The Insight into Protein-Ligand Interactions, a Novel Way of Buffering Protein Noise in Gene Expression.

Random fluctuations are often considered detrimental in the context of gene regulation. Studies aimed at discovering the noise-buffering strategies are important. In this study, we demonstrated a novel design of attenuating noise at protein-level. The protein-ligand interaction dramatically reduced noise so that the coefficient of variation (COV) became roughly 1/3. Remarkably, in comparison to the other two noise-buffering methods, the negative feedback control and the incoherent feedforward loop, the COV of the target protein in the case of protein-ligand interaction appeared to be less than 1/2 of that of the other two methods. The high correlation of the target protein and the ligand grants the present method great ability to buffer noise. Further, it buffers noise at the stage after translation so it is also capable of attenuating the noise inherited from the process of translation.

Inhibitors Alter the Stochasticity of Regulatory Proteins to Force Cells to Switch to the Other State in the Bistable System.

The cellular behaviors under the control of genetic circuits are subject to stochastic fluctuations, or noise. The stochasticity in gene regulation, far from a nuisance, has been gradually appreciated for its unusual function in cellular activities. In this work, with Chemical Master Equation (CME), we discovered that the addition of inhibitors altered the stochasticity of regulatory proteins. For a bistable system of a mutually inhibitory network, such a change of noise led to the migration of cells in the bimodal distribution. We proposed that the consumption of regulatory protein caused by the addition of inhibitor is not the only reason for pushing cells to the specific state; the change of the intracellular stochasticity is also the main cause for the redistribution. For the level of the inhibitor capable of driving 99% of cells, if there is no consumption of regulatory protein, 88% of cells were guided to the specific state. It implied that cells were pushed, by the inhibitor, to the specific state due to the change of stochasticity.

Driving Cells to the Desired State in a Bimodal Distribution through Manipulation of Internal Noise with Biologically Practicable Approaches.

The stochastic nature of gene regulatory networks described by Chemical Master Equation (CME) leads to the distribution of proteins. A deterministic bistability is usually reflected as a bimodal distribution in stochastic simulations. Within a certain range of the parameter space, a bistable system exhibits two stable steady states, one at the low end and the other at the high end. Consequently, it appears to have a bimodal distribution with one sub-population (mode) around the low end and the other around the high end. In most cases, only one mode is favorable, and guiding cells to the desired state is valuable. Traditionally, the population was redistributed simply by adjusting the concentration of the inducer or the stimulator. However, this method has limitations; for example, the addition of stimulator cannot drive cells to the desired state in a common bistable system studied in this work. In fact, it pushes cells only to the undesired state. In addition, it causes a position shift of the modes, and this shift could be as large as the value of the mode itself. Such a side effect might damage coordination, and this problem can be avoided by applying a new method presented in this work. We illustrated how to manipulate the intensity of internal noise by using biologically practicable methods and utilized it to prompt the population to the desired mode. As we kept the deterministic behavior untouched, the aforementioned drawback was overcome. Remarkably, more than 96% of cells has been driven to the desired state. This method is genetically applicable to biological systems exhibiting a bimodal distribution resulting from bistability. Moreover, the reaction network studied in this work can easily be extended and applied to many other systems.