The three-dimensional organization of chromatin is thought to play an important role in controlling gene expression. Specificity in expression is achieved through the interaction of transcription ...factors and other nuclear proteins with particular sequences of DNA. At unphysiological concentrations many of these nuclear proteins can phase-separate in the absence of DNA, and it has been hypothesized that, in vivo, the thermodynamic forces driving these phases help determine chromosomal organization. However it is unclear how DNA, itself a long polymer subject to configurational transitions, interacts with three-dimensional protein phases. Here we show that a long compressible polymer can be coupled to interacting protein mixtures, leading to a
transition where polymer collapse is coincident with a locally stabilized liquid droplet. We use lattice Monte-Carlo simulations and a mean-field theory to show that these phases can be stable even in regimes where both polymer collapse and coexisting liquid phases are unstable in isolation, and that these new transitions can be either abrupt or continuous. For polymers with internal linear structure we further show that changes in the concentration of bulk components can lead to changes in three-dimensional polymer structure. In the nucleus there are many distinct proteins that interact with many different regions of chromatin, potentially giving rise to many different Prewet phases. The simple systems we consider here highlight chromatin's role as a lower-dimensional surface whose interactions with proteins are required for these novel phases.
In various biological systems information from many noisy molecular receptors must be integrated into a collective response. A striking example is the thermal imaging organ of pit vipers. Single ...nerve fibers in the organ reliably respond to mK temperature increases, a thousand times more sensitive than their molecular sensors, thermo-TRP ion channels. Here, we propose a mechanism for the integration of this molecular information. In our model, amplification arises due to proximity to a dynamical bifurcation, separating a regime with frequent and regular action potentials (APs), from a regime where APs are irregular and infrequent. Near the transition, AP frequency can have an extremely sharp dependence on temperature, naturally accounting for the thousand-fold amplification. Furthermore, close to the bifurcation, most of the information about temperature available in the TRP channels' kinetics can be read out from the timing of APs even in the presence of readout noise. While proximity to such bifurcation points typically requires fine-tuning of parameters, we propose that having feedback act from the order parameter (AP frequency) onto the control parameter robustly maintains the system in the vicinity of the bifurcation. This robustness suggests that similar feedback mechanisms might be found in other sensory systems which also need to detect tiny signals in a varying environment.
E. coli use a regular lattice of receptors and attached kinases to detect and amplify faint chemical signals. Kinase output is characterized by precise adaptation to a wide range of background ligand ...levels and large gain in response to small relative changes in ligand concentration. These characteristics are well described by models which achieve their gain through equilibrium cooperativity. But these models are challenged by two experimental results. First, neither adaptation nor large gain are present in receptor binding assays. Second, in cells lacking adaptation machinery, fluctuations can sometimes be enormous, with essentially all kinases transitioning together. Here we introduce a far-from equilibrium model in which receptors gate the spread of activity between neighboring kinases. This model achieves large gain through a mechanism we term lattice ultrasensitivity (LU). In our LU model, kinase and receptor states are separate degrees of freedom, and kinase kinetics are dominated by chemical rates far-from-equilibrium rather than by equilibrium allostery. The model recapitulates the successes of past models, but also matches the challenging experimental findings. Importantly, unlike past lattice critical models, our LU model does not require parameters to be fine tuned for function.
The three-dimensional organization of chromatin is thought to play an important role in controlling gene expression. Specificity in expression is achieved through the interaction of transcription ...factors and other nuclear proteins with particular sequences of DNA. At unphysiological concentrations many of these nuclear proteins can phase-separate in the absence of DNA, and it has been hypothesized that, in vivo, the thermodynamic forces driving these phases help determine chromosomal organization. However it is unclear how DNA, itself a long polymer subject to configurational transitions, interacts with three-dimensional protein phases. Here we show that a long compressible polymer can be coupled to interacting protein mixtures, leading to a generalized prewetting transition where polymer collapse is coincident with a locally stabilized liquid droplet. We use lattice Monte-Carlo simulations and a mean-field theory to show that these phases can be stable even in regimes where both polymer collapse and coexisting liquid phases are unstable in isolation, and that these new transitions can be either abrupt or continuous. For polymers with internal linear structure we further show that changes in the concentration of bulk components can lead to changes in three-dimensional polymer structure. In the nucleus there are many distinct proteins that interact with many different regions of chromatin, potentially giving rise to many different Prewet phases. The simple systems we consider here highlight chromatin's role as a lower-dimensional surface whose interactions with proteins are required for these novel phases.
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