[ { "id": "authors:sacbt-zcq12", "collection": "authors", "collection_id": "sacbt-zcq12", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20181010-111625116", "type": "article", "title": "Self-Amplifying Pulsatile Protein Dynamics without Positive Feedback", "author": [ { "family_name": "Martinez-Corral", "given_name": "Rosa", "clpid": "Martinez-Corral-R" }, { "family_name": "Raimundez", "given_name": "Elba", "clpid": "Raimundez-E" }, { "family_name": "Lin", "given_name": "Yihan", "clpid": "Lin-Yihan" }, { "family_name": "Elowitz", "given_name": "Michael B.", "orcid": "0000-0002-1221-0967", "clpid": "Elowitz-M-B" }, { "family_name": "Garcia-Ojalvo", "given_name": "Jordi", "clpid": "Garcia-Ojalvo-J" } ], "abstract": "Many proteins exhibit dynamic activation patterns in the form of irregular pulses. Such behavior is typically attributed to a combination of positive and negative feedback loops in the underlying regulatory network. However, the presence of positive feedbacks is difficult to demonstrate unequivocally, raising the question of whether stochastic pulses can arise from negative feedback only. Here, we use the protein kinase A (PKA) system, a key regulator of the yeast pulsatile transcription factor Msn2, as a case example to show that irregular pulses of protein activity can arise from a negative feedback loop alone. Simplification to two variables reveals that a combination of zero-order ultrasensitivity, timescale separation between the activator and the repressor, and an effective delay in the feedback are sufficient to amplify a perturbation into a pulse. The same circuit topology can account for both activation and inactivation pulses, pointing toward a general mechanism of stochastic pulse generation.", "doi": "10.1016/j.cels.2018.08.012", "issn": "2405-4712", "publisher": "Elsevier", "publication": "Cell Systems", "publication_date": "2018-10-24", "series_number": "4", "volume": "7", "issue": "4", "pages": "453-462" }, { "id": "authors:acvew-kqv48", "collection": "authors", "collection_id": "acvew-kqv48", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20111209-090440032", "type": "article", "title": "Dynamical Consequences of Bandpass Feedback Loops in a Bacterial Phosphorelay", "author": [ { "family_name": "Sen", "given_name": "Shaunak", "orcid": "0000-0002-1412-8633", "clpid": "Sen-Shaunak" }, { "family_name": "Garcia-Ojalvo", "given_name": "Jordi", "clpid": "Garcia-Ojalvo-J" }, { "family_name": "Elowitz", "given_name": "Michael B.", "orcid": "0000-0002-1221-0967", "clpid": "Elowitz-M-B" } ], "abstract": "Under conditions of nutrient limitation, Bacillus subtilis cells terminally differentiate into a dormant spore state. Progression to sporulation is controlled by a genetic circuit consisting of a phosphorelay embedded in multiple transcriptional feedback loops, which is used to activate the master regulator Spo0A by phosphorylation. These transcriptional regulatory interactions are \"bandpass\"-like, in the sense that activation occurs within a limited band of Spo0A~P concentrations. Additionally, recent results show that the phosphorelay activation occurs in pulses, in a cell-cycle dependent fashion. However, the impact of these pulsed bandpass interactions on the circuit dynamics preceding sporulation remains unclear. In order to address this question, we measured key features of the bandpass interactions at the single-cell level and analyzed them in the context of a simple mathematical model. The model predicted the emergence of a delayed phase shift between the pulsing activity of the different sporulation genes, as well as the existence of a stable state, with elevated Spo0A activity but no sporulation, embedded within the dynamical structure of the system. To test the model, we used time-lapse fluorescence microscopy to measure dynamics of single cells initiating sporulation. We observed the delayed phase shift emerging during the progression to sporulation, while a re-engineering of the sporulation circuit revealed behavior resembling the predicted additional state. These results show that periodically-driven bandpass feedback loops can give rise to complex dynamics in the progression towards sporulation.", "doi": "10.1371/journal.pone.0025102", "pmcid": "PMC3182994", "issn": "1932-6203", "publisher": "Public Library of Science", "publication": "PLoS ONE", "publication_date": "2011-09-29", "series_number": "9", "volume": "6", "issue": "9", "pages": "Art. No. e25102" }, { "id": "authors:za8bf-a2q74", "collection": "authors", "collection_id": "za8bf-a2q74", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20110715-110958369", "type": "article", "title": "Mutual Inactivation of Notch Receptors and Ligands Facilitates Developmental Patterning", "author": [ { "family_name": "Sprinzak", "given_name": "David", "clpid": "Sprinzak-D" }, { "family_name": "Lakhanpal", "given_name": "Amit", "clpid": "Lakhanpal-A" }, { "family_name": "LeBon", "given_name": "Lauren", "clpid": "LeBon-L" }, { "family_name": "Garcia-Ojalvo", "given_name": "Jordi", "clpid": "Garcia-Ojalvo-J" }, { "family_name": "Elowitz", "given_name": "Michael B.", "orcid": "0000-0002-1221-0967", "clpid": "Elowitz-M-B" } ], "abstract": "Developmental patterning requires juxtacrine signaling in order to tightly coordinate the fates of neighboring cells. Recent work has shown that Notch and Delta, the canonical metazoan juxtacrine signaling receptor and ligand, mutually inactivate each other in the same cell. This cis-interaction generates mutually exclusive sending and receiving states in individual cells. It generally remains unclear, however, how this mutual inactivation and the resulting switching behavior can impact developmental patterning circuits. Here we address this question using mathematical modeling in the context of two canonical pattern formation processes: boundary formation and lateral inhibition. For boundary formation, in a model motivated by Drosophila wing vein patterning, we find that mutual inactivation allows sharp boundary formation across a broader range of parameters than models lacking mutual inactivation. This model with mutual inactivation also exhibits robustness to correlated gene expression perturbations. For lateral inhibition, we find that mutual inactivation speeds up patterning dynamics, relieves the need for cooperative regulatory interactions, and expands the range of parameter values that permit pattern formation, compared to canonical models. Furthermore, mutual inactivation enables a simple lateral inhibition circuit architecture which requires only a single downstream regulatory step. Both model systems show how mutual inactivation can facilitate robust fine-grained patterning processes that would be difficult to implement without it, by encoding a difference-promoting feedback within the signaling system itself. Together, these results provide a framework for analysis of more complex Notch-dependent developmental systems.", "doi": "10.1371/journal.pcbi.1002069", "pmcid": "PMC3111533", "issn": "1553-734X", "publisher": "Public Library of Science", "publication": "PLoS Computational Biology", "publication_date": "2011-06", "series_number": "6", "volume": "7", "issue": "6", "pages": "Art. No. e1002069" }, { "id": "authors:pgs47-kh709", "collection": "authors", "collection_id": "pgs47-kh709", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20100526-144631743", "type": "article", "title": "Cis-interactions between Notch and Delta generate mutually exclusive signalling states", "author": [ { "family_name": "Sprinzak", "given_name": "David", "clpid": "Sprinzak-D" }, { "family_name": "Lakhanpal", "given_name": "Amit", "clpid": "Lakhanpal-A" }, { "family_name": "LeBon", "given_name": "Lauren", "clpid": "LeBon-L" }, { "family_name": "Santat", "given_name": "Leah A.", "clpid": "Santat-L-A" }, { "family_name": "Fontes", "given_name": "Michelle E.", "clpid": "Fontes-M-E" }, { "family_name": "Anderson", "given_name": "Graham A.", "clpid": "Anderson-G-A" }, { "family_name": "Garcia-Ojalvo", "given_name": "Jordi", "clpid": "Garcia-Ojalvo-J" }, { "family_name": "Elowitz", "given_name": "Michael B.", "orcid": "0000-0002-1221-0967", "clpid": "Elowitz-M-B" } ], "abstract": "The Notch\u2013Delta signalling pathway allows communication between neighbouring cells during development^1. It has a critical role in the formation of 'fine-grained' patterns, generating distinct cell fates among groups of initially equivalent neighbouring cells and sharply delineating neighbouring regions in developing tissues. The Delta ligand has been shown to have two activities: it transactivates Notch in neighbouring cells and cis-inhibits Notch in its own cell. However, it remains unclear how Notch integrates these two activities and how the resulting system facilitates pattern formation. Here we report the development of a quantitative time-lapse microscopy platform for analysing Notch\u2013Delta signalling dynamics in individual mammalian cells, with the aim of addressing these issues. By controlling both cis- and trans-Delta concentrations, and monitoring the dynamics of a Notch reporter, we measured the combined cis\u2013trans input\u2013output relationship in the Notch\u2013Delta system. The data revealed a striking difference between the responses of Notch to trans- and cis-Delta: whereas the response to trans-Delta is graded, the response to cis-Delta is sharp and occurs at a fixed threshold, independent of trans-Delta. We developed a simple mathematical model that shows how these behaviours emerge from the mutual inactivation of Notch and Delta proteins in the same cell. This interaction generates an ultrasensitive switch between mutually exclusive sending (high Delta/low Notch) and receiving (high Notch/low Delta) signalling states. At the multicellular level, this switch can amplify small differences between neighbouring cells even without transcription-mediated feedback. This Notch\u2013Delta signalling switch facilitates the formation of sharp boundaries and lateral-inhibition patterns in models of development, and provides insight into previously unexplained mutant behaviours.", "doi": "10.1038/nature08959", "pmcid": "PMC2886601", "issn": "0028-0836", "publisher": "Nature Publishing Group", "publication": "Nature", "publication_date": "2010-05-06", "series_number": "7294", "volume": "465", "issue": "7294", "pages": "86-91" }, { "id": "authors:36tpr-v6j20", "collection": "authors", "collection_id": "36tpr-v6j20", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20091125-110115141", "type": "article", "title": "Architecture-Dependent Noise Discriminates Functionally Analogous Differentiation Circuits", "author": [ { "family_name": "\u00c7a\u011fatay", "given_name": "Tolga", "clpid": "\u00c7a\u011fatay-T" }, { "family_name": "Turcotte", "given_name": "Marc", "clpid": "Turcotte-M" }, { "family_name": "Elowitz", "given_name": "Michael B.", "orcid": "0000-0002-1221-0967", "clpid": "Elowitz-M-B" }, { "family_name": "Garcia-Ojalvo", "given_name": "Jordi", "clpid": "Garcia-Ojalvo-J" }, { "family_name": "S\u00fcel", "given_name": "G\u00fcrol M.", "clpid": "S\u00fcel-G-M" } ], "abstract": "Gene regulatory circuits with different architectures (patterns of regulatory interactions) can generate similar dynamics. This raises the question of why a particular circuit architecture is selected to implement a given cellular process. To investigate this problem, we compared the Bacillus subtilis circuit that regulates differentiation into the competence state to an engineered circuit with an alternative architecture (SynEx) in silico and in vivo. Time-lapse microscopy measurements showed that SynEx cells generated competence dynamics similar to native cells and reconstituted the physiology of differentiation. However, architectural differences between the circuits altered the dynamic distribution of stochastic fluctuations (noise) during circuit operation. This distinction in noise causes functional differences between the circuits by selectively controlling the timing of competence episodes and response of the system to various DNA concentrations. These results reveal a tradeoff between temporal precision and physiological response range that is controlled by distinct noise characteristics of alternative circuit architectures.", "doi": "10.1016/j.cell.2009.07.046", "issn": "0092-8674", "publisher": "Cell Press", "publication": "Cell", "publication_date": "2009-10-30", "series_number": "3", "volume": "139", "issue": "3", "pages": "512-522" }, { "id": "authors:t1g1s-xgm65", "collection": "authors", "collection_id": "t1g1s-xgm65", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20141114-080404724", "type": "article", "title": "Tunability and Noise Dependence in Differentiation Dynamics", "author": [ { "family_name": "S\u00fcel", "given_name": "G\u00fcrol M.", "clpid": "S\u00fcel-G-M" }, { "family_name": "Kulkarni", "given_name": "Rajan P.", "clpid": "Kulkarni-R-P" }, { "family_name": "Dworkin", "given_name": "Jonathan", "clpid": "Dworkin-J" }, { "family_name": "Garcia-Ojalvo", "given_name": "Jordi", "clpid": "Garcia-Ojalvo-J" }, { "family_name": "Elowitz", "given_name": "Michael B.", "orcid": "0000-0002-1221-0967", "clpid": "Elowitz-M-B" } ], "abstract": "The dynamic process of differentiation depends on the architecture, quantitative parameters, and noise of underlying genetic circuits. However, it remains unclear how these elements combine to control cellular behavior. We analyzed the probabilistic and transient differentiation of Bacillus subtilis cells into the state of competence. A few key parameters independently tuned the frequency of initiation and the duration of competence episodes and allowed the circuit to access different dynamic regimes, including oscillation. Altering circuit architecture showed that the duration of competence events can be made more precise. We used an experimental method to reduce global cellular noise and showed that noise levels are correlated with frequency of differentiation events. Together, the data reveal a noise-dependent circuit that is remarkably resilient and tunable in terms of its dynamic behavior.", "doi": "10.1126/science.1137455", "issn": "0036-8075", "publisher": "American Association for the Advancement of Science", "publication": "Science", "publication_date": "2007-03-23", "series_number": "5819", "volume": "315", "issue": "5819", "pages": "1716-1719" }, { "id": "authors:gsagm-5zn04", "collection": "authors", "collection_id": "gsagm-5zn04", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200428-150756338", "type": "article", "title": "An excitable gene regulatory circuit induces transient cellular differentiation", "author": [ { "family_name": "S\u00fcel", "given_name": "G\u00fcrol M.", "clpid": "S\u00fcel-G-M" }, { "family_name": "Garcia-Ojalvo", "given_name": "Jordi", "clpid": "Garcia-Ojalvo-J" }, { "family_name": "Liberman", "given_name": "Louisa M.", "clpid": "Liberman-L-M" }, { "family_name": "Elowitz", "given_name": "Michael B.", "orcid": "0000-0002-1221-0967", "clpid": "Elowitz-M-B" } ], "abstract": "Certain types of cellular differentiation are probabilistic and transient. In such systems individual cells can switch to an alternative state and, after some time, switch back again. In Bacillus subtilis, competence is an example of such a transiently differentiated state associated with the capability for DNA uptake from the environment. Individual genes and proteins underlying differentiation into the competent state have been identified, but it has been unclear how these genes interact dynamically in individual cells to control both spontaneous entry into competence and return to vegetative growth. Here we show that this behaviour can be understood in terms of excitability in the underlying genetic circuit. Using quantitative fluorescence time-lapse microscopy, we directly observed the activities of multiple circuit components simultaneously in individual cells, and analysed the resulting data in terms of a mathematical model. We find that an excitable core module containing positive and negative feedback loops can explain both entry into, and exit from, the competent state. We further tested this model by analysing initiation in sister cells, and by re-engineering the gene circuit to specifically block exit. Excitable dynamics driven by noise naturally generate stochastic and transient responses, thereby providing an ideal mechanism for competence regulation.", "doi": "10.1038/nature04588", "issn": "0028-0836", "publisher": "Nature Publishing Group", "publication": "Nature", "publication_date": "2006-03-23", "series_number": "7083", "volume": "440", "issue": "7083", "pages": "545-550" }, { "id": "authors:0avf9-tz931", "collection": "authors", "collection_id": "0avf9-tz931", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:GARpnas04", "type": "article", "title": "Modeling a synthetic multicellular clock: Repressilators coupled by quorum sensing", "author": [ { "family_name": "Garcia-Ojalvo", "given_name": "Jordi", "clpid": "Garcia-Ojalvo-J" }, { "family_name": "Elowitz", "given_name": "Michael B.", "orcid": "0000-0002-1221-0967", "clpid": "Elowitz-M-B" }, { "family_name": "Strogatz", "given_name": "Steven H.", "clpid": "Strogatz-S-H" } ], "abstract": "Diverse biochemical rhythms are generated by thousands of cellular oscillators that somehow manage to operate synchronously. In fields ranging from circadian biology to endocrinology, it remains an exciting challenge to understand how collective rhythms emerge in multicellular structures. Using mathematical and computational modeling, we study the effect of coupling through intercell signaling in a population of Escherichia coli cells expressing a synthetic biological clock. Our results predict that a diverse and noisy community of such genetic oscillators interacting through a quorum-sensing mechanism should self-synchronize in a robust way, leading to a substantially improved global rhythmicity in the system. As such, the particular system of coupled genetic oscillators considered here might be a good candidate to provide the first quantitative example of a synchronization transition in a population of biological oscillators.", "doi": "10.1073/pnas.0307095101", "pmcid": "PMC503725", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2004-07-27", "series_number": "30", "volume": "101", "issue": "30", "pages": "10955-10960" } ]