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Publications about 'gene expression'
Articles in journal or book chapters
  1. V. H. Nagaraj, J. M. Greene, A. M. Sengupta, and and E.D. Sontag. Translation inhibition and resource balance in the TX-TL cell-free gene expression system. Synthetic Biology, 2017. Note: In press. Preprint in biorxiv 10.1101/142869 with same title, May 2017.Keyword(s): cell-free systems, in vitro synthetic biology.
    Abstract:
    Utilizing the synthetic transcription-translation (TX-TL) system, this paper studies the impact of nucleotide triphosphates (NTPs) and magnesium (Mg2+), on gene expression, in the context of the counterintuitive phenomenon of suppression of gene expression at high NTP concentration. Measuring translation rates for different Mg2+ and NTP concentrations, we observe a complex resource dependence. We demonstrate that translation is the rate-limiting process that is directly inhibited by high NTP concentrations. Additional Mg2+ can partially reverse this inhibition. In several experiments, we observe two maxima of the translation rate viewed as a function of both Mg2+ and NTP concentration, which can be explained in terms of an NTP-independent effect on the ribosome complex and an NTP- Mg2+ titration effect. The non-trivial compensatory effects of abundance of different vital resources signals the presence of complex regulatory mechanisms to achieve optimal gene expression.


  2. T.H. Segall-Shapiro, E. D. Sontag, and C. A. Voigt. Constant gene expression at any copy number using feedforward stabilized promoters. Submitted to Nature Biotechnology, 2017. Keyword(s): synthetic biology, systems biology, genetic circuits, gene copy number.
    Abstract:
    This paper deals with the design of promoters that maintain constant levels of expression, whether they are carried at single copy in the genome or on high-copy plasmids. The design is based on an incoherent feedforward loop (iFFL) with a perfectly non-cooperative repression. The circuits are implemented in E. coli using Transcription Activator Like Effectors (TALEs). The resulting stabilized promoters generate near identical expression across different genome locations and plasmid backbones (pSC101, p15a, ColE1, pUC), and also provide robustness to strain mutations and growth media. Further, their strength is tunable and can be used to maintain constant ratios between proteins.


  3. J.A. Ascensao, P. Datta, B. Hancioglu, E.D. Sontag, M.L. Gennaro, and O.A. Igoshin. Non-monotonic response dynamics of glyoxylate shunt genes in Mycobacterium tuberculosis. PLoS Computational Biology, 12:e1004741, 2016. [PDF]
    Abstract:
    Understanding how dynamical responses of biological networks are constrained by underlying network topology is one of the fundamental goals of systems biology. Here we employ monotone systems theory to formulate a theorem stating necessary conditions for non-monotonic time-response of a biochemical network to a monotonic stimulus. We apply this theorem to analyze the non-monotonic dynamics of the sigmaB-regulated glyoxylate shunt gene expression in Mycobacterium tuberculosis cells exposed to hypoxia. We first demonstrate that the known network structure is inconsistent with observed dynamics. To resolve this inconsistency we employ the formulated theorem, modeling simulations and optimization along with follow-up dynamic experimental measurements. We show a requirement for post-translational modulation of sigmaB activity in order to reconcile the network dynamics with its topology. The results of this analysis make testable experimental predictions and demonstrate wider applicability of the developed methodology to a wide class of biological systems.


  4. M. Margaliot, E.D. Sontag, and T. Tuller. Entrainment to periodic initiation and transition rates in a computational model for gene translation. PLoS ONE, 9(5):e96039, 2014. [WWW] [PDF] [doi:10.1371/journal.pone.0096039] Keyword(s): ribosomes, entrainment, nonlinear systems, stability, contractions, contractive systems.
    Abstract:
    A recent biological study has demonstrated that the gene expression pattern entrains to a periodically varying abundance of tRNA molecules. This motivates developing mathematical tools for analyzing entrainment of translation elongation to intra-cellular signals such as tRNAs levels and other factors affecting translation. We consider a recent deterministic mathematical model for translation called the Ribosome Flow Model (RFM). We analyze this model under the assumption that the elongation rate of the tRNA genes and/or the initiation rate are periodic functions with a common period T. We show that the protein synthesis pattern indeed converges to a unique periodic trajectory with period T. The analysis is based on introducing a novel property of dynamical systems, called contraction after a short transient (CAST), that may be of independent interest. We provide a sufficient condition for CAST and use it to prove that the RFM is CAST, and that this implies entrainment. Our results support the conjecture that periodic oscillations in tRNA levels and other factors related to the translation process can induce periodic oscillations in protein levels, and suggest a new approach for engineering genes to obtain a desired, periodic, synthesis rate.


  5. S. Prabakaran, J. Gunawardena, and E.D. Sontag. Paradoxical results in perturbation-based signaling network reconstruction. Biophysical Journal, 106:2720-2728, 2014. [PDF]
    Abstract:
    This paper describes a potential pitfall of perturbation-based approaches to network inference It is shows experimentally, and then explained mathematically, how even in the simplest signaling systems, perturbation methods may lead to paradoxical conclusions: for any given pair of two components X and Y, and depending upon the specific intervention on Y, either an activation or a repression of X could be inferred. The experiments are performed in an in vitro minimal system, thus isolating the effect and showing that it cannot be explained by feedbacks due to unknown intermediates; this system utilizes proteins from a pathway in mammalian (and other eukaryotic) cells that play a central role in proliferation, gene expression, differentiation, mitosis, cell survival, and apoptosis and is a perturbation target of contemporary therapies for various types of cancers. The results show that the simplistic view of intracellular signaling networks being made up of activation and repression links is seriously misleading, and call for a fundamental rethinking of signaling network analysis and inference methods.


  6. T.H. Segall-Shapiro, A.J. Meyer, A.D. Ellington, E.D. Sontag, and C.A. Voigt. A `resource allocator' for transcription based on a highly fragmented T7 RNA polymerase. Molecular Systems Biology, 10:742-, 2014. [WWW] [PDF] Keyword(s): systems biology, synthetic biology, gene expression.
    Abstract:
    A transcriptional system is built based on a 'resource allocator' that sets a core RNAP concentration, which is then shared by multiple sigma fragments, which provide specificity. Adjusting the concentration of the core sets the maximum transcriptional capacity available to a synthetic system.


  7. V. Shimoga, J.T. White, Y. Li, E.D. Sontag, and L. Bleris. Synthetic mammalian transgene negative autoregulation. Molecular Systems Biology, 9:670-, 2013. [PDF] Keyword(s): systems biology, synthetic biology, gene expression.
    Abstract:
    Using synthetic circuits stably integrated in human kidney cells, we study the effect of negative feedback regulation on cell-wide (extrinsic) and gene-specific (intrinsic) sources of uncertainty. We develop a theoretical approach to extract the two noise components from experiments and show that negative feedback reduces extrinsic noise while marginally increasing intrinsic noise, resulting to significant total noise reduction. We compare the results to simple negative regulation, where a constitutively transcribed transcription factor represses a reporter protein. We observe that the control architecture also reduces the extrinsic noise but results in substantially higher intrinsic fluctuations. We conclude that negative feedback is the most efficient way to mitigate the effects of extrinsic fluctuations by a sole regulatory wiring.


  8. L. Bleris, Z. Xie, D. Glass, A. Adadey, E.D. Sontag, and Y. Benenson. Synthetic incoherent feed-forward circuits show adaptation to the amount of their genetic template. Molecular Systems Biology, 7:519-, 2011. [PDF] Keyword(s): adaptation, feedforward loops, systems biology, synthetic biology.
    Abstract:
    Natural and synthetic biological networks must function reliably in the face of fluctuating stoichiometry of their molecular components. These fluctuations are caused in part by changes in relative expression efficiency and the DNA template amount of the network-coding genes. Gene product levels could potentially be decoupled from these changes via built-in adaptation mechanisms, thereby boosting network reliability. Here we show that a mechanism based on an incoherent feed-forward motif enables adaptive gene expression in mammalian cells. We modeled, synthesized, and tested transcriptional and post-transcriptional incoherent loops and found that in all cases the gene product adapts to changes in DNA template abundance. We also observed that the post-transcriptional form results in superior adaptation behavior, higher absolute expression levels, and lower intrinsic fluctuations. Our results support a previously-hypothesized endogenous role in gene dosage compensation for such motifs and suggest that their incorporation in synthetic networks will improve their robustness and reliability.


  9. M. Chaves, R. Albert, and E.D. Sontag. Robustness and fragility of Boolean models for genetic regulatory networks. J. Theoret. Biol., 235(3):431-449, 2005. [PDF] Keyword(s): systems biology, biochemical networks, boolean systems, gene and protein networks.
    Abstract:
    Interactions between genes and gene products give rise to complex circuits that enable cells to process information and respond to external signals. Theoretical studies often describe these interactions using continuous, stochastic, or logical approaches. Here we propose a framework for gene regulatory networks that combines the intuitive appeal of a qualitative description of gene states with a high flexibility in incorporating stochasticity in the duration of cellular processes. We apply our methods to the regulatory network of the segment polarity genes, thus gaining novel insights into the development of gene expression patterns. For example, we show that very short synthesis and decay times can perturb the wild type pattern. On the other hand, separation of timescales between pre- and post-translational processes and a minimal prepattern ensure convergence to the wild type expression pattern regardless of fluctuations.


  10. E.D. Sontag, A. Kiyatkin, and B.N. Kholodenko. Inferring dynamic architecture of cellular networks using time series of gene expression, protein and metabolite data. Bioinformatics, 20(12):1877-1886, 2004. Note: Supplementary materials are here: http://www.math.rutgers.edu/(tilde)sontag/FTPDIR/sontag-kiyatkin-kholodenko-informatics04-supplement.pdf. [PDF] [doi:http://dx.doi.org/10.1093/bioinformatics/bth173] Keyword(s): systems biology, biochemical networks, systems identification, gene and protein networks, reverse engineering.
    Abstract:
    High-throughput technologies have facilitated the acquisition of large genomics and proteomics data sets. However, these data provide snapshots of cellular behavior, rather than help us reveal causal relations. Here, we propose how these technologies can be utilized to infer the topology and strengths of connections among genes, proteins, and metabolites by monitoring time-dependent responses of cellular networks to experimental interventions. We show that all connections leading to a given network node, e.g., to a particular gene, can be deduced from responses to perturbations none of which directly influences that node, e.g., using strains with knock-outs to other genes. To infer all interactions from stationary data, each node should be perturbed separately or in combination with other nodes. Monitoring time series provides richer information and does not require perturbations to all nodes.



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Last modified: Thu Nov 23 10:40:56 2017
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