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Differentiation of developing olfactory neurons analysed in terms of coupled epigenetic landscapes.

Alsing AK, Sneppen K - Nucleic Acids Res. (2013)

Bottom Line: The proposed model combines nucleosomes and associated read-write enzymes as mediators of a cis-acting positive feedback with a trans-acting negative feedback, thereby coupling the local epigenetic landscape of the individual OR genes in a way that allow one and only one gene to be active at any time.The model pinpoint that singular gene selection does not require transient mechanisms, enhancer elements or transcription factors to separate choice from maintenance.Intriguingly, it predicts that OR transgenes placed in close proximity should always be expressed simultaneously, though rarely.

View Article: PubMed Central - PubMed

Affiliation: Center for Models of Life, Niels Bohr Institute, University of Copenhagen, Blegdamsvej 17, 2100 Copenhagen, Denmark.

ABSTRACT
The olfactory system integrates signals from receptors expressed in olfactory sensory neurons. Each sensory neuron expresses only one of many similar olfactory receptors (ORs). The choice of receptor is made stochastically early in the differentiation process and is maintained throughout the life of the neuron. The underlying mechanism of this stochastic commitment to one of multiple similar OR genes remains elusive. We present a theoretical analysis of a mechanism that invokes important epigenetic properties of the system. The proposed model combines nucleosomes and associated read-write enzymes as mediators of a cis-acting positive feedback with a trans-acting negative feedback, thereby coupling the local epigenetic landscape of the individual OR genes in a way that allow one and only one gene to be active at any time. The model pinpoint that singular gene selection does not require transient mechanisms, enhancer elements or transcription factors to separate choice from maintenance. In addition, our hypothesis allow us to combine all reported characteristics of singular OR gene selection, in particular that OR genes are silenced from OR transgenes. Intriguingly, it predicts that OR transgenes placed in close proximity should always be expressed simultaneously, though rarely.

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Simulation of  genes, each covered by  nucleosomes. The simulation shows that one gene is turned on early, whereas all other genes remain silenced throughout the simulation. In fact, with these parameters, all these genes stay silenced up to at least t = 5000 time units. Sketches in the right panel illustrate the OR gene state at the final time of the simulation. Crossed promoters indicate silent genes. In color version nucleosomes with silent and active modifications are shown as red and blue, respectively. Other parameters of the simulation are , overall repression factor r = 1, hill coefficient of repression h = 2 and noise conversion .
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gkt181-F2: Simulation of genes, each covered by nucleosomes. The simulation shows that one gene is turned on early, whereas all other genes remain silenced throughout the simulation. In fact, with these parameters, all these genes stay silenced up to at least t = 5000 time units. Sketches in the right panel illustrate the OR gene state at the final time of the simulation. Crossed promoters indicate silent genes. In color version nucleosomes with silent and active modifications are shown as red and blue, respectively. Other parameters of the simulation are , overall repression factor r = 1, hill coefficient of repression h = 2 and noise conversion .

Mentions: Our model of OR gene expression captures the basic property of the system, namely, the exclusive expression of just one gene out a large highly homologous gene population. We initiate the system with all nucleosomes in the silent state consistent with the observations by Magklara et al. (34). Within the simulations, we identify the state of the individual gene, i, as active, when the active fraction of nucleosomes, ai, exceeds 2/3. Figure 2 shows a simulation of N = 10 genes covered by L = 50 nucleosomes each. Gene 5 achieves activation as the number of active nucleosomes exceeds 33 at time . Stochastic fluctuation and internal local bias towards the active state move the subsystem into a dominant active state. Activation increases the globally acting negative feedback, thus reinforcing the dominant gene by decreasing the probability for local activation of other genes.Figure 2.


Differentiation of developing olfactory neurons analysed in terms of coupled epigenetic landscapes.

Alsing AK, Sneppen K - Nucleic Acids Res. (2013)

Simulation of  genes, each covered by  nucleosomes. The simulation shows that one gene is turned on early, whereas all other genes remain silenced throughout the simulation. In fact, with these parameters, all these genes stay silenced up to at least t = 5000 time units. Sketches in the right panel illustrate the OR gene state at the final time of the simulation. Crossed promoters indicate silent genes. In color version nucleosomes with silent and active modifications are shown as red and blue, respectively. Other parameters of the simulation are , overall repression factor r = 1, hill coefficient of repression h = 2 and noise conversion .
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3643594&req=5

gkt181-F2: Simulation of genes, each covered by nucleosomes. The simulation shows that one gene is turned on early, whereas all other genes remain silenced throughout the simulation. In fact, with these parameters, all these genes stay silenced up to at least t = 5000 time units. Sketches in the right panel illustrate the OR gene state at the final time of the simulation. Crossed promoters indicate silent genes. In color version nucleosomes with silent and active modifications are shown as red and blue, respectively. Other parameters of the simulation are , overall repression factor r = 1, hill coefficient of repression h = 2 and noise conversion .
Mentions: Our model of OR gene expression captures the basic property of the system, namely, the exclusive expression of just one gene out a large highly homologous gene population. We initiate the system with all nucleosomes in the silent state consistent with the observations by Magklara et al. (34). Within the simulations, we identify the state of the individual gene, i, as active, when the active fraction of nucleosomes, ai, exceeds 2/3. Figure 2 shows a simulation of N = 10 genes covered by L = 50 nucleosomes each. Gene 5 achieves activation as the number of active nucleosomes exceeds 33 at time . Stochastic fluctuation and internal local bias towards the active state move the subsystem into a dominant active state. Activation increases the globally acting negative feedback, thus reinforcing the dominant gene by decreasing the probability for local activation of other genes.Figure 2.

Bottom Line: The proposed model combines nucleosomes and associated read-write enzymes as mediators of a cis-acting positive feedback with a trans-acting negative feedback, thereby coupling the local epigenetic landscape of the individual OR genes in a way that allow one and only one gene to be active at any time.The model pinpoint that singular gene selection does not require transient mechanisms, enhancer elements or transcription factors to separate choice from maintenance.Intriguingly, it predicts that OR transgenes placed in close proximity should always be expressed simultaneously, though rarely.

View Article: PubMed Central - PubMed

Affiliation: Center for Models of Life, Niels Bohr Institute, University of Copenhagen, Blegdamsvej 17, 2100 Copenhagen, Denmark.

ABSTRACT
The olfactory system integrates signals from receptors expressed in olfactory sensory neurons. Each sensory neuron expresses only one of many similar olfactory receptors (ORs). The choice of receptor is made stochastically early in the differentiation process and is maintained throughout the life of the neuron. The underlying mechanism of this stochastic commitment to one of multiple similar OR genes remains elusive. We present a theoretical analysis of a mechanism that invokes important epigenetic properties of the system. The proposed model combines nucleosomes and associated read-write enzymes as mediators of a cis-acting positive feedback with a trans-acting negative feedback, thereby coupling the local epigenetic landscape of the individual OR genes in a way that allow one and only one gene to be active at any time. The model pinpoint that singular gene selection does not require transient mechanisms, enhancer elements or transcription factors to separate choice from maintenance. In addition, our hypothesis allow us to combine all reported characteristics of singular OR gene selection, in particular that OR genes are silenced from OR transgenes. Intriguingly, it predicts that OR transgenes placed in close proximity should always be expressed simultaneously, though rarely.

Show MeSH