Effect of transcription reinitiation in stochastic gene expression

TL;DR

This paper investigates how transcription reinitiation affects stochastic gene expression, revealing that it can variably influence mRNA mean and variability depending on the gene network model.

Contribution

It demonstrates that RNAP-II based reinitiation can have diverse effects on mRNA levels and variability, and proposes a new perspective on feedback mechanisms in gene regulation.

Findings

Reinitiation decreases mRNA mean and Fano factor in constitutive networks.

Reinitiation can increase or decrease mRNA mean and variability in other network types.

Constitutive networks with reinitiation act like negative feedback circuits.

Abstract

Gene expression (GE) is an inherently random or stochastic or noisy process. The randomness in different steps of GE, e.g., transcription, translation, degradation, etc., leading to cell-to-cell variations in mRNA and protein levels. This variation appears in organisms ranging from microbes to metazoans. Stochastic gene expression has important consequences for cellular function. The random fluctuations in protein levels produce variability in cellular behavior. It is beneficial in some contexts and harmful to others. These situations include stress response, metabolism, development, cell cycle, circadian rhythms, and aging. Different model studies e.g., constitutive, two-state, etc., reveal that the fluctuations in mRNA and protein levels arise from different steps of gene expression among which the steps in transcription have the maximum effect. The pulsatile mRNA production through RNAP-II based reinitiation of transcription is an important part of gene transcription. Though, the effect of that process on mRNA and protein levels is very little known. The addition of any biochemical step in the constitutive or two-state process generally decreases the mean and increases the Fano factor. In this study, we have shown that the RNAP-II based reinitiation process in gene transcription can have different effects on both mean and Fano factor at mRNA levels in different model systems. It decreases the mean and Fano factor both at the mRNA levels in the constitutive network whereas in other networks it can simultaneously increase or decrease both quantities or it can have mixed-effect at mRNA levels. We propose that a constitutive network with reinitiation behaves like a product independent negative feedback circuit whereas other networks behave as either product independent positive or negative or mixed feedback circuit.