Genetic noise control via protein oligomerization
© Ghim and Almaas; licensee BioMed Central Ltd. 2008
Received: 14 June 2008
Accepted: 03 November 2008
Published: 03 November 2008
Gene expression in a cell entails random reaction events occurring over disparate time scales. Thus, molecular noise that often results in phenotypic and population-dynamic consequences sets a fundamental limit to biochemical signaling. While there have been numerous studies correlating the architecture of cellular reaction networks with noise tolerance, only a limited effort has been made to understand the dynamic role of protein-protein interactions.
We have developed a fully stochastic model for the positive feedback control of a single gene, as well as a pair of genes (toggle switch), integrating quantitative results from previous in vivo and in vitro studies. In particular, we explicitly account for the fast binding-unbinding kinetics among proteins, RNA polymerases, and the promoter/operator sequences of DNA. We find that the overall noise-level is reduced and the frequency content of the noise is dramatically shifted to the physiologically irrelevant high-frequency regime in the presence of protein dimerization. This is independent of the choice of monomer or dimer as transcription factor and persists throughout the multiple model topologies considered. For the toggle switch, we additionally find that the presence of a protein dimer, either homodimer or heterodimer, may significantly reduce its random switching rate. Hence, the dimer promotes the robust function of bistable switches by preventing the uninduced (induced) state from randomly being induced (uninduced).
The specific binding between regulatory proteins provides a buffer that may prevent the propagation of fluctuations in genetic activity. The capacity of the buffer is a non-monotonic function of association-dissociation rates. Since the protein oligomerization per se does not require extra protein components to be expressed, it provides a basis for the rapid control of intrinsic or extrinsic noise. The stabilization of regulatory circuits and epigenetic memory in general is of direct implications to organism fitness. Our results also suggest possible avenues for the design of synthetic gene circuits with tunable robustness for a wide range of engineering purposes.
Recent experiments on isogenic populations of microbes with single-cell resolution [1–3] have demonstrated that stochastic fluctuations, or noise, can override genetic and environmental determinism. In fact, the presence of noise may significantly affect the fitness of an organism . The traditional approach for modeling the process of molecular synthesis and degradation inside a cell is by deterministic rate equations, where the continuous change of arbitrarily small fractions of molecules is controlled instantaneously and frequently represented through sigmoidal dose-response relations. However, the rate-equation approaches can not explain the observed phenotypic variability in an isogenic population in stable environments. In particular, when molecules involved in feedback control exist in low copy numbers, noise may give rise to significant cell-to-cell variation as many regulatory events are triggered by molecules with very low copy numbers ≲ 100 . A well known example is the regulation of inorganic trace elements , such as iron, copper, and zinc. While these trace elements are essential for the activity of multiple enzymes, their presence may quickly turn cytotoxic unless their concentrations are carefully controlled.
Although the presence of phenotypic variation due to stochastic fluctuations need not be detrimental for a population of cells , elaborate regulatory mechanisms have evolved to attenuate noise . Several systems-biology studies have recently focused on a select set gene-regulatory circuits, in particular those with feedback control. Feedback control circuits have been identified as important for multiple species and proven responsible for noise reduction and increased functional stability in many housekeeping genes through negative autoregulation , long cascades of ultrasensitive signaling , bacterial chemotaxis , and the circadian clock . Additionally, recent studies on iron homeostasis [13, 14] in E. coli highlight the noise-reducing capability mediated by small RNAs.
Here, we study reversible protein-protein binding as a novel source for genetic noise control. In particular, we have quantitatively analyzed the effects of protein oligomerization on noise in positive autoregulatory circuits as well as a simple toggle-switch . The all-or-none threshold behavior of positive-feedback circuits typically improves robustness against "leaky" switching. However, due to their functional purposes, gene circuits involved in developmental processes or stress responses that often accompany genome-wide changes in gene expression are intrinsically noisier than negative feedback circuits.
It is frequently observed that transcription factors exist in oligomeric form , and protein oligomerization is an important subset of protein-protein interactions, constituting a recurring theme in enzymatic proteins as well as regulatory proteins. Well studied examples include the λ-phage repressor, λ CI (dimer), the TrpR (dimer), LacR (tetramer), and Lrp (hexadecamer or octamer). While many of the RNA-binding proteins dimerize exclusively in the cytosol, the LexA repressor , the leucine-zipper activator [18, 19], and the Arc repressor  have been shown to form an oligomer either in the cytosol ("dimer path") or on the DNA by sequential binding ("monomer path"). Previously, the efficacy of monomer and dimer transcription-regulation paths to reduce noise was separately studied for a negative-feedback autoregulatory circuit . In contrast, we have focused on oligomerization in positive-feedback autoregulatory circuits, as well as genetic toggle switches based on the mutual repression of genes . We find that cytosolic transcription-factor oligomerization acts as a significant buffer for abundance-fluctuations in the monomer, overall reducing noise in the circuit. Additionally, the noise-power spectral density is shifted from the low-to the high-frequency regime. In the toggle switch, cytosolic oligomerization may significantly stabilize the functional state of the circuit. This is especially evident for heterodimerization.
Yet another interesting case of ligand-binding-mediated receptor oligomerization has been reported [22, 23], where the formation of various structures of oligomers may act to buffer the intracellular signaling against noise. Although our modeling and analysis is based on prokaryotic cells, we expect our main findings to be organism independent since protein oligomers, especially homodimers, is such a common occurrence across the species , with homodimers comprising 12.6% of the high-fidelity human proteome [25, 26].
Results and Discussion
Dimerization breaks long-time noise correlations in autogenous circuit
Note that the feedback loop is not explicit in Fig. 1 but implicitly included through the dependence of RNAp-promoter binding equilibrium on the binding status of the TF-operator pair. The sign (positive or negative) and strength of the feedback control is determined by the relative magnitude of the dissociation constants between RNAp and DNA which is either free or TF-bound. For instance, topology DA1 has positive feedback control if K30 = k30/q30 > K32 = k32/q32, and K30 corresponds to the level of constitutive transcription (transcription initiation in the absence of bound transcription factor). For each topology, we study the dependence of noise characteristics on the kinetic rates by varying the dimer lifetime, binding affinity, and the individual association/dissociation rates (see Table and Fig. 1). While we only discuss positive feedback control of the autogenous circuit in this paper, we have obtained corresponding results for negative feedback control [Additional file 1].
Probability rates for positive autogenous circuit
P1 + P1 → P2
P2 → P1 + P1
P2 + D00 → D20
D20 → P2 + D00
P1 + D00 → D10
D10 → P1 + D00
P1 + D10 → D20
D20 → P1 + D10
R + D00 → D01
D01 → R + D00
R + D10 → D11
D11 → R + D10
R + D20 → D21
D21 → R + D20
Dx1 → C + Dx0
tsx-tsl elongation & decay
C → M + R
M → P1 + M
M → ∅
P1 → ∅
7 × 10-4
P2 → ∅
0.7–3.5 × 10-4
A heuristic explanation can be found from Jacobian analysis of a deterministic dynamical system, which is justified for small perturbations around a steady state. When a random fluctuation shifts the monomer copy number away from its steady-state value, the decay toward the steady state can be described by the system Jacobian. The disparity in the magnitude of the (negative) eigenvalues of the Jacobian matrix for the MO versus the DA circuits signifies that the perturbed state is buffered by fast settlement of the monomer-dimer equilibrium. This buffering occurs before random fluctuation can accumulate, possibly with catastrophic physiological effects, explaining the coarse long-time patterns observed in the MO model in contrast with the DA circuits (Fig. 2).
Frequency-selective whitening of Brownian noise
The noise reduction is in the physiologically relevant low-frequency regime, and in Fig. 4 we have indicated the typical values for a cell cycle and mRNA lifetime. Although stochastic fluctuations impose a fundamental limit in cellular information processing, multiple noise sources may affect cellular physiology non-additively. For a living cell, fluctuations are especially relevant when their correlation time is comparable to, or longer than, the cell cycle. At the same time, short-time scale fluctuations (relative to the cell cycle) are more easily attenuated or do not propagate . Additionally, the observed flat region in the PSD of the DA circuits implies that as far as mid-range frequency fluctuations are concerned, we can safely approximate them as a white noise. This insight may shed light on the reliability of approximation schemes for effective stochastic dynamics in protein-only models.
Increased lifetime of dimer plays an important role
Relative Fano factors of protein abundance distributions
γ2 = γ1/10
γ2 = γ1/2
Effects of homo-dimerization in genetic toggle switch
The exceptionally stable lysogeny of the phage λ, for which the spontaneous loss rate is ≲ 10-7 per cell per generation [31, 32], has motivated the synthesis of a genetic toggle switch . Toggle switch is constructed from a pair of genes, which we will denote as gene A and B, that transcriptionally repress each other's expression. This mutual negative regulation can be considered an effective positive feedback loop and provides the basis for the multiple steady states. The existence of multistability, in turn, may be exploited as a device for epigenetic memory or for decision making .
As the general attributes of positive feedback with cooperativity suggest, a genetic toggle switch responds to external cues in an ultrasensitive way: When the strength of a signal approaches a threshold value, the gene expression state can be flipped by a small change in the signal. For example, the concentration of protein A (B) may rapidly switch from high to low and vice versa. However, previous studies of a synthetic toggle switch have shown that the noise-induced state switching is a rare event [15, 34, 35]. In the ensuing analysis, we aim to delineate the origin of this exceptional stability.
In a simple model, the monomer-only (MO) toggle, regulatory proteins only exist in monomeric form. Although an external signal is not explicitly included, random fluctuations in the abundance of the circuit's molecular components will occasionally flip the toggle-state for the two protein species. Drawing on the results from our analysis of positive autoregulatory gene circuits, we hypothesize that dimerization in the regulatory proteins of the toggle switch will serve to stabilize its performance against noise. We allow the protein products of each gene to form a homodimer, being either AA or BB, which is similar to the cI-cro system in phage λ . The dissociation constant for the dimers is defined as K1 = q1/k1, where k1 is the rate of two monomers forming a complex, and q1 the rate of the complex breaking up into its two constituents.
When monomer is the functional form of the repressor molecule (Fig. 5(a)) and K1 is large (limit of low dimer affinity), the protein populations are dominated by monomers. Hence, the circuit effectively behaves as an MO toggle. As K1 decreases, we see that the level of random switching is suppressed: Analogous to the autogenous circuit, the dimer pool stabilizes the protein monomer population. However, the noise suppression is not monotonic with increasing dimer binding affinity. Indeed, for very large binding affinities (small K1), the number of random switching events is increased since the monomer is only available in low copy numbers. Consequently in this limit, it becomes more likely that a small fluctuation in the monomer abundance can cause a dramatic change in the overall gene expression profile. The noise-stabilizing effect of dimerization is also reflected in the corresponding PSDs [Additional file 1]. For instance, we observe a marked suppression of low-frequency fluctuations in the monomer abundance with increasing K1.
In Fig. 5(b) we show corresponding sample time series for the case of a dimeric repressor, all other properties being the same as in (a). While the overall trends are similar, we do note the following difference. Contrary to the monomeric repressor case, there are very few toggle events in the strong binding limit: Since the signaling molecules (dimers) of the dominant gene (the "on"-gene) tend to exist in large copy numbers, a significant fluctuation is needed to flip the state of the toggle switch. In the case of monomeric repression, the signaling molecule exists in low abundance in this limit. Thus, the dominant protein species in the dimeric-repressor system is able to maintain much better control over the state of the toggle switch.
Heterodimerization in genetic toggle switch
We have also considered the case of heterodimerization in the toggle switch, since the noise- and functional stabilization of the switch may be directly affected by the composition and source of the dimers. Note that, the gene-regulation activity is conferred by the two monomer proteins A and B and not the heterodimer AB. However, we find that the presence of (inactive) heterodimers gives rise to very similar noise-stabilizing effects as that of homodimers (Fig. 7). In fact, the existence of heterodimer state allows the dominant protein species to effectively suppress the (active) monomers of the minority species. Thus the heterodimer circuit shows dramatically enhanced functional stability as compared to the case of homodimeric repressors, not sharing the discussed vulnerability of MO circuit to intrinsic noise. Although, to our knowledge, this is a purely hypothetical toggle-switch design, it provides a general strategy for noise control in synthetic gene circuits, along with previously proposed approach of overlapping upstream regulatory domains .
Cells have evolved distinct strategies to combat the fundamental limits imposed by intrinsic and environmental fluctuations. We investigated the role of protein oligomerization on noise originating from the random occurrence of reaction events and the discrete nature of molecules. Recent efforts to correlate network structure with functional aspects may provide valuable insights into approaches for network-level noise control . While negative feedback is one of the most abundantly observed patterns to achieve the goal of stability, it begs the question of how cells reliably change the expression of genes from one state to another. The ultrasensitive response circuit, exemplified by the ubiquitous signal transduction cascades in eukaryotic cells, has been proposed as an answer to this question [40, 41].
In addition to the combinatorial expansion of functional specificity, we argue that the availability of oligomeric states contributes to the attenuation of stochastic fluctuations in protein abundance. In positive autoregulatory gene circuits, where the abundance of an expressed protein controls its own synthesis rate, dimerization provides a buffer serving to mitigate random fluctuations associated with the bursty transcription-translation process. We find that short-time binding-unbinding dynamics reduce the overall noise level by converting potentially pathological low-frequency noise to physiologically unimportant, and easily attenuated, high-frequency noise .
Noise-induced switching generally signals a defect in cellular information processing. Untimely exit from latency in the lambda-phage system directly implies, as the immediate consequence to viruses, increased chance of being targeted by a host immune system. In the case of a bacterium, the expression of a specific set of sugar uptake genes when the sugar is absent from the external medium is a considerable waste of cellular resources. For example, lac operon of E. coli can be considered to have the circuitry of mutual antagonism between the lacI gene and lactose uptake-catabolic genes . A difference lies in the non-transcriptional deactivation of the allosteric transcription factor LacI. LacY, lactose permease, indirectly regulates LacI by increasing lactose uptake, which in turn catalytically deactivates LacI. Likewise, many pili operons of Gram-negative bacteria are also known to utilize heritable expression states, which are of crucial role in pathogenesis [43, 44].
We expect that the random flipping of gene expression states in the examples of positive-feedback-based genetic switches may very well be closely coupled with the fitness of an organism. Phenomenological models relating the fitness of an organism to random phenotypic switching in fluctuating environments have provided important insights into the role of noise , but still many questions remain unanswered. Applying these insights to the design of a synthetic gene switch demonstrates the potential use of affinity-manipulation for synthetic biology, where the construction of genetic circuits with tunable noise-resistance is of central importance. In particular, our analysis highlights the potential utility of heterodimerization to stabilize ultrasensitive switches against random fluctuations. In practice, small ligand molecules may be employed to regulate and tune the binding affinity of regulatory proteins, being either monomers or dimers. Our results further suggest that the structure of the protein-interaction network  may provide important insights on methods for genome-level noise control in synthetic and natural systems.
To evaluate the general role of protein oligomerization in a broad functional context, we studied the two most common motifs found in genetic regulatory circuits: positive autoregulation and the bistable switch. The reaction scheme studied is summarized in Fig. 1, where the binding/unbinding reactions between RNAp and promoter or between TF and operator are made explicit. Each distinct binding status of DNA is associated with a unique transcription initiation rate, and then the overall rate of mRNA synthesis is a weighted average of the initiation rates for distinct binding status, where the weights are given by the relative abundance of each configuration at equilibrium, determined by the calculation of binding energy . Note that, neither binding equilibrium nor empirical Hill-type cooperativity is assumed ad hoc. In particular, we split the lumped transcription process into two separate events, (i) isomerization of closed RNAp-promoter complex to its open form and (ii) transcription elongation followed by termination. This is to reflect the availability of the free promoter while the transcription machinery proceeds along the coding sequence of a gene as soon as the promoter region is cleared of the RNAp holoenzyme. Otherwise, the promoter would be inaccessible during a whole transcription event, altering the random mRNA synthesis dynamics.
To realize the genetic toggle switch in a stochastic setting, we keep track of the microscopic origin of cooperativity that gives rise to bistability. Among various strategies, we employ multiple operator sites which have the same binding affinity with the repressor. The resultant circuitry is, in essence, two autogenous circuits, A and B, which are connected through the active form of their expressed proteins (the active form being either monomer or dimer). The connection is implemented by allowing the active form of proteins A (B) to bind the operator sites of gene B (A). In order to make the interaction between the two genes repressive, unlike positive autogenous circuits, K31 and K32 in Fig. 1 are now greater than K30, making the protein transcriptional repressors. For reasons of analytical simplicity, we have studied the symmetric toggle switch, where the reaction descriptions of each component follow those of the autogenous circuit. Again, the quantitative characteristics of macromolecular binding-unbinding are chosen based on the phage lambda-E. coli system. The only exception is related to the multiple operator sites, where the second repressor binds an operator site with higher binding affinity when the first site is already occupied by the repressor protein . We introduce three different dimerization schemes. Three different dimerization scheme have been introduced: (i) homodimerization with monomeric repressor, (ii) homodimerization with dimeric repressor, and (iii) heterodimerization with monomeric repressor. By solving for the stationary states of the deterministic rate equations, we could identify the bistability region in parameter space to which all the model systems under consideration belong.
While the deterministic rate equation approach or Langevin dynamics explicitly gives the time-evolution of molecular concentration in the form of ordinary differential equations, chemical master equation (CME) describes the evolution of a molecular number state as a continuous-time jump Markov process. To generate the statistically correct trajectories dictated by CME, we used the Gillespie direct  and Next Reaction (Gibson-Bruck)  algorithms, both based on the exact chemical master equation. The Dizzy package  were used as the core engine of the simulations. To ensure that calculations were undertaken in a steady state, we solved the deterministic set of equations for steady state using every combination of parameters investigated. We employed these deterministic steady-state solutions as initial conditions for the stochastic simulations. For each model system, we generated 105 ensemble runs with identical initial conditions and used the instantaneous protein copy number at a fixed time point t = 5000 sec. To achieve high-quality power spectra in the low- and high-frequency limits, we ran time courses (~105 sec) with higher sampling frequency (20 measure points per sec).
To calculate the average switching rate, we generated time series of minimum length 3·107 sec (approximately corresponding to 1 year). We identify a state change in the toggle switch by monitoring the ratio of the monomer and dimer abundance for the two protein species. In order to avoid counting short-time fluctuations that do not correspond to a prolonged change of the toggle state, we a applied sliding-window average to the time series, using a window size of 1000 sec.
The authors thank Dr. Navid for thoughtful discussion and suggestions. This work was performed under the auspices of the U. S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344 and funded by the Laboratory Directed Research and Development Program (project 06-ERD-061) at LLNL.
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