Signal-dependent dynamics of transcription factor translocation controls gene expression

Hao, Nan; O’Shea, Erin K.

doi:10.1038/nsmb.2192

Cited by 287 publications

(433 citation statements)

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“…Posttranscriptional modifications of proteins are a natural substrate in which to implement analog chemical computation, and Jacob's old adage of bricolage suggests that signal transduction in cells might exploit this freedom to temporarily process signals. The canonical receptor systems as well as ion channels (30) possess a rich repertoire of interactions and modifications that could implement computation (31). One should note also a distinction between embryonic signaling where both the emitter and the receiver can be jointly tuned by evolution to process information and true environmental sensing where the signal has a more autonomous origin.…”

Section: Discussionmentioning

confidence: 99%

Decisions on the fly in cellular sensory systems

Siggia

Vergassola

2013

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

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Cells send and receive signals through pathways that have been defined in great detail biochemically, and it is often presumed that the signals convey only level information. Cell signaling in the presence of noise is extensively studied but only rarely is the speed required to make a decision considered. However, in the immune system, rapidly developing embryos, and cellular response to stress, fast and accurate actions are required. Statistical theory under the rubric of "exploit-explore" quantifies trade-offs between decision speed and accuracy and supplies rigorous performance bounds and algorithms that realize them. We show that common protein phosphorylation networks can implement optimal decision theory algorithms and speculate that the ubiquitous chemical modifications to receptors during signaling actually perform analog computations. We quantify performance trade-offs when the cellular system has incomplete knowledge of the data model. For the problem of sensing the time when the composition of a ligand mixture changes, we find a nonanalytic dependence on relative concentrations and specify the number of parameters needed for near-optimal performance and how to adjust them. The algorithms specify the minimal computation that has to take place on a single receptor before the information is pooled across the cell.signal transduction | sequential probability ratio test T he exigencies of operations research during the second world war led to the following problem: Given a stream of data that is drawn from one of two prescribed models M1 or M2, what is the quickest way to decide between them subject to bounds on the errors? The solution found by Wald (1, 2) computes the ratio of two conditional probabilities using the data up to time t, RðtÞ ¼ Pðdataj M1Þ=Pðdataj M2Þ;[1]and calls M1 when R > H1 and M2 when R < H2 and waits for more data otherwise. The thresholds H control the errors; e.g., larger H1 decreases the odds of deciding M1 when the data come from M2. For the task of distinguishing two Gaussians with different means, the average decision time for Wald's algorithm is a factor two times shorter than using a fixed averaging time for the same error rate. This is a simple example of a general class of problems termed "exploit-explore"; i.e., either decide or accumulate more data (3, 4). They are used in medical statistics to decide when a clinical trial has generated enough data for a conclusion. For the problems that concern us, the next step in complexity was taken by Shiryaev (5-7), who considered the optimal detection of change points. A stream of data is presented and the model changes from M1 to M2 at an unknown time θ. The algorithm calls the change point at time t to minimize a linear combination of the false positive rate (e.g., t ≤ θ) and the decision time mean ðt − θÞ when t > θ. Again the algorithm "knows" the models M1, M2.Another step in complexity, about which we have little to say, corresponds to situations where the statistics of the hypotheses to be discriminated are not available or ...

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Section: Discussionmentioning

confidence: 99%

Decisions on the fly in cellular sensory systems

Siggia

Vergassola

2013

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

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“…To test if activation of the general stress response is sufficient to inhibit Hsf1, we introduced our transcriptional fluorescent reporters into a strain genetically engineered for Pka inhibition by the ATP-analog 1-NM-PP1 (this genetic background will be referred to as PKAas, for analog sensitive, and 1-NM-PP1 will be referred to as the Pka inhibitor) (Bishop et al, 2000;Hao and O'Shea, 2012). As expected, the Pka inhibitor caused induction of the general stress response in PKAas but not wild-type cells (Figure 3.2A).…”

Section: Activation Of Msn2/4 Is Sufficient To Inactivate Hsf1 In Youmentioning

confidence: 99%

Defining the Essential Function of Yeast Hsf1 Reveals a Compact Transcriptional Program for Maintaining Eukaryotic Proteostasis

Solís

Pandey

et al. 2018

Molecular Cell

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All rights reserved. I am especially thankful to my mom, dad and brother, all of whom were critical for getting me to grad school in the first place. I'm also forever thankful that they were always there to support and listen to me through my many struggles, even when the problems I was describing were unrelatable or unintelligibly described. know it would have been significantly less silly, ludicrous and off-putting to everyone else ix on the periphery if Patrick weren't down the hall from me, but I'm so glad I didn't have to live in that counterfactual universe. We have spent countless hours talking about science, politics, our personal lives, and many other things that I hope never get repeated, and I have enjoyed it all so very much.I have also been extremely fortunate for my academic advisors Vlad Denic and Edo Airoldi, along with my mentor and friend David Pincus. The three of them put an incredible amount of time into helping and guiding me as I grew as a scientist. When I reflect on the progress I've made since I started graduate school, I know that it would not have been possible without them constantly pushing me to be better. While it wasn't always fun or easy, I am so thankful for the time, energy and effort they put into me personally. They all went so far beyond what could reasonably be expected from an advisor, and even though all three were at challenging early stages of their own careers, they made an exceptional effort to help me as I started my own. I will always be thankful and grateful to Edo, Vlad and Dave for molding me into the scientist that I am today. In order to adapt when stress causes the folding environment to deteriorate, cells need a mechanism to adjust the availability of chaperones according to need. One simple mechanism employed by some bacteria to regulate expression of chaperones during heat shock involves RNA secondary structure that occludes the ribosome binding site at low 2 temperatures, but melts at high temperature de-repressing translation during thermal stress (Cimdins et al., 2014). However, rather than regulating each chaperone gene individually, eukaryotic cells have evolved a highly conserved feedback mechanism that coordinates up-regulation of many proteostasis factors in response to stress. The first indication of this mechanism were made by Ferruccio Ritossa in 1962 when he noticed a novel pattern of "puffs" on the polytene salivary gland chromosomes of Drosophila larvae that were subjected to a serendipitous heat shock when a co-worker increased their incubator's temperature (Ritossa, 1996). Subsequent controlled experiments revealed that shifting larvae from 25°C to 30°C caused puffs that were stable at the lower temperature to rapidly dissipate and induced the appearance of novel, reproducible puffs (Ritossa, 1962). It was soon revealed that the temperature stress caused by the actions of an unwitting co-worker has spurred the first observation of the dramatic changes in gene expression that comprise the heat shock response.It was subsequently revealed tha...

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“…For example, a linear response to mating pheromone has been described for the yeast mating mitogen-activated protein (MAP) kinase cascade (8). Additionally, specific transcriptional activators such as yeast Msn2 or Crz1 and mammalian NF-B transmit linear signals to their cognate promoters by modulating their nuclear accumulation (9)(10)(11)(12).…”

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confidence: 99%

Different Mechanisms Confer Gradual Control and Memory at Nutrient- and Stress-Regulated Genes in Yeast

Rienzo

Poveda-Huertes

Aydin

et al. 2015

Molecular and Cellular Biology

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c Cells respond to environmental stimuli by fine-tuned regulation of gene expression. Here we investigated the dose-dependent modulation of gene expression at high temporal resolution in response to nutrient and stress signals in yeast. The GAL1 activity in cell populations is modulated in a well-defined range of galactose concentrations, correlating with a dynamic change of histone remodeling and RNA polymerase II (RNAPII) association. This behavior is the result of a heterogeneous induction delay caused by decreasing inducer concentrations across the population. Chromatin remodeling appears to be the basis for the dynamic GAL1 expression, because mutants with impaired histone dynamics show severely truncated dose-response profiles. In contrast, the GRE2 promoter operates like a rapid off/on switch in response to increasing osmotic stress, with almost constant expression rates and exclusively temporal regulation of histone remodeling and RNAPII occupancy. The Gal3 inducer and the Hog1 mitogen-activated protein (MAP) kinase seem to determine the different dose-response strategies at the two promoters. Accordingly, GAL1 becomes highly sensitive and dose independent if previously stimulated because of residual Gal3 levels, whereas GRE2 expression diminishes upon repeated stimulation due to acquired stress resistance. Our analysis reveals important differences in the way dynamic signals create dose-sensitive gene expression outputs.C ells continuously adapt their protein composition to changing environmental conditions. The regulation of gene expression is one of the fundamental mechanisms to adjust the global protein repertoire of the cell in order to maintain cell function and integrity in response to environmental challenges. Budding yeast is a powerful model to unravel the modes of transcriptional adaptation at the levels both of specific genes and of the whole organism (1, 2). Additionally, the basic structure of the signaling cascades responding to environmental perturbations is conserved from yeast to humans. It implies the alteration of core kinase activities, which modulate the expression of defense genes through a range of specific transcription factors. Extensive knowledge which precisely describes the molecular machinery and its global impact on gene expression in response to many types of stress has accumulated (3-7). However, the vast majority of these studies are performed with harsh environmental insults and therefore saturating stimulation. As a consequence, only very limited information or approaches are available to understand how cells adapt their gene expression programs to small or gradual changes in their environment.It is assumed that cells have acquired mechanisms that ensure a transcriptional response which is finely adjusted according to the strength of the stress or stimulation. However, the nature of the signaling molecules which confer gradual transcription outputs remains to be determined in most cases. Fine-tuning of gene expression responses can occur with different purposes, and th...

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Signal-dependent dynamics of transcription factor translocation controls gene expression

Cited by 287 publications

References 30 publications

Decisions on the fly in cellular sensory systems

Decisions on the fly in cellular sensory systems

Defining the Essential Function of Yeast Hsf1 Reveals a Compact Transcriptional Program for Maintaining Eukaryotic Proteostasis

Different Mechanisms Confer Gradual Control and Memory at Nutrient- and Stress-Regulated Genes in Yeast

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