Szischik, C. L. | bioRxiv Science

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↗