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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.

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Model for positive feedback in nucleosome modifications, with regulation by a TF that recruits a histone-modifying enzyme. The system is comprised of N nucleosomes of three types: M, U and A, representing nucleosomes that are methylated, unmodified or acetylated at a specific histone residue. Interconversions occur by modification and demodification reactions (black arrows) that can be stimulated (red arrows) by M or A nucleosomes anywhere in the system (Dodd et al, 2007). Bias in the positive-feedback reactions is introduced by the parameter μ, and the strength of the TF-stimulated modification reaction (in this case histone acetylation) is set by σ. The behaviour of the system is examined by iteration of the sequence of reactions, as indicated by the flowchart. Diamonds are points where alternative reactions are chosen, based on the indicated probabilities. Thus, in each time step, there is a probability σ that a positive-feedback reaction is attempted, or else a ‘noise' reaction is attempted. In each time step, there is also a probability σ that a TF-stimulated acetylation is attempted.
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f2: Model for positive feedback in nucleosome modifications, with regulation by a TF that recruits a histone-modifying enzyme. The system is comprised of N nucleosomes of three types: M, U and A, representing nucleosomes that are methylated, unmodified or acetylated at a specific histone residue. Interconversions occur by modification and demodification reactions (black arrows) that can be stimulated (red arrows) by M or A nucleosomes anywhere in the system (Dodd et al, 2007). Bias in the positive-feedback reactions is introduced by the parameter μ, and the strength of the TF-stimulated modification reaction (in this case histone acetylation) is set by σ. The behaviour of the system is examined by iteration of the sequence of reactions, as indicated by the flowchart. Diamonds are points where alternative reactions are chosen, based on the indicated probabilities. Thus, in each time step, there is a probability σ that a positive-feedback reaction is attempted, or else a ‘noise' reaction is attempted. In each time step, there is also a probability σ that a TF-stimulated acetylation is attempted.

Mentions: We previously introduced a simplified numerical model of positive feedback in nucleosome modification for investigation of epigenetic cell memory (Dodd et al, 2007). The model considers a patch of N nucleosomes carrying mutually exclusive modifications, for example, methylation or acetylation of a specific lysine residue (such as lysine 9 of histone H3), giving three types of nucleosome with regard to this modification: methylated (M), unmodified (U) or acetylated (A). Nucleosome interconversions can occur by a positive feedback process, where acetylated nucleosomes recruit specific HDMs and HATs, while methylated nucleosomes recruit HDACs and HMTs that can act on any other nucleosome in the patch (Figure 2). As well as these local positive feedback reactions, non-feedback or ‘noisy' interconversions can occur independently of the local nucleosomes, for example, through the action of non-recruited enzymes or enzymes bound to nucleosomes outside the patch. The relative strengths of the feedback and noise processes is parameterized by α (Figure 2), with the feedback-to-noise ratio, F defined as F=α(1−α). We found that with increasing N and F, the patch of nucleosomes becomes increasingly bistable, existing in either a highly acetylated or a highly methylated state with rare transitions between the states. Bistability also required the positive feedback reactions leading to one modification to be of similar efficiency to those leading to the opposing modification (Dodd et al, 2007).


Ultrasensitive gene regulation by positive feedback loops in nucleosome modification.

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

Model for positive feedback in nucleosome modifications, with regulation by a TF that recruits a histone-modifying enzyme. The system is comprised of N nucleosomes of three types: M, U and A, representing nucleosomes that are methylated, unmodified or acetylated at a specific histone residue. Interconversions occur by modification and demodification reactions (black arrows) that can be stimulated (red arrows) by M or A nucleosomes anywhere in the system (Dodd et al, 2007). Bias in the positive-feedback reactions is introduced by the parameter μ, and the strength of the TF-stimulated modification reaction (in this case histone acetylation) is set by σ. The behaviour of the system is examined by iteration of the sequence of reactions, as indicated by the flowchart. Diamonds are points where alternative reactions are chosen, based on the indicated probabilities. Thus, in each time step, there is a probability σ that a positive-feedback reaction is attempted, or else a ‘noise' reaction is attempted. In each time step, there is also a probability σ that a TF-stimulated acetylation is attempted.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: Model for positive feedback in nucleosome modifications, with regulation by a TF that recruits a histone-modifying enzyme. The system is comprised of N nucleosomes of three types: M, U and A, representing nucleosomes that are methylated, unmodified or acetylated at a specific histone residue. Interconversions occur by modification and demodification reactions (black arrows) that can be stimulated (red arrows) by M or A nucleosomes anywhere in the system (Dodd et al, 2007). Bias in the positive-feedback reactions is introduced by the parameter μ, and the strength of the TF-stimulated modification reaction (in this case histone acetylation) is set by σ. The behaviour of the system is examined by iteration of the sequence of reactions, as indicated by the flowchart. Diamonds are points where alternative reactions are chosen, based on the indicated probabilities. Thus, in each time step, there is a probability σ that a positive-feedback reaction is attempted, or else a ‘noise' reaction is attempted. In each time step, there is also a probability σ that a TF-stimulated acetylation is attempted.
Mentions: We previously introduced a simplified numerical model of positive feedback in nucleosome modification for investigation of epigenetic cell memory (Dodd et al, 2007). The model considers a patch of N nucleosomes carrying mutually exclusive modifications, for example, methylation or acetylation of a specific lysine residue (such as lysine 9 of histone H3), giving three types of nucleosome with regard to this modification: methylated (M), unmodified (U) or acetylated (A). Nucleosome interconversions can occur by a positive feedback process, where acetylated nucleosomes recruit specific HDMs and HATs, while methylated nucleosomes recruit HDACs and HMTs that can act on any other nucleosome in the patch (Figure 2). As well as these local positive feedback reactions, non-feedback or ‘noisy' interconversions can occur independently of the local nucleosomes, for example, through the action of non-recruited enzymes or enzymes bound to nucleosomes outside the patch. The relative strengths of the feedback and noise processes is parameterized by α (Figure 2), with the feedback-to-noise ratio, F defined as F=α(1−α). We found that with increasing N and F, the patch of nucleosomes becomes increasingly bistable, existing in either a highly acetylated or a highly methylated state with rare transitions between the states. Bistability also required the positive feedback reactions leading to one modification to be of similar efficiency to those leading to the opposing modification (Dodd et al, 2007).

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