Limits...
Effects of promoter leakage on dynamics of gene expression.

Huang L, Yuan Z, Liu P, Zhou T - BMC Syst Biol (2015)

Bottom Line: Quantitative analysis of simple molecular networks is an important step forward understanding fundamental intracellular processes.We first derive the analytical distribution of gene product, and then analyze effects of promoter leakage on expression dynamics including bursting kinetics.Specifically, promoter leakage is a universal mechanism of reducing expression noise, controlling phenotypes in different environments and making the gene produce generate fewer bursts.

View Article: PubMed Central - PubMed

Affiliation: Guangdong Province Key Laboratory of Computational Science, School of Mathematics and Computational Science, Sun Yat-Sen University, Guangzhou, 510275, PR China. hlfang208@163.com.

ABSTRACT

Background: Quantitative analysis of simple molecular networks is an important step forward understanding fundamental intracellular processes. As network motifs occurring recurrently in complex biological networks, gene auto-regulatory circuits have been extensively studied but gene expression dynamics remain to be fully understood, e.g., how promoter leakage affects expression noise is unclear.

Results: In this work, we analyze a gene model with auto regulation, where the promoter is assumed to have one active state with highly efficient transcription and one inactive state with very lowly efficient transcription (termed as promoter leakage). We first derive the analytical distribution of gene product, and then analyze effects of promoter leakage on expression dynamics including bursting kinetics. Interestingly, we find that promoter leakage always reduces expression noise and that increasing the leakage rate tends to simplify phenotypes. In addition, higher leakage results in fewer bursts.

Conclusions: Our results reveal the essential role of promoter leakage in controlling expression dynamics and further phenotype. Specifically, promoter leakage is a universal mechanism of reducing expression noise, controlling phenotypes in different environments and making the gene produce generate fewer bursts.

Show MeSH

Related in: MedlinePlus

A schematic diagram for effect of promoter leakage on expression dynamics. (A) schematic description of two-state gene auto-regulatory model with leakage, where gene product is produced not only at the ON state with high efficiency but also at the OFF state with very low efficiency (termed as promoter leakage); (B) representative time series for changes in the number of gene products (left) and effect of leakage on population distribution (right).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4384279&req=5

Fig1: A schematic diagram for effect of promoter leakage on expression dynamics. (A) schematic description of two-state gene auto-regulatory model with leakage, where gene product is produced not only at the ON state with high efficiency but also at the OFF state with very low efficiency (termed as promoter leakage); (B) representative time series for changes in the number of gene products (left) and effect of leakage on population distribution (right).

Mentions: Many theoretical models of gene expression have been proposed and become more and more subtle, from the initial one-state model [1,2] to the common two-state model [3] to those considering many detailed processes or factors, such as chromatin remodeling [4-6], TATA-box- mediated promoter [7-9], transcription additional re-initiation [10], growth rate [11], copy number variations [12], recruitment of transcription factors [13,14], alternative splicing [15]. In spite of these, few gene models in previous studies considered promoter leakage. Here, by promoter leakage we mean that transcription efficiency at the promoter inactive state is much lower than that at the promoter active state. In fact, it has been experimentally verified that transcription takes place not only at the active state but also at the inactive state of promoter, e.g., different nucleosome protein binding sites can lead to different expression efficiencies, some of which are high whereas the others are very low [16,17]; a basal transcription rate at each open promoter state implies that the promoter has leakage; and transcription can take place at some promoter state with a very low rate due to the pre-initiation complex formed at the TATA box [7]. Some studies have shown that increasing the leakage rate may eliminate bistability [18] whereas decreasing the leakage rate of protein production can lead to persistent oscillations [19,20]. But there has been no systematic study on how promoter leakage affects dynamics of gene expression including the noise in gene product, probability distribution, and bursting kinetics (characterized by burst size and burst frequency). This paper will address these issues by analyzing three cases: the common ON-OFF model, the ON-OFF model with negative regulation and the ON-OFF model with positive regulation, referring to schematic FigureĀ 1(A). We will present a systematic investigation for each case.Figure 1


Effects of promoter leakage on dynamics of gene expression.

Huang L, Yuan Z, Liu P, Zhou T - BMC Syst Biol (2015)

A schematic diagram for effect of promoter leakage on expression dynamics. (A) schematic description of two-state gene auto-regulatory model with leakage, where gene product is produced not only at the ON state with high efficiency but also at the OFF state with very low efficiency (termed as promoter leakage); (B) representative time series for changes in the number of gene products (left) and effect of leakage on population distribution (right).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4384279&req=5

Fig1: A schematic diagram for effect of promoter leakage on expression dynamics. (A) schematic description of two-state gene auto-regulatory model with leakage, where gene product is produced not only at the ON state with high efficiency but also at the OFF state with very low efficiency (termed as promoter leakage); (B) representative time series for changes in the number of gene products (left) and effect of leakage on population distribution (right).
Mentions: Many theoretical models of gene expression have been proposed and become more and more subtle, from the initial one-state model [1,2] to the common two-state model [3] to those considering many detailed processes or factors, such as chromatin remodeling [4-6], TATA-box- mediated promoter [7-9], transcription additional re-initiation [10], growth rate [11], copy number variations [12], recruitment of transcription factors [13,14], alternative splicing [15]. In spite of these, few gene models in previous studies considered promoter leakage. Here, by promoter leakage we mean that transcription efficiency at the promoter inactive state is much lower than that at the promoter active state. In fact, it has been experimentally verified that transcription takes place not only at the active state but also at the inactive state of promoter, e.g., different nucleosome protein binding sites can lead to different expression efficiencies, some of which are high whereas the others are very low [16,17]; a basal transcription rate at each open promoter state implies that the promoter has leakage; and transcription can take place at some promoter state with a very low rate due to the pre-initiation complex formed at the TATA box [7]. Some studies have shown that increasing the leakage rate may eliminate bistability [18] whereas decreasing the leakage rate of protein production can lead to persistent oscillations [19,20]. But there has been no systematic study on how promoter leakage affects dynamics of gene expression including the noise in gene product, probability distribution, and bursting kinetics (characterized by burst size and burst frequency). This paper will address these issues by analyzing three cases: the common ON-OFF model, the ON-OFF model with negative regulation and the ON-OFF model with positive regulation, referring to schematic FigureĀ 1(A). We will present a systematic investigation for each case.Figure 1

Bottom Line: Quantitative analysis of simple molecular networks is an important step forward understanding fundamental intracellular processes.We first derive the analytical distribution of gene product, and then analyze effects of promoter leakage on expression dynamics including bursting kinetics.Specifically, promoter leakage is a universal mechanism of reducing expression noise, controlling phenotypes in different environments and making the gene produce generate fewer bursts.

View Article: PubMed Central - PubMed

Affiliation: Guangdong Province Key Laboratory of Computational Science, School of Mathematics and Computational Science, Sun Yat-Sen University, Guangzhou, 510275, PR China. hlfang208@163.com.

ABSTRACT

Background: Quantitative analysis of simple molecular networks is an important step forward understanding fundamental intracellular processes. As network motifs occurring recurrently in complex biological networks, gene auto-regulatory circuits have been extensively studied but gene expression dynamics remain to be fully understood, e.g., how promoter leakage affects expression noise is unclear.

Results: In this work, we analyze a gene model with auto regulation, where the promoter is assumed to have one active state with highly efficient transcription and one inactive state with very lowly efficient transcription (termed as promoter leakage). We first derive the analytical distribution of gene product, and then analyze effects of promoter leakage on expression dynamics including bursting kinetics. Interestingly, we find that promoter leakage always reduces expression noise and that increasing the leakage rate tends to simplify phenotypes. In addition, higher leakage results in fewer bursts.

Conclusions: Our results reveal the essential role of promoter leakage in controlling expression dynamics and further phenotype. Specifically, promoter leakage is a universal mechanism of reducing expression noise, controlling phenotypes in different environments and making the gene produce generate fewer bursts.

Show MeSH
Related in: MedlinePlus