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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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Predictions of sensitivity to enhancers and to double gene dosage: (A) Effect of small alterations in OR specific μ on the probability of switching on for the associated OR gene. Individual decrease (light grey bars) or zonal increase (dark grey bars) in the activation asymmetry μ might represent the effect of an enhancer element or the removal of zonal specific TFs. Each data set from 1000 simulations, with  genes, each covered by  nucleosomes, , , r = 1, and h = 2. (B) Comparison between wild-type case, and an engineered situation where one gene contributed with double gene dosage to the feedback R. The likelihood of turning on the ‘doubled’ gene shown with light grey bars is smaller than for a normal gene to an extent that depend on μ. In case the ‘doubled’ gene is constructed as a tandem repeat, possibly with two reporter proteins inserted, the two identical promoters should become active together, but with smaller probability than the wild-type system. A reduction in probability that will pinpoint the effective value of μ. Each data set from 1000 simulations, with  genes, each covered by  nucleosomes, noise , r = 1, and h = 2.
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gkt181-F5: Predictions of sensitivity to enhancers and to double gene dosage: (A) Effect of small alterations in OR specific μ on the probability of switching on for the associated OR gene. Individual decrease (light grey bars) or zonal increase (dark grey bars) in the activation asymmetry μ might represent the effect of an enhancer element or the removal of zonal specific TFs. Each data set from 1000 simulations, with genes, each covered by nucleosomes, , , r = 1, and h = 2. (B) Comparison between wild-type case, and an engineered situation where one gene contributed with double gene dosage to the feedback R. The likelihood of turning on the ‘doubled’ gene shown with light grey bars is smaller than for a normal gene to an extent that depend on μ. In case the ‘doubled’ gene is constructed as a tandem repeat, possibly with two reporter proteins inserted, the two identical promoters should become active together, but with smaller probability than the wild-type system. A reduction in probability that will pinpoint the effective value of μ. Each data set from 1000 simulations, with genes, each covered by nucleosomes, noise , r = 1, and h = 2.

Mentions: Enhancer elements with features similar to the locus control region of the visual pigment genes have been identified for some subfamilies of OR genes (25,27,31). However, such elements are yet to be identified for all OR genes of the super gene family (31). In the context of our standard olfactory nucleosome modification model, we envision enhancer elements as a mean of disposing the OR gene for epigenetic activation. Decreasing the probability, μ, of a recruited event towards the silent state for one subsystem by as little as 15% greatly increase the frequency of that subsystem being activated, see Figure 5A. Such an increase in frequency for H-element associated genes has been reported (31,52,66).Figure 5.


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

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

Predictions of sensitivity to enhancers and to double gene dosage: (A) Effect of small alterations in OR specific μ on the probability of switching on for the associated OR gene. Individual decrease (light grey bars) or zonal increase (dark grey bars) in the activation asymmetry μ might represent the effect of an enhancer element or the removal of zonal specific TFs. Each data set from 1000 simulations, with  genes, each covered by  nucleosomes, , , r = 1, and h = 2. (B) Comparison between wild-type case, and an engineered situation where one gene contributed with double gene dosage to the feedback R. The likelihood of turning on the ‘doubled’ gene shown with light grey bars is smaller than for a normal gene to an extent that depend on μ. In case the ‘doubled’ gene is constructed as a tandem repeat, possibly with two reporter proteins inserted, the two identical promoters should become active together, but with smaller probability than the wild-type system. A reduction in probability that will pinpoint the effective value of μ. Each data set from 1000 simulations, with  genes, each covered by  nucleosomes, noise , r = 1, and h = 2.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

gkt181-F5: Predictions of sensitivity to enhancers and to double gene dosage: (A) Effect of small alterations in OR specific μ on the probability of switching on for the associated OR gene. Individual decrease (light grey bars) or zonal increase (dark grey bars) in the activation asymmetry μ might represent the effect of an enhancer element or the removal of zonal specific TFs. Each data set from 1000 simulations, with genes, each covered by nucleosomes, , , r = 1, and h = 2. (B) Comparison between wild-type case, and an engineered situation where one gene contributed with double gene dosage to the feedback R. The likelihood of turning on the ‘doubled’ gene shown with light grey bars is smaller than for a normal gene to an extent that depend on μ. In case the ‘doubled’ gene is constructed as a tandem repeat, possibly with two reporter proteins inserted, the two identical promoters should become active together, but with smaller probability than the wild-type system. A reduction in probability that will pinpoint the effective value of μ. Each data set from 1000 simulations, with genes, each covered by nucleosomes, noise , r = 1, and h = 2.
Mentions: Enhancer elements with features similar to the locus control region of the visual pigment genes have been identified for some subfamilies of OR genes (25,27,31). However, such elements are yet to be identified for all OR genes of the super gene family (31). In the context of our standard olfactory nucleosome modification model, we envision enhancer elements as a mean of disposing the OR gene for epigenetic activation. Decreasing the probability, μ, of a recruited event towards the silent state for one subsystem by as little as 15% greatly increase the frequency of that subsystem being activated, see Figure 5A. Such an increase in frequency for H-element associated genes has been reported (31,52,66).Figure 5.

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