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

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.

Key players in the genetic switch of bacteriophage TP901-1.

After infection of a sensitive host temperate phages may enter either a lytic or a lysogenic pathway leading to new phage assembly or silencing as a prophage, respectively. The decision about which pathway to enter is centered in the genetic switch of the phage. In this work, we explore the bistable genetic switch of bacteriophage TP901-1 through experiments and statistical mechanical modeling. We examine the activity of the lysogenic promoter P(R) at different concentrations of the phage repressor, CI, and compare the effect of CI on P(R) in the presence or absence of the phage-encoded MOR protein expressed from the lytic promoter P(L). We find that the presence of large amounts of MOR prevents repression of the P(R) promoter, verifying that MOR works as an antirepressor. We compare our experimental data with simulations based on previous mathematical formulations of this switch. Good agreement between data and simulations verify the model of CI repression of P(R). By including MOR in the simulations, we are able to discard a model that assumes that CI and MOR do not interact before binding together at the DNA to repress P(R). The second model of Pr repression assumes the formation of a CI:MOR complex in the cytoplasm. We suggest that a CI:MOR complex may exist in different forms that either prevent or invoke P(R) repression, introducing a new twist on mixed feedback systems.

Modeling of the genetic switch of bacteriophage TP901-1: A heteromer of CI and MOR ensures robust bistability.

The lytic-lysogenic switch of the temperate lactococcal phage TP901-1 is fundamentally different from that of phage lambda. In phage TP901-1, the lytic promoter P(L) is repressed by CI, whereas repression of the lysogenic promoter P(R) requires the presence of both of the antagonistic regulator proteins, MOR and CI. We model the central part of the switch and compare the two cases for P(R) repression: the one where the two regulators interact only on the DNA and the other where the two regulators form a heteromer complex in the cytoplasm prior to DNA binding. The models are analyzed for bistability, and the predicted promoter repression folds are compared to experimental data. We conclude that the experimental data are best reproduced the latter case, where a heteromer complex forms in solution. We further find that CI sequestration by the formation of MOR:CI complexes in cytoplasm makes the genetic switch robust.