58 results found
Menon G, Krishnan J, 2021, Spatial localization meets biomolecular networks, Nature Communications, Vol: 12, Pages: 1-21, ISSN: 2041-1723
Spatial organization through localization/compartmentalization of species is a ubiquitous but poorlyunderstood feature of cellular biomolecular networks. Current technologies in systems and syntheticbiology (spatial proteomics, imaging, synthetic compartmentalization) necessitate a systematicapproach to elucidating the interplay of networks and spatial organization. We develop a systemsframework towards this end and focus on the effect of spatial localization of network componentsrevealing its multiple facets: (i) As a key distinct regulator of network behaviour, and an enabler of newnetwork capabilities (ii) As a potent new regulator of pattern formation and self-organization (iii) As anoften hidden factor impacting inference of temporal networks from data (iv) As an engineering tool forrewiring networks and network/circuit design. These insights, transparently arising from the most basicconsiderations of networks and spatial organization, have broad relevance in natural and engineeredbiology and in related areas such as cell-free systems, systems chemistry and bionanotechnology
Ramesh V, Krishnan J, 2021, Symmetry breaking meets multisite modification, eLife, Vol: 10, Pages: 1-57, ISSN: 2050-084X
Multisite modification is a basic way of conferring functionality to proteins, and a key component of post-translational modification networks. Additional interest in multisite modification stems from its capability of acting as complex information processors. In this paper we connect two seemingly disparate themes: symmetry and multisite modification. We examine different classes of random modification networks of substrates involving separate or common enzymes. We demonstrate that under different instances of symmetry of the modification network (invoked explicitly or implicitly and discussed in the literature), the biochemistry of multisite modification can lead to the symmetry being broken. This is shown computationally and consolidated analytically, revealing parameter regions where this can (and in fact does) happen, and characteristics of the symmetry broken state. We discuss the relevance of these results in situations where exact symmetry is not present. Overall, through our study we show how symmetry breaking (i) can confer new capabilities to protein networks, including concentration robustness of different combinations of species (in conjunction with multiple steady states) (ii) could have been the basis for ordering of multisite modification, which is widely observed in cells (iii) can significantly impact information processing in multisite modification and in cell signalling networks/pathways where multisite modification is present (iv) can be a fruitful new angle for engineering in synthetic biology and chemistry. All in all, the emerging conceptual synthesis provides a new vantage point for the elucidation and the engineering of molecular systems at the junction of chemical and biological systems.
Suwanmajo T, Ramesh V, Krishnan J, 2020, Exploring cyclic networks of multisite modification reveals origins of information processing characteristics, Scientific Reports, Vol: 10, ISSN: 2045-2322
Multisite phosphorylation (and generally multisite modification) is a basic way of encoding substrate function and circuits/networks of post-translational modifications (PTM) are ubiquitous in cell signalling. The information processing characteristics of PTM systems are a focal point of broad interest. The ordering of modifications is a key aspect of multisite modification, and a broad synthesis of the impact of ordering of modifications is still missing. We focus on a basic class of multisite modification circuits: the cyclic mechanism, which corresponds to the same ordering of phosphorylation and dephosphorylation, and examine multiple variants involving common/separate kinases and common/separate phosphatases. This is of interest both because it is encountered in concrete cellular contexts, and because it serves as a bridge between ordered (sequential) mechanisms (representing one type of ordering) and random mechanisms (which have no ordering). We show that bistability and biphasic dose response curves of the maximally modified phosphoform are ruled out for basic structural reasons independent of parameters, while oscillations can result with even just one shared enzyme. We then examine the effect of relaxing some basic assumptions about the ordering of modification. We show computationally and analytically how bistability, biphasic responses and oscillations can be generated by minimal augmentations to the cyclic mechanism even when these augmentations involved reactions operating in the unsaturated limit. All in all, using this approach we demonstrate (1) how the cyclic mechanism (with single augmentations) represents a modification circuit using minimal ingredients (in terms of shared enzymes and sequestration of enzymes) to generate bistability and oscillations, when compared to other mechanisms, (2) new design principles for rationally designing PTM systems for a variety of behaviour, (3) a basis and a necessary step for understanding the origins and robus
Krishnan J, Lu L, Alam-Nazki A, 2020, The interplay of spatial organization and biochemistry in building blocks of signalling networks, Journal of the Royal Society Interface, ISSN: 1742-5662
Gorgoni B, Zhao Y-B, Krishnan J, et al., 2019, Destabilisation of eukaryote mRNAs by 5’ proximal stop codons can occur independently of the nonsense-mediated mRNA decay pathway, Cells, Vol: 8, ISSN: 2073-4409
In eukaryotes, the binding of poly(A) binding protein (PAB) to the poly(A) tail is central to maintaining mRNA stability. PABP interacts with the translation termination apparatus, and with eIF4G to maintain 3′–5′ mRNA interactions as part of an mRNA closed loop. It is however unclear how ribosome recycling on a closed loop mRNA is influenced by the proximity of the stop codon to the poly(A) tail, and how post-termination ribosome recycling affects mRNA stability. We show that in a yeast disabled for nonsense mediated mRNA decay (NMD), a PGK1 mRNA with an early stop codon at codon 22 of the reading frame is still highly unstable, and that this instability cannot be significantly countered even when 50% stop codon readthrough is triggered. In an NMD-deficient mutant yeast, stable reporter alleles with more 3′ proximal stop codons could not be rendered unstable through Rli1-depletion, inferring defective Rli1 ribosome recycling is insufficient in itself to trigger mRNA instability. Mathematical modelling of a translation system including the effect of ribosome recycling and poly(A) tail shortening supports the hypothesis that impaired ribosome recycling from 5′ proximal stop codons may compromise initiation processes and thus destabilize the mRNA. A model is proposed wherein ribosomes undergo a maturation process during early elongation steps, and acquire competency to re-initiate on the same mRNA as translation elongation progresses beyond the very 5′ proximal regions of the mRNA.
Menon G, Krishnan J, 2019, Design Principles for Compartmentalization and Spatial Organization of Synthetic Genetic Circuits, ACS SYNTHETIC BIOLOGY, Vol: 8, Pages: 1601-1619, ISSN: 2161-5063
Krishnan J, Floros I, 2019, Adaptive information processing of network modules to dynamic and spatial stimuli, BMC Systems Biology, Vol: 13, ISSN: 1752-0509
BackgroundAdaptation and homeostasis are basic features of information processing in cells and seen in a broad range of contexts. Much of the current understanding of adaptation in network modules/motifs is based on their response to simple stimuli. Recently, there have also been studies of adaptation in dynamic stimuli. However a broader synthesis of how different circuits of adaptation function, and which circuits enable a broader adaptive behaviour in classes of more complex and spatial stimuli is largely missing.ResultsWe study the response of a variety of adaptive circuits to time-varying stimuli such as ramps, periodic stimuli and static and dynamic spatial stimuli. We find that a variety of responses can be seen in ramp stimuli, making this a basis for discriminating between even similar circuits. We also find that a number of circuits adapt exactly to ramp stimuli, and dissect these circuits to pinpoint what characteristics (architecture, feedback, biochemical aspects, information processing ingredients) allow for this. These circuits include incoherent feedforward motifs, inflow-outflow motifs and transcritical circuits. We find that changes in location in such circuits where a signal acts can result in non-adaptive behaviour in ramps, even though the location was associated with exact adaptation in step stimuli. We also demonstrate that certain augmentations of basic inflow-outflow motifs can alter the behaviour of the circuit from exact adaptation to non-adaptive behaviour. When subject to periodic stimuli, some circuits (inflow-outflow motifs and transcritical circuits) are able to maintain an average output independent of the characteristics of the input. We build on this to examine the response of adaptive circuits to static and dynamic spatial stimuli. We demonstrate how certain circuits can exhibit a graded response in spatial static stimuli with an exact maintenance of the spatial mean-value. Distinct features which emerge from the consideration of
Krishnan J, Suwanmajo T, 2018, Exploring the intrinsic behaviour of multisite phosphorylation systems as part of signalling pathways, Journal of the Royal Society Interface, Vol: 15, Pages: 1-26, ISSN: 1742-5662
Multisite phosphorylation is a basic way of chemically encoding substrate function and a recurring feature of cell signalling pathways. A number of studies have explored information processing characteristics of multisite phosphorylation, through studies of the intrinsic kinetics. Many of these studies focus on the module in isolation. In this paper, we build a bridge to connect the behaviour of multisite modification in isolation to that as part of pathways. We study the effect of activation of the enzymes (which are basic ways in which the module may be regulated), as well the effects of the modified substrates being involved in further modifications or exiting reaction compartments. We find that these effects can induce multiple kinds of transitions, including to behaviour not seen intrinsically in the multisite modification module. We then build on these insights to investigate how these multisite modification systems can be tuned by enzyme activation to realize a range of information processing outcomes for the design of synthetic phosphorylation circuits. Connecting the complexity of multisite modification kinetics, with the pathways in which they are embedded, serves as a basis for teasing out many aspects of their interaction, providing insights of relevance in systems biology, synthetic biology/chemistry and chemical information processing.
Menon G, Okeke C, Krishnan J, 2017, Modelling compartmentalization towards elucidation and engineering of spatial organization in biochemical pathways, Scientific Reports, Vol: 7, ISSN: 2045-2322
Compartmentalization is a fundamental ingredient, central to the functioning of biological systems at multiple levels. At the cellular level, compartmentalization is a key aspect of the functioning of biochemical pathways and an important element used in evolution. It is also being exploited in multiple contexts in synthetic biology. Accurate understanding of the role of compartments and designing compartmentalized systems needs reliable modelling/systems frameworks. We examine a series of building blocks of signalling and metabolic pathways with compartmental organization. We systematically analyze when compartmental ODE models can be used in these contexts, by comparing these models with detailed reaction-transport models, and establishing a correspondence between the two. We build on this to examine additional complexities associated with these pathways, and also examine sample problems in the engineering of these pathways. Our results indicate under which conditions compartmental models can and cannot be used, why this is the case, and what augmentations are needed to make them reliable and predictive. We also uncover other hidden consequences of employing compartmental models in these contexts. Or results contribute a number of insights relevant to the modelling, elucidation, and engineering of biochemical pathways with compartmentalization, at the core of systems and synthetic biology.
Menon G, Krishnan J, 2016, Bridging the gap between modules in isolation and as part of networks: a systems framework for elucidating interaction and regulation of signalling modules, Journal of Chemical Physics, Vol: 145, ISSN: 1089-7690
While signalling and biochemical modules have been the focus of numerous studies, they are typically studied in isolation, with no examination of the effects of the ambient network. In this paper we formulate and develop a systems framework, rooted in dynamical systems, to understand such effects, by studying the interaction of signalling modules. The modules we consider are (i) basic covalent modification, (ii) monostable switches, (iii) bistable switches, (iv) adaptive modules, and (v) oscillatory modules. We systematically examine the interaction of these modules by analyzing (a) sequential interaction without shared components, (b) sequential interaction with shared components, and (c) oblique interactions. Our studies reveal that the behaviour of a module in isolation may be substantially different from that in a network, and explicitly demonstrate how the behaviour of a given module, the characteristics of the ambient network, and the possibility of shared components can result in new effects. Our global approach illuminates different aspects of the structure and functioning of modules, revealing the importance of dynamical characteristics as well as biochemical features; this provides a methodological platform for investigating the complexity of natural modules shaped by evolution, elucidating the effects of ambient networks on a module in multiple cellular contexts, and highlighting the capabilities and constraints for engineering robust synthetic modules. Overall, such a systems framework provides a platform for bridging the gap between non-linear information processing modules, in isolation and as parts of networks, and a basis for understanding new aspects of natural and engineered cellular networks.
Seaton D, Krishnan J, 2016, Model-based analysis of cell cycle responses to dynamically varying environments, PLOS Computational Biology, Vol: 12, ISSN: 1553-734X
Cell cycle progression is carefully coordinated with a cell’s intra- and extracellular environment. While some pathways have been identified that communicate information from the environment to the cell cycle, a systematic understanding of how this information is dynamically processed is lacking. We address this by performing dynamic sensitivity analysis of three mathematical models of the cell cycle in Saccharomyces cerevisiae. We demonstrate that these models make broadly consistent qualitative predictions about cell cycle progression under dynamically changing conditions. For example, it is shown that the models predict anticorrelated changes in cell size and cell cycle duration under different environments independently of the growth rate. This prediction is validated by comparison to available literature data. Other consistent patterns emerge, such as widespread nonmonotonic changes in cell size down generations in response to parameter changes. We extend our analysis by investigating glucose signalling to the cell cycle, showing that known regulation of Cln3 translation and Cln1,2 transcription by glucose is sufficient to explain the experimentally observed changes in cell cycle dynamics at different glucose concentrations. Together, these results provide a framework for understanding the complex responses the cell cycle is capable of producing in response to dynamic environments.
Liu C, Krishnan J, Xu X-Y, 2015, Intrinsic and induced drug resistance mechanisms at the cellular and tissue scales, Integrative Biology, ISSN: 1757-9694
Alam-Nazki A, Krishnan J, 2015, Spatial control of biochemical modification cascades and pathways, Biophysical Journal, Vol: 108, Pages: 2912-2924, ISSN: 0006-3495
Information transmission in cells occurs through complex networks of proteins and genes and is relayed through cascades of biochemical modifications, which are typically studied through ordinary differential equations. However, it is becoming increasingly clear that spatial factors can strongly influence chemical information transmission in cells. In this article, we systematically disentangle the effects of space in signaling cascades. This is done by examining the effects of localization/compartmentalization and diffusion of enzymes and substrates in multiple variants of chemical modification cascades. This includes situations where the modified form of species at one stage 1) acts as an enzyme for the next stage; 2) acts as a substrate for the next stage; and 3) is involved in phosphotransfer. Our analysis reveals the multiple effects of space in signal transduction cascades. Although in some cases space plays a modulatory effect (itself of interest), in other cases, spatial regulation and control can profoundly affect the nature of information processing as a result of the subtle interplay between the patterns of localization of species, diffusion, and the nature of the modification cascades. Our results provide a platform for disentangling the role of space and spatial control in multiple cellular contexts and a basis for engineering spatial control in signaling cascades through localization/compartmentalization.
Krishnan J, Suwanmajo T, 2015, Mixed mechanisms in multi-site phosphorylation, Journal of the Royal Society Interface, Vol: 12, ISSN: 1742-5689
Multi-site phosphorylation is ubiquitous in cell biology and has been widely studied experimentally and theoretically. The underlying chemical modification mechanisms are typically assumed to be distributive or processive. In this paper, we study the behaviour of mixed mechanisms that can arise either because phosphorylation and dephosphorylation involve different mechanisms or because phosphorylation and/or dephosphorylation can occur through a combination of mechanisms. We examine a hierarchy of models to assess chemical information processing through different mixed mechanisms, using simulations, bifurcation analysis and analytical work. We demonstrate how mixed mechanisms can show important and unintuitive differences from pure distributive and processive mechanisms, in some cases resulting in monostable behaviour with simple dose–response behaviour, while in other cases generating new behaviour-like oscillations. Our results also suggest patterns of information processing that are relevant as the number of modification sites increases. Overall, our work creates a framework to examine information processing arising from complexities of multi-site modification mechanisms and their impact on signal transduction.
Zhao Y-B, Krishnan J, 2015, Probabilistic Boolean Modeling and Analysis framework for mRNA translation, IEEE/ACM Transactions on Computational Biology and Bioinformatics, ISSN: 1557-9964
Liu C, Krishnan J, Xu XY, 2015, Intrinsic and induced drug resistance mechanisms: in silico investigations at the cellular and tissue scales, INTEGRATIVE BIOLOGY, Vol: 7, Pages: 1044-1060, ISSN: 1757-9694
Krishnan J, Mois K, Suwanmajo T, 2014, The behaviour of basic autocatalytic modules in isolation and embedded in networks, Journal of Chemical Physics, ISSN: 1089-7690
Zhao Y-B, Krishnan J, 2014, mRNA translation and protein synthesis: A comparison of modelling methodologies and a new PBN based approach, BMC Systems Biology
Liu C, Krishnan J, Xu X-Y, 2013, Towards an integrated systems-based modelling framework for drug transport and its effect on tumour cells, Journal of Biological Engineering
Suwanmajo T, Krishnan J, 2013, Biphasic Responses in multisite phosphorylation systems, Journal of the Royal Society Interface
Krishnan J, Alam-Nazki A, 2013, Elucidating design principles underlying attractive and repulsive gradient sensing in eukaryotic chemotaxis
Alam-Nazki A, Krishnan J, 2013, Covalent modification cycles through the spatial prism, Biophysical Journal, Vol: 105, Pages: 1720-1731
Liu C, Krishnan J, Xu X-Y, 2013, Investigating the effects of ABC-transporter mediated acquired drug resistance mechanisms at the cell and tissue scale, Integrative Biology
Seaton D, Krishnan J, 2012, Effects of multiple enzyme-substrate interaction in basic units of cellular signal processing, Physical Biology
Alam-Nazki A, Krishnan J, 2012, An investigation of spatial signal transduction in cellular networks, BMC Systems Biology
Krishnan J, Liu C, 2012, An investigation of signal transduction and irreversible decision making in monostable and bistable circuits, Systems and Synthetic Biology: A Systematic View, Editors: kulkarni, Stan, Raman
Liu C, Krishnan J, Xu X-Y, 2012, An investigation of effects of drugs on solid tunmours within a systems-based mathematical modelling framework, Innovative simulation methods in healthcare
Betney R, de Silva E, Mertens C, et al., 2012, Regulation of release factor expression through a translational negative feedback loop: a systems analysis, RNA
Seaton D, Krishnan J, 2012, Multispecific Interactions in Enzymatic Signalling Cascades, Information Processing in Cells and Tissues, Publisher: Springer, Pages: 67-73
Liu C, Krishnan J, Xu XY, 2011, A systems-based mathematical modelling framework for investigating the effect of drugs on solid tumours, THEORETICAL BIOLOGY AND MEDICAL MODELLING, Vol: 8, ISSN: 1742-4682
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