Cis-Antisense Transcription Gives Rise to Tunable Genetic Switch Behavior: A Mathematical Modeling Approach.

Antoni E Bordoy,Anushree Chatterjee

doi:10.1371/journal.pone.0133873

Abstract

Antisense transcription has been extensively recognized as a regulatory mechanism for gene expression across all kingdoms of life. Despite the broad importance and extensive experimental determination of cis-antisense transcription, relatively little is known about its role in controlling cellular switching responses. Growing evidence suggests the presence of non-coding cis-antisense RNAs that regulate gene expression via antisense interaction. Recent studies also indicate the role of transcriptional interference in regulating expression of neighboring genes due to traffic of RNA polymerases from adjacent promoter regions. Previous models investigate these mechanisms independently, however, little is understood about how cells utilize coupling of these mechanisms in advantageous ways that could also be used to design novel synthetic genetic devices. Here, we present a mathematical modeling framework for antisense transcription that combines the effects of both transcriptional interference and cis-antisense regulation. We demonstrate the tunability of transcriptional interference through various parameters, and that coupling of transcriptional interference with cis-antisense RNA interaction gives rise to hypersensitive switches in expression of both antisense genes. When implementing additional positive and negative feed-back loops from proteins encoded by these genes, the system response acquires a bistable behavior. Our model shows that combining these multiple-levels of regulation allows fine-tuning of system parameters to give rise to a highly tunable output, ranging from a simple-first order response to biologically complex higher-order response such as tunable bistable switch. We identify important parameters affecting the cellular switch response in order to provide the design principles for tunable gene expression using antisense transcription. This presents an important insight into functional role of antisense transcription and its importance towards design of synthetic biological switches.

Highlights

Tunable regulation of gene expression is essential to overcome multitude of adverse environmental conditions encountered by biological systems [1,2]
We assume pX is a constitutive promoter with fixed average RNA polymerase (RNAP) binding and initiation times, whereas pY is an inducible promoter with a variable RNAP binding time, but a fixed RNAP initiation time
Our mathematical model highlights the regulatory advantage offered by coupled effects of transcriptional interference (TI) and antisense RNA regulation (AR) based regulation during antisense transcription

Summary

Introduction

Tunable regulation of gene expression is essential to overcome multitude of adverse environmental conditions encountered by biological systems [1,2]. Non-coding genomic regions and closely spaced promoters observed in genome-wide studies have revealed the role of transcription in controlling gene expression [3,4,5,6,7]. Often, when both DNA strands are transcribed in the same genomic locus, convergent arrangements of promoters are observed, leading to antisense transcription (Fig 1A). Translation inhibition, whereby binding of the asRNA prevents translation of the mRNA by usually blocking its ribosomal binding site (RBS) [23] or, less commonly, other mRNA regions [24]. mRNA doi:10.1371/journal.pone.0133873.g001

Methods

Results

Conclusion