Limits...
Ultrasensitive gene regulation by positive feedback loops in nucleosome modification.

Sneppen K, Micheelsen MA, Dodd IB - Mol. Syst. Biol. (2008)

Bottom Line: We show theoretically that by recruiting a histone-modifying enzyme, a TF binding non-cooperatively to a single site can change the balance between opposing positive feedback loops in histone modification to produce a large change in gene expression in response to a small change in concentration of the TF.This mechanism can also generate bistable promoter responses, allowing a gene to be on in some cells and off in others, despite the cells being in identical conditions.In addition, the system provides a simple means by which the activities of many TFs could be integrated at a promoter.

View Article: PubMed Central - PubMed

Affiliation: Center for Models of Life, Niels Bohr Institute, Blegdamsvej, Copenhagen, Denmark.

ABSTRACT
Eukaryotic transcription involves the synergistic interaction of many different proteins. However, the question remains how eukaryotic promoters achieve ultrasensitive or threshold responses to changes in the concentration or activity of a single transcription factor (TF). We show theoretically that by recruiting a histone-modifying enzyme, a TF binding non-cooperatively to a single site can change the balance between opposing positive feedback loops in histone modification to produce a large change in gene expression in response to a small change in concentration of the TF. This mechanism can also generate bistable promoter responses, allowing a gene to be on in some cells and off in others, despite the cells being in identical conditions. In addition, the system provides a simple means by which the activities of many TFs could be integrated at a promoter.

Show MeSH
Ultrasensitivity and bistable expression in response to TF stimulation. The steps in Figure 2 were iterated for systems with various numbers of nucleosomes N, feedback-to-noise ratios F=α(1−α), and different levels of recruited HAT activity σ. The system was biased towards methylation by setting μ=2/3 (see Figure 2). The upper panels show the average fraction of acetylated nucleosomes 〈A〉 versus σ. The lower panels show the probabilities (lighter colours for higher) for the system to exist with a particular fraction of A nucleosomes A for the cases where F=5. The h values were obtained by fitting the curves to 〈A〉−A0∞σh/(k+σh), varying A0, K and h.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2387233&req=5

f3: Ultrasensitivity and bistable expression in response to TF stimulation. The steps in Figure 2 were iterated for systems with various numbers of nucleosomes N, feedback-to-noise ratios F=α(1−α), and different levels of recruited HAT activity σ. The system was biased towards methylation by setting μ=2/3 (see Figure 2). The upper panels show the average fraction of acetylated nucleosomes 〈A〉 versus σ. The lower panels show the probabilities (lighter colours for higher) for the system to exist with a particular fraction of A nucleosomes A for the cases where F=5. The h values were obtained by fitting the curves to 〈A〉−A0∞σh/(k+σh), varying A0, K and h.

Mentions: In Figure 3, we show the results of iterating the reaction steps of Figure 2 when, by default, the patch contains a low proportion of A-type nucleosomes due to an imbalance in the feedback reactions due to μ=2/3 (i.e., M-favouring reactions are twice as likely as A-favouring reactions). As the strength of the TF-stimulated HAT reaction is increased (σ increased from 0 to 1), the average steady-state fraction of acetylated nucleosomes, 〈A〉, increases to the point where A nucleosomes dominate the patch. Depending on the parameters, the model is able to give a range of ultrasensitive responses of 〈A〉 to increases in σ (Figure 3, upper panels), as quantified by the Hill coefficient h, with h>1 indicating ultrasensitivity (Koshland et al, 1982; Ferrell, 1996). If promoter activity is taken to be proportional to 〈A〉 and σ is taken to be proportional to TF activity, such that the only source of non-linearity in the system is the nucleosome modification reactions, then it is clear that this mechanism alone can generate an ultrasensitive response of promoter activity to TF activity.


Ultrasensitive gene regulation by positive feedback loops in nucleosome modification.

Sneppen K, Micheelsen MA, Dodd IB - Mol. Syst. Biol. (2008)

Ultrasensitivity and bistable expression in response to TF stimulation. The steps in Figure 2 were iterated for systems with various numbers of nucleosomes N, feedback-to-noise ratios F=α(1−α), and different levels of recruited HAT activity σ. The system was biased towards methylation by setting μ=2/3 (see Figure 2). The upper panels show the average fraction of acetylated nucleosomes 〈A〉 versus σ. The lower panels show the probabilities (lighter colours for higher) for the system to exist with a particular fraction of A nucleosomes A for the cases where F=5. The h values were obtained by fitting the curves to 〈A〉−A0∞σh/(k+σh), varying A0, K and h.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2387233&req=5

f3: Ultrasensitivity and bistable expression in response to TF stimulation. The steps in Figure 2 were iterated for systems with various numbers of nucleosomes N, feedback-to-noise ratios F=α(1−α), and different levels of recruited HAT activity σ. The system was biased towards methylation by setting μ=2/3 (see Figure 2). The upper panels show the average fraction of acetylated nucleosomes 〈A〉 versus σ. The lower panels show the probabilities (lighter colours for higher) for the system to exist with a particular fraction of A nucleosomes A for the cases where F=5. The h values were obtained by fitting the curves to 〈A〉−A0∞σh/(k+σh), varying A0, K and h.
Mentions: In Figure 3, we show the results of iterating the reaction steps of Figure 2 when, by default, the patch contains a low proportion of A-type nucleosomes due to an imbalance in the feedback reactions due to μ=2/3 (i.e., M-favouring reactions are twice as likely as A-favouring reactions). As the strength of the TF-stimulated HAT reaction is increased (σ increased from 0 to 1), the average steady-state fraction of acetylated nucleosomes, 〈A〉, increases to the point where A nucleosomes dominate the patch. Depending on the parameters, the model is able to give a range of ultrasensitive responses of 〈A〉 to increases in σ (Figure 3, upper panels), as quantified by the Hill coefficient h, with h>1 indicating ultrasensitivity (Koshland et al, 1982; Ferrell, 1996). If promoter activity is taken to be proportional to 〈A〉 and σ is taken to be proportional to TF activity, such that the only source of non-linearity in the system is the nucleosome modification reactions, then it is clear that this mechanism alone can generate an ultrasensitive response of promoter activity to TF activity.

Bottom Line: We show theoretically that by recruiting a histone-modifying enzyme, a TF binding non-cooperatively to a single site can change the balance between opposing positive feedback loops in histone modification to produce a large change in gene expression in response to a small change in concentration of the TF.This mechanism can also generate bistable promoter responses, allowing a gene to be on in some cells and off in others, despite the cells being in identical conditions.In addition, the system provides a simple means by which the activities of many TFs could be integrated at a promoter.

View Article: PubMed Central - PubMed

Affiliation: Center for Models of Life, Niels Bohr Institute, Blegdamsvej, Copenhagen, Denmark.

ABSTRACT
Eukaryotic transcription involves the synergistic interaction of many different proteins. However, the question remains how eukaryotic promoters achieve ultrasensitive or threshold responses to changes in the concentration or activity of a single transcription factor (TF). We show theoretically that by recruiting a histone-modifying enzyme, a TF binding non-cooperatively to a single site can change the balance between opposing positive feedback loops in histone modification to produce a large change in gene expression in response to a small change in concentration of the TF. This mechanism can also generate bistable promoter responses, allowing a gene to be on in some cells and off in others, despite the cells being in identical conditions. In addition, the system provides a simple means by which the activities of many TFs could be integrated at a promoter.

Show MeSH