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

Bordoy AE, Chatterjee A - PLoS ONE (2015)

Bottom Line: Here, we present a mathematical modeling framework for antisense transcription that combines the effects of both transcriptional interference and cis-antisense regulation.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, CO, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

Antisense transcription mechanisms in a set of convergent genes.(A) General set of convergent promoters driving expression of genes X and Y synthesizing transcripts x and y (bold arrows), respectively. Such a system is susceptible to TI and produces overlapping transcripts that may participate in AR. (B) AR can cause translational inhibition, mRNA degradation and transcriptional attenuation due to the interactions that may exist between full-length sense and antisense transcripts as well as truncated RNA produced as a result of RNAP collisions, one of the reported TI mechanisms. (C) Mechanisms of TI: Occlusion caused by passage of an opposing elongating RNAP on the antisense promoter which hinders binding of RNAP to the sense promoter; Sitting duck interference, dislodgement of an initiation complex due to collision with an opposing elongating RNAP; and Collision between opposing elongating RNAP molecules that produces truncated RNA of different sizes susceptible to participate in AR. Both TI and AR mechanisms are likely to be coupled during antisense transcription.
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pone.0133873.g001: Antisense transcription mechanisms in a set of convergent genes.(A) General set of convergent promoters driving expression of genes X and Y synthesizing transcripts x and y (bold arrows), respectively. Such a system is susceptible to TI and produces overlapping transcripts that may participate in AR. (B) AR can cause translational inhibition, mRNA degradation and transcriptional attenuation due to the interactions that may exist between full-length sense and antisense transcripts as well as truncated RNA produced as a result of RNAP collisions, one of the reported TI mechanisms. (C) Mechanisms of TI: Occlusion caused by passage of an opposing elongating RNAP on the antisense promoter which hinders binding of RNAP to the sense promoter; Sitting duck interference, dislodgement of an initiation complex due to collision with an opposing elongating RNAP; and Collision between opposing elongating RNAP molecules that produces truncated RNA of different sizes susceptible to participate in AR. Both TI and AR mechanisms are likely to be coupled during antisense transcription.

Mentions: 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 [3–7]. Often, when both DNA strands are transcribed in the same genomic locus, convergent arrangements of promoters are observed, leading to antisense transcription (Fig 1A). This phenomenon plays an important role in cell differentiation [8], stress responses [9,10], pathogenic processes [11,12], virulence [13], and development of life-threatening diseases [14–17]. Regulatory mechanisms linked with antisense transcription include cis-antisense RNA regulation (AR) and transcriptional interference (TI).


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

Bordoy AE, Chatterjee A - PLoS ONE (2015)

Antisense transcription mechanisms in a set of convergent genes.(A) General set of convergent promoters driving expression of genes X and Y synthesizing transcripts x and y (bold arrows), respectively. Such a system is susceptible to TI and produces overlapping transcripts that may participate in AR. (B) AR can cause translational inhibition, mRNA degradation and transcriptional attenuation due to the interactions that may exist between full-length sense and antisense transcripts as well as truncated RNA produced as a result of RNAP collisions, one of the reported TI mechanisms. (C) Mechanisms of TI: Occlusion caused by passage of an opposing elongating RNAP on the antisense promoter which hinders binding of RNAP to the sense promoter; Sitting duck interference, dislodgement of an initiation complex due to collision with an opposing elongating RNAP; and Collision between opposing elongating RNAP molecules that produces truncated RNA of different sizes susceptible to participate in AR. Both TI and AR mechanisms are likely to be coupled during antisense transcription.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4519249&req=5

pone.0133873.g001: Antisense transcription mechanisms in a set of convergent genes.(A) General set of convergent promoters driving expression of genes X and Y synthesizing transcripts x and y (bold arrows), respectively. Such a system is susceptible to TI and produces overlapping transcripts that may participate in AR. (B) AR can cause translational inhibition, mRNA degradation and transcriptional attenuation due to the interactions that may exist between full-length sense and antisense transcripts as well as truncated RNA produced as a result of RNAP collisions, one of the reported TI mechanisms. (C) Mechanisms of TI: Occlusion caused by passage of an opposing elongating RNAP on the antisense promoter which hinders binding of RNAP to the sense promoter; Sitting duck interference, dislodgement of an initiation complex due to collision with an opposing elongating RNAP; and Collision between opposing elongating RNAP molecules that produces truncated RNA of different sizes susceptible to participate in AR. Both TI and AR mechanisms are likely to be coupled during antisense transcription.
Mentions: 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 [3–7]. Often, when both DNA strands are transcribed in the same genomic locus, convergent arrangements of promoters are observed, leading to antisense transcription (Fig 1A). This phenomenon plays an important role in cell differentiation [8], stress responses [9,10], pathogenic processes [11,12], virulence [13], and development of life-threatening diseases [14–17]. Regulatory mechanisms linked with antisense transcription include cis-antisense RNA regulation (AR) and transcriptional interference (TI).

Bottom Line: Here, we present a mathematical modeling framework for antisense transcription that combines the effects of both transcriptional interference and cis-antisense regulation.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, CO, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus