Biology subjects

Ventura, A. C.

Publications and source records attributed to Ventura, A. C..

5 recordsLinked to original sources

bioRxiv2024

The advantage of periodic over constant signalling in microRNA-mediated repression

Cells have been found out to exploit oscillatory rather than constant gene expression to encode biological information. Temporal features of oscillations such as pulse frequency and amplitude have been shown determinant for the outcome of signaling pathways. However, little effort has been devoted to unveiling the role of pulsatility in the context of post-transcriptional gene regulation, where microRNAs (miRNAs) - repressors of gene expression - act by binding to RNAs. Here we study the effects of periodic against constant miRNA synthesis. We model periodic pulses of miRNA synthesis in a minimal miRNA-target RNA network by ODEs, and we compare the RNA repression to that resulting from constant synthesis of the repressor. We find that a pulsatile synthesis can induce more effective target RNA repression in the same timespan, despite an identical amount of repressor. In particular, a stronger fold repression is induced if the miRNA is synthesized at optimal frequencies, thereby showing a frequency preference behaviour - also known as "band-pass filtering". Moreover, we show that the preference for specific input frequencies is determined by relative miRNA and target kinetic rates, thereby highlighting a potential mechanism of selective target regulation. Such ability to differentially regulate distinct targets might represent a functional advantage in post-transcriptional repression, where multiple competing targets are regulated by the same miRNA. Thereby analyzing a model with two RNA target species, we show how competition influences the frequency-dependent RNA repression. Eventually, we find that periodic miRNA expression can lead to exclusive frequency-dependent repression on distinct RNA species, and we show how this depends on their relative kinetics of interaction with the repressor. Our findings might have implications for experimental studies aimed at understanding how periodic patterns drive biological responses through miRNA-mediated signalling, and provide suggestions for validation in a synthetic miRNA-target network.

biophysics↗

bioRxiv2024

Transient frequency preference responses in cell signaling systems

Ligand-receptor systems, covalent modification cycles, and transcriptional networks are the fundamental components of cell signaling and gene expression systems. While their behavior in reaching a steady state regime under step-like stimulation is well understood, their response under repetitive stimulation, particularly at early time stages is poorly characterized. This is despite the fact that early-stage responses to external inputs are arguably as informative as late-stage ones. In simple systems, a periodic stimulation elicits an initial transient response, followed by periodic behavior. Transient responses are relevant when the stimulation has a limited time span, or when the stimulated components timescale is slow as compared to the timescales of the downstream processes, in which case these fast processes may be capturing only those transients. In this study, we analyze the frequency response of simple motifs at different time stages. We use dose-conserved pulsatile input signals, meaning that the amplitude or the duration of the pulses varies along with frequency to conserve input dose, and consider different metrics versus frequency curves. We show that in ligand-receptor systems, there is a frequency preference response (band-pass filter) in some specific metrics during the transient stages, which is not present in the periodic regime. We suggest this is a general system-level mechanism that cells may use to filter input signals that have consequences for higher order circuits. Additionally, we evaluate how the described behavior in isolated motifs is reflected in similar types of responses in cascades and pathways of which they are a part. Our studies suggest that transient frequency preferences are important dynamic features of cell signaling and gene expression systems, which have been overlooked.

biophysics↗

bioRxiv2023

Degeneracy in negative feedback (NFBL) and incoherent feedforward (IFFL) loops: Adaptation and resonance

Degeneracy in dynamic models refers to these situations where multiple combinations of parameter values produce identical patterns for the observable variable. We investigate this phenomenon in two qualitatively different adaptive circuit mechanisms: nonlinear feedback loop (NFBL) and incoherent feedback loop (IFFL). We use minimal models of these circuit types together with analytical calculations, regular perturbation analysis, dynamical systems tools and numerical simulations. In response to constant (or step-constant) inputs, NFBLs and IFFLs produce and overshoot allowing the observable variable to return to a value closer to baseline than the peak (adaptation). We identify the dynamic principles underlying the emergence of degeneracy in adaptive patterns both within and across circuit types in representative NFBL and IFFL models in terms of biologically plausible parameters. We identify the conditions under which degeneracy persists in response to oscillatory inputs with arbitrary frequencies, giving rise to resonance and phasonance degeneracy. This naturally extends to the response of adaptive systems to time-dependent inputs within a relatively large class. By using phase-plane analysis, we provide a mechanistic, dynamical systems-based interpretation of degeneracy. Our results have implication for the understanding of adaptive systems, for the relationship between adaptive and resonant/phasonant systems, for the understanding of complex biochemical circuits, for neuronal computation, and for the development of methods for circuit and dynamical systems reconstruction based on experimental or observational data.

systems biology↗

bioRxiv2021

Frequency preference response in covalent modification cycles under substrate sequestration conditions

Covalent modification cycles (CMCs) are basic units of signaling systems and their properties are well understood. However, the behavior of such systems has been mostly characterized in situations where the substrate is in excess over the modifying enzymes. Experimental data on protein abundance suggest that the enzymes and their target proteins are present in comparable concentrations, leading to a different scenario in which the substrate is mostly sequestered by the enzymes. In this enzyme-in-excess regime, CMCs have been shown to exhibit signal termination, the ability of the product to return to a stationary value lower than the its peak in response to constant stimulation, while this stimulation is still active, with possible implications for the ability of systems to adapt to environmental inputs. We characterize the conditions leading to signal termination in CMCs in the enzyme-in-excess regime. We also demonstrate that this behavior leads to a preferred frequency response (band-pass filters) when the cycle is subjected to periodic stimulation, while the literature reports that CMCs investigated so far behave as low pass filters. We characterize the relationship between signal termination and the preferred frequency response to periodic inputs and we explore the dynamic mechanism underlying these phenomena. Finally, we describe how the behavior of CMCs is reflected in similar types of responses in the cascades of which they are part. Evidence of protein abundance in vivo shows that enzymes and substrates are present in comparable concentrations, thus suggesting that signal termination and frequency preference response to periodic inputs are also important dynamic features of cell signaling systems, which have been overlooked.

systems 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↗