Biology subjects

Colman-Lerner, A.

Publications and source records attributed to Colman-Lerner, A..

5 recordsLinked to original sources

bioRxiv2022

High selectivity of frequency induced transcriptional responses

Cells continuously interact with their environment, detect its changes and generate responses accordingly. This requires interpreting the variations and, in many occasions, producing changes in gene expression. In this paper we use information theory and a simple transcription model to analyze the extent to which the resulting gene expression is able to identify and assess the intensity of extracellular stimuli when they are encoded in the amplitude, duration or frequency of a transcription factors nuclear concentration. We find that the maximal information transmission is, for the three codifications, ~ 1.5 - 1.8 bits, i.e., approximately 3 ranges of input strengths can be distinguished in all cases. The types of promoters that yield maximum transmission for the three modes are all similarly fast and have a high activation threshold. The three input modulation modes differ, however, in the sensitivity to changes in the parameters that characterize the promoters, with frequency modulation being the most sensitive and duration modulation, the least. This turns out to be key for signal identification. Namely, we show that, because of this sensitivity difference, it is possible to find promoter parameters that yield an information transmission within 90% of its maximum value for duration or amplitude modulation and less than 1 bit for frequency modulation. The reverse situation cannot be found within the framework of a single promoter transcription model. This means that pulses of transcription factors in the nucleus can selectively activate the promoter that is tuned to respond to frequency modulations while prolonged nuclear accumulation would activate several promoters at the same time. Thus, frequency modulation is better suited than the other encoding modes to allow the identification of external stimuli without requiring other mediators of the transduction.

systems biology↗

bioRxiv2018

Heat-stress triggers MAPK crosstalk to turn on the hyper-osmotic response pathway

Cells make decisions based on a combination of external and internal signals. In yeast, the high osmolarity response (HOG) is a mitogen-activated protein kinase (MAPK) pathway that responds to a variety of stimuli, and it is central to the general stress response. Here we studied the effect of heat-stress (HS) on HOG. Using live-cell reporters and genetics, we show that HS promotes Hog1 phosphorylation and gene expression, exclusively via the Sln1 phosphorelay branch, and that the strength of the activation is larger in yeast adapted to high external osmolarity. HS stimulation of HOG is indirect. First, we found that it depends on the operation of a second MAPK pathway, the cell-wall integrity (CWI), a well-known mediator of HS. Second, we show that HS causes glycerol loss via the channel Fps1, and that strictly requires the CWI MAPK Slt2. Third, blocking glycerol efflux also blocks HOG activation, strongly suggesting that it is the resulting loss of turgor by the loss of the accompanying water what causes HOG stimulation. Thus, taken together, our findings highlight a central role for Fps1, and the metabolism of glycerol, in the communication between the yeast MAPK pathways, essential for survival and reproduction in changing environments.

cell biology↗

bioRxiv2018

Properties of cell signaling pathways and gene expression systems operating far from steady-state

Ligand-receptor systems, covalent modification cycles, and transcriptional networks are basic units of signaling systems and their steady-state properties are well understood. However, the behavior of such systems before steady-state is poorly characterized. Here, we analyzed the properties of the input-output curves for each of these systems as they approach steady-state. In ligand-receptor systems, the EC50 (concentration of the ligand that occupies 50% of the receptors) is higher before the system reaches steady-state. Based on this behavior, we have previously defined PRESS (for pre-equilibrium sensing and signaling), a general \"systems level\" mechanism cells may use to overcome input saturation. Originally, we showed that, given a step stimulation, PRESS operates when the kinetics of ligand-receptor binding are slower than the downstream signaling steps. Now, we show that, provided the input increases slowly, it is not essential for the ligand binding reaction itself to be slow. In addition, we demonstrate that covalent modification cycles and gene expression systems may also operate in PRESS mode. Thus, nearly all biochemical processes may operate in PRESS mode, suggesting that this mechanism may be ubiquitous in cell signaling systems.

systems biology↗

bioRxiv2016

Cell-to-cell variability in the yeast pheromone response: high throughput screen identifiesgenes with different effects on transmitted signal and response

Populations of isogenic cells often respond coherently to signals despite differences in protein abundance and cell state. Our previous work in the Saccharomyces cerevisiae pheromone response system (PRS) uncovered processes that reduced cell-to-cell variation in signal and response. To understand these and other processes that controlled variation, we generated a whole-genome collection of haploid strains with deletions in non-essential genes and used high-throughput flow cytometry to screen more than 1000. We identified 50 \"variation genes\" required for normal cell-to-cell variability in signal and response. Some genes affected only signal variability, signal strength, or system output, defining these quantities as separable \"axes\" of system behavior. Two genes affected cytoplasmic microtubule function.

systems biology↗

bioRxiv2016

Cell-to-cell variability in the yeast pheromone response: Cytoplasmic microtubule functionstabilizes signal generation and promotes accurate fate choice

In a companion paper, we carried out a high-throughput screen to identify genes that suppressed cell-to-cell variability in signaling in yeast. Two genes affected cytoplasmic microtubules that can connect the nucleus to a signaling site on the membrane. Here, we show that microtubule perturbations that affected polymerization and depolymerization, membrane attachment, and force generation increased variability. For some perturbations, \"outlier\" cells drove the increased variability. Bypass experiments that activated the PRS ectopically at downstream points indicated that microtubule-dependent processes might stabilize the membrane-recruited scaffold protein Ste5. The variability caused by microtubule perturbations required the MAP kinase Fus3. Microtubule perturbations hindered stable scaffold formation and decreased the accuracy of a polarity-dependent fate choice. Our experiments suggest that membrane-attached microtubules stabilize signaling by scaffold-bound Fus3, and are consistent with a model in which signaling irregularities from changes in microtubule function are amplified by cross-stimulatory feedbacks among PRS proteins. The fact that microtubule perturbations also cause aberrant fate and polarity decisions during embryonic development and cancer initiation suggests that similar variation-reducing processes might also operate in metazoans.

systems biology↗