Limits...
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

Effect of TI and AR on switch response.(A) TI model predicts the rate of production of truncated (dashed) and full-length RNA (bold). Interactions between different species arise due to presence of secondary structures and complementary sequences. RNA duplexes are targeted for fast degradation. (B, C) Different switch responses of full-length x and y levels depending on presence or absence of TI and AR. Sharpest response is obtained when both mechanisms are coupled, H denotes value of Hill coefficient.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4519249&req=5

pone.0133873.g005: Effect of TI and AR on switch response.(A) TI model predicts the rate of production of truncated (dashed) and full-length RNA (bold). Interactions between different species arise due to presence of secondary structures and complementary sequences. RNA duplexes are targeted for fast degradation. (B, C) Different switch responses of full-length x and y levels depending on presence or absence of TI and AR. Sharpest response is obtained when both mechanisms are coupled, H denotes value of Hill coefficient.

Mentions: We postulate that both full-length RNA and a fraction of the truncated RNA may play a role in regulating expression of antisense gene through silencing of the antisense RNA. A model based on the proposed mechanism of TI and AR during antisense transcription is shown in Fig 5A. The underlying hypothesis is that RNA interaction between complementary sense and antisense truncated as well as full-length RNA species allows sharpening of the switch response compared to TI or AR mechanism alone. Using a two part mathematical model we first estimate the rate of generation of full-length RNA species (kx and ky) and truncated RNA species ( and ) using the discrete TI model, and then use these transcription rates to solve equations 5–12 (Fig 2, Methods section).


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

Bordoy AE, Chatterjee A - PLoS ONE (2015)

Effect of TI and AR on switch response.(A) TI model predicts the rate of production of truncated (dashed) and full-length RNA (bold). Interactions between different species arise due to presence of secondary structures and complementary sequences. RNA duplexes are targeted for fast degradation. (B, C) Different switch responses of full-length x and y levels depending on presence or absence of TI and AR. Sharpest response is obtained when both mechanisms are coupled, H denotes value of Hill coefficient.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0133873.g005: Effect of TI and AR on switch response.(A) TI model predicts the rate of production of truncated (dashed) and full-length RNA (bold). Interactions between different species arise due to presence of secondary structures and complementary sequences. RNA duplexes are targeted for fast degradation. (B, C) Different switch responses of full-length x and y levels depending on presence or absence of TI and AR. Sharpest response is obtained when both mechanisms are coupled, H denotes value of Hill coefficient.
Mentions: We postulate that both full-length RNA and a fraction of the truncated RNA may play a role in regulating expression of antisense gene through silencing of the antisense RNA. A model based on the proposed mechanism of TI and AR during antisense transcription is shown in Fig 5A. The underlying hypothesis is that RNA interaction between complementary sense and antisense truncated as well as full-length RNA species allows sharpening of the switch response compared to TI or AR mechanism alone. Using a two part mathematical model we first estimate the rate of generation of full-length RNA species (kx and ky) and truncated RNA species ( and ) using the discrete TI model, and then use these transcription rates to solve equations 5–12 (Fig 2, Methods section).

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