesce, C. Gustavo; Colman‐Lerner, Alejandro; Lok, Larry; Pincus, David; Serra, Eduard; Holl, Mark R.; Benjamin, Kirsten R.; Gordon, Andrew H.; Brent, Roger

doi:10.1038/nature07513

Cited by 217 publications

(307 citation statements)

References 50 publications

(62 reference statements)

Supporting

Mentioning

280

Contrasting

Order By: Relevance

“…We characterized the feedback loop at the yeast hypoxia regulator ROX1 in molecular detail, and we harnessed this system as a test bed to study how feedback confers stability against naturally occurring mutations. Given the precedent for negative feedback as a determinant of quantitative behaviors of inducible circuits (20)(21)(22)(23)(24), we also investigated the role of Rox1 feedback in expression regulation during oxygen response.…”

mentioning

confidence: 99%

Negative feedback confers mutational robustness in yeast transcription factor regulation

Denby

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Organismal fitness depends on the ability of gene networks to function robustly in the face of environmental and genetic perturbations. Understanding the mechanisms of this stability is one of the key aims of modern systems biology. Dissecting the basis of robustness to mutation has proven a particular challenge, with most experimental models relying on artificial DNA sequence variants engineered in the laboratory. In this work, we hypothesized that negative regulatory feedback could stabilize gene expression against the disruptions that arise from natural genetic variation. We screened yeast transcription factors for feedback and used the results to establish ROX1 (Repressor of hypOXia) as a model system for the study of feedback in circuit behaviors and its impact across genetically heterogeneous populations. Mutagenesis experiments revealed the mechanism of Rox1 as a direct transcriptional repressor at its own gene, enabling a regulatory program of rapid induction during environmental change that reached a plateau of moderate steady-state expression. Additionally, in a given environmental condition, Rox1 levels varied widely across genetically distinct strains; the ROX1 feedback loop regulated this variation, in that the range of expression levels across genetic backgrounds showed greater spread in ROX1 feedback mutants than among strains with the ROX1 feedback loop intact. Our findings indicate that the ROX1 feedback circuit is tuned to respond to perturbations arising from natural genetic variation in addition to its role in induction behavior. We suggest that regulatory feedback may be an important element of the network architectures that confer mutational robustness across biology.R obustness of organismal function in the face of perturbations is critical for fitness. Since the seminal work of Waddington (1), biologists have remarked on the stability of phenotypes against environmental and genetic variation, and understanding how organisms achieve robustness remains one of the major challenges in systems biology (2-4). Much of the search for molecular mechanisms of robustness has focused on gene regulation. Characteristics of regulatory networks that confer robustness include pathway redundancy and master regulatory organization (5), phenotypic capacitors (6-8), paired activating and inhibiting inputs (9), and cooperative and feed-forward regulation (10). Additionally, negative regulatory feedback, in which a biomolecule represses its own abundance, can buffer variation in gene expression (11,12), and negative feedback loops have been shown to underlie robustness to variable environmental conditions and stochastic intracellular change (13-15). Negative feedback may also confer network stability against the effects of mutations (3, 16), but evidence for negative feedback as a driver of mutational robustness in vivo has been at a premium (17); the relevance of this principle to natural genetic variation remains largely unknown.In this work, we focused on negative feedback in yeast hypoxia regulation motiva...

show abstract

mentioning

confidence: 99%

Negative feedback confers mutational robustness in yeast transcription factor regulation

Denby

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Additional Fus3-mediated feedback loops have been described to impinge on the RGS Sst2, a negative regulator of the heterotrimeric G protein coupled to the pheromone receptor. One involves phosphorylation at Ser-539, which slows the rate of Sst2 degradation but does not seem to alter pheromone sensitivity [21]; the second, likely ocurring at Thr-134 within its N-terminal DEP domain, reduces the Sst2-mediated membrane recruitment of the scaffold protein Ste5 [63]. Both phosphorylation events occur within a MAPK consensus target site (Ser or Thr, followed by Pro).…”

Section: Wiring Backwards: Phosphorylation-based Feedback Loops In Yementioning

confidence: 99%

Fine regulation of Saccharomyces cerevisiae MAPK pathways by post‐translational modifications

Molina

Cid

Martı́n

2010

Yeast

View full text Add to dashboard Cite

Saccharomyces cerevisiae has been widely used as a model eukaryotic organism to elucidate the molecular mechanisms that operate upon activation of signalling pathways. For over two decades, many clues to the regulation of mitogen-activated protein kinase (MAPK) pathways have derived from basic research in yeast. Here we review aspects of MAPK pathway fine-tuning, such as the functional implication of feedback loops or regulatory inputs from other pathways, mediated by post-transcriptional modifications on their components. The impact of recent phosphoproteomic approaches in this particular field is also discussed.

show abstract

“…A loss of FRET was observed upon dissociation of the hetero-trimeric G-protein in α-factor treated cells 48,57 . Moreover, dissociation of the repressor Dig1p from the transcription factor Ste12p has also been probed by FRET.…”

mentioning

confidence: 99%

“…Moreover, dissociation of the repressor Dig1p from the transcription factor Ste12p has also been probed by FRET. Since this dissociation is triggered by phosphorylation of Ste12p and Dig1p by Fus3p, the loss of FRET reports faithfully on the nuclear activity of the MAPK 48 .…”

mentioning

confidence: 99%

See 1 more Smart Citation

Fluorescent-Based Quantitative Measurements of Signal Transduction in Single Cells

Pelet¹,

Peter²

2011

Design and Analysis of Biomolecular Circuits

View full text Add to dashboard Cite

Budding yeast (Saccharomyces cerevisiae) has been widely used as a model system to study fundamental biological processes. Genetic and biochemical approaches have allowed in the last decades to uncover the key components involved in many signaling pathways. Generally, most techniques measure the average behavior of a population of cells, and thus missed important cell-to-cell variations. With the recent progress with fluorescent proteins, new avenues have been opened to quantitatively study the dynamics of signaling in single living cells. In this chapter, we describe several techniques based on fluorescence measurements to quantify the activation of biological pathways. Flow cytometry allows for rapid quantification of the total fluorescence of a large number of single cells. In contrast, microscopy offers a lower throughput but allows to follow with a high temporal resolution the localization of proteins at sub-cellular resolution. Finally, advanced functional imaging techniques such as FRET and FCS offer the possibility to directly visualize the formation of protein complexes or to quantify the activity of proteins in vivo. Together these techniques present powerful new approaches to study cellular signaling and will greatly increase our understanding of the regulation of signaling networks in budding yeast and beyond. FLUORESCENT-BASED QUANTITATIVE MEASUREMENTS OF SIGNAL TRANSDUCTION IN SINGLE CELLS Serge Pelet and Matthias Peter Institute of Biochemistry, Department of Biology, ETH Zürich Abstract:Budding yeast (Saccharomyces cerevisiae) has been widely used as a model system to study fundamental biological processes. Genetic and biochemical approaches have allowed in the last decades to uncover the key components involved in many signaling pathways. Generally, most techniques measure the average behavior of a population of cells, and thus missed important cell-tocell variations. With the recent progress with fluorescent proteins, new avenues have been opened to quantitatively study the dynamics of signaling in single living cells. In this chapter, we describe several techniques based on fluorescence measurements to quantify the activation of biological pathways. Flow cytometry allows for rapid quantification of the total fluorescence of a large number of single cells. In contrast, microscopy offers a lower throughput but allows to follow with a high temporal resolution the localization of proteins at sub-cellular resolution. Finally, advanced functional imaging techniques such as FRET and FCS offer the possibility to directly visualize the formation of protein complexes or to quantify the activity of proteins in vivo.Together these techniques present powerful new approaches to study cellular signaling and will greatly increase our understanding of the regulation of signaling networks in budding yeast and beyond.

show abstract

Negative feedback that improves information transmission in yeast signalling

Cited by 217 publications

References 50 publications

Negative feedback confers mutational robustness in yeast transcription factor regulation

Negative feedback confers mutational robustness in yeast transcription factor regulation

Fine regulation of Saccharomyces cerevisiae MAPK pathways by post‐translational modifications

Fluorescent-Based Quantitative Measurements of Signal Transduction in Single Cells

Contact Info

Product

Resources

About