Gene Regulation by Riboswitches with and without Negative Feedback Loop

TL;DR

This paper presents a kinetic model of riboswitch function, analyzing how transcription speed, folding, and metabolite binding influence gene regulation, and explores the impact of negative feedback on gene expression dynamics.

Contribution

It introduces a systems-level kinetic network model for riboswitches and investigates the effects of negative feedback on gene regulation and response times.

Findings

Efficient riboswitch function depends on a balance of transcription and folding rates.

Negative feedback can suppress gene expression by nearly 10-fold.

Feedback accelerates response time and reduces steady-state protein levels.

Abstract

Riboswitches, structured elements in the untranslated regions of messenger RNAs, regulate gene expression by binding specific metabolites. We introduce a kinetic network model that describes the functions of riboswitches at the systems level. Using experimental data for flavin mono nucleotide riboswitch as a guide we show that efficient function, implying a large dynamic range without compromising the requirement to suppress transcription, is determined by a balance between the transcription speed, the folding and unfolding rates of the aptamer, and the binding rates of the metabolite. We also investigated the effect of negative feedback accounting for binding to metabolites, which are themselves the products of genes that are being regulated. For a range of transcription rates negative feedback suppresses gene expression by nearly 10 fold. Negative feedback speeds the gene expression response time, and suppresses the change of steady state protein concentration by half relative to that without feedback, when there is a modest spike in DNA concentration. A dynamic phase diagram expressed in terms of transcription speed, folding rates, and metabolite binding rates predicts different scenarios in riboswitch-mediated transcription regulation.