Publications
Martinez-Corral R*, Park M*, Biette K*, Friedrich D, Scholes C, Khalil A S, Gunawardena J, DePace A H.
Cell Systems 2023.14(4):324-339.e7
Transcriptional synergy, whereby transcription is higher under a combination of transcription factors (TFs) than under each individually, is commonly understood to arise from physical interactions among the TFs and the transcriptional machinery. Here we combine experiments in a cell line-based synthetic platform, and a novel modelling approach, to show that synergy can also emerge if two TFs bind to the same, shared site, without physically interacting while bound. We interpret this as evidence for “kinetic synergy”, which emerges from the functional interactions among the TFs, and find that it depends nontrivially on the TFs’ DNA binding kinetics. These findings are broadly relevant for our understanding of transcriptional control by TF combinations in eukaryotic genomes. This work is a collaboration with experimentalists in the group of Prof. Angela DePace at Harvard Medical School and Prof. Ahmad (Mo) Khalil at Boston University. Watch a summary of this work (starting time 1:04:35)
Allosteric conformational ensembles have unlimited capacity for integrating information.
Biddle B*, Martinez-Corral R*, Wong F, Gunawardena J.
eLife, 2021. 10, e65498.
In this work we theoretically show that allostery can be a biophysical mechanism to generate very flexible higher-order cooperativities (HOCs), which quantify the extent by which ligand binding at one site in a macromolecule is affected by bound ligand at multiple other sites. We used the linear framework to develop a general model for allostery, with arbitrary numbers of conformations and sites, therefore subsuming and generalising previous allostery models. We developed a new method of coarse-graining, which revealed that HOCs can emerge from allostery in a very flexible way. Given the increased awareness of conformational flexibility in cellular regulatory processes, particularly in gene regulation, we suggest that allostery-mediated HOCs might underlie complex input-output behaviour, like the steep sigmoidal response of the classical Drosophila gene hunchback to the transcription factor bicoid. Watch a summary of this work (starting time 54:40).
Metabolic basis of brain-like electrical signalling in bacterial communities.
Martinez-Corral R, Liu J, Prindle A, Süel G M, Garcia-Ojalvo J.
Philosophical Transactions of the Royal Society B. 2019. 374(1774):20180382.
Previous research from the Süel group at University of California San Diego had discovered and characterised population-level oscillations in electrical signalling and metabolism in bacterial communities (biofilms) of Bacillus subtilis grown in microfluidic devices. Here we developed a spatially extended model of a single biofilm, where we investigated the coupling between glutamate metabolism and electrical signalling underlying the generation of the oscillations. Under this model, metabolic stress caused by lack of glutamate in the biofilm center is transmitted to the periphery by potassium-mediated electrical signalling. Potassium and glutamate are two central ions in the nervous system, and this biofilm phenomenon is reminiscent of cortical spreading depression in the brain. These findings have implications for our evolutionary understanding of the nervous system, and more broadly for the role of electrical signalling in non-excitable cell types.
Self-amplifying pulsatile protein dynamics without positive feedback.
Martinez-Corral R, Raimundez E, Lin Y, Elowitz M B, Garcia-Ojalvo J.
Cell Systems. 2018. 453-462.e1.
In this work we theoretically show that stochastic pulses can emerge in circuits of interacting molecules as a result of negative feedback and ultransensitivity. Therefore, a positive feedback interaction is not required, contrary to previous models in the field. This work was motivated by the stochastic pulses in nuclear localisation observed in the yeast transcription factor Msn2, whose regulation does not seem to involve any positive feedback.
Bistable emergence of oscillations in growing Bacillus subtilis biofilms.
Martinez-Corral R, Liu J, Süel G M, Garcia-Ojalvo J.
PNAS. 2018. 115(36): E8333-E8340.
We developed a delay-differential equation model of B. subtilis biofilm oscillations that, in combination with experiments, revealed that the oscillations emerge through what is known as a supercritical Hopf bifurcation. In other words, as the biofilm grows, its growth rate and membrane potential transitions from being constant to being oscillatory in an abrupt manner, and over a range of sizes, the two behaviours can occur (bistability). As a consequence, oscillations can be triggered by a perturbation, like transiently stopping the media flow in the microfluidics system. Moreover, this analysis revealed that the minimum size at which oscillations emerge is not fixed, as initially thought, but is reduced with higher basal stress, explaining the effect of lower glutamate concentrations experimentally observed.
Diversity of fate outcomes in cell pairs under lateral inhibition.
Guisoni N*, Martinez-Corral R*, Garcia-Ojalvo J, de Navascues J.
Development. 2017. 144(7):1177-1186.
In this work we proposed that the outcome of Notch/Delta signalling between pairs of cells can be modulated by the cell-cell contact area. In the Drosophila intestine, stem cells are found interspersed in the tissue. When they divide, each cell in the pair can either differentiate or remain as a stem cell in a Notch-dependent manner. Using a mathematical model, we found that cell pair fates could either be symmetric or asymmetric depending on a parameter that could be related to the contact area. In agreement with this, we found a correlation between cell pair fate and contact area experimentally, suggesting that stem cell fate can be modulated by mechanical and geometrical tissue properties. The work was a collaboration with the experimentalist Dr Joaquín de Navascués (currently at University of Essex).
Coupling between distant biofilms and emergence of nutrient time-sharing.
Liu J, Martinez-Corral R*, Prindle A*, Lee D Y D, Larkin J, Gabalda-Sagarra M, Garcia-Ojalvo J, Süel G M.
Science. 2017. 356(6338):638-642.
We combined modelling and experiments to show that oscillations of neighboring biofilms in the same chamber can become coupled, with oscillation peaks coinciding (in-phase) or alternating (anti-phase) depending on the glutamate concentration of the media. Biofilms switched from in-phase to anti-phase dynamics as the nutrient was reduced, but had counterintuitively higher growth in low than in high glutamate, which we interpreted in terms of a nutrient time-sharing strategy.
* denotes equal contribution