Publications

2024

1. Preprint

   RNA gradients can guide condensates toward promoters: implications for enhancer-promoter contacts and condensate-promoter kissing

   David Goh, Deepti Kannan, Pradeep Natarajan, and 2 more authors

   bioRxiv, 2024

   Abs URL

   We study how protein condensates respond to a site of active RNA transcription (i.e., a gene promoter) due to electrostatic protein-RNA interactions. Our results indicate that condensates can show directed motion towards the promoter, driven by gradients in the RNA concentration. Analytical theory, consistent with simulations, predicts that the droplet velocity has a non-monotonic dependence on the distance to the promoter. We explore the consequences of this gradient-sensing mechanism for enhancer-promoter (E-P) communication using polymer simulations of the intervening chromatin chain. Directed motion of enhancer-bound condensates can, together with loop extrusion by cohesin, collaboratively increase the enhancer-promoter contact probability. Finally, we investigate under which conditions condensates can exhibit oscillations in their morphology and in the distance to the promoter. Oscillatory dynamics are caused by a delayed response of transcription to condensate-promoter contact and negative feedback from the accumulation of RNA at the promoter, which results in charge repulsion.Competing Interest StatementA.K.C serves as a consultant (titled Academic Partner) for Flagship Pioneering, as a consultant and member of the Board of Directors of Flagship’s affiliated company, Apriori Bio, as a consultant and Scientific Advisory Board Member of another affiliated company, Metaphore Bio, and as an ad hoc consultant for Dewpoint Therapeutics. A.K.C. has financial interests in the above companies.

2. Preprint

   

   Active RNA synthesis patterns nuclear condensates

   Salman F. Banani⁼, Andriy Goychuk⁼, Pradeep Natarajan⁼, and 6 more authors

   bioRxiv, 2024

   Abs URL

   Biomolecular condensates are membraneless compartments that organize biochemical processes in cells. In contrast to well-understood mechanisms describing how condensates form and dissolve, the principles underlying condensate patterning – including their size, number and spacing in the cell – remain largely unknown. We hypothesized that RNA, a key regulator of condensate formation and dissolution, influences condensate patterning. Using nucleolar fibrillar centers (FCs) as a model condensate, we found that inhibiting ribosomal RNA synthesis significantly alters the patterning of FCs. Physical theory and experimental observations support a model whereby active RNA synthesis generates a non-equilibrium state that arrests condensate coarsening and thus contributes to condensate patterning. Altering FC condensate patterning by expression of the FC component TCOF1 impairs ribosomal RNA processing, linking condensate patterning to biological function. These results reveal how non-equilibrium states driven by active chemical processes regulate condensate patterning, which is important for cellular biochemistry and function.Competing Interest StatementJ.E.H. is a consultant for Camp4 Therapeutics. R.A.Y. is a founder and shareholder of Syros Pharmaceuticals, Camp4 Therapeutics, Omega Therapeutics, Dewpoint Therapeutics, and Paratus Sciences, and has consulting or advisory roles at Precede Biosciences and Novo Nordisk. A.K.C serves as a consultant (titled Academic Partner) for Flagship Pioneering. He also serves as a consultant and member of the Board of Directors of Flagship’s affiliated company, Apriori Bio, and as a consultant and Scientific Advisory Board Member of another affiliated company, Metaphore Bio. He is an ad hoc consultant for Dewpoint Therapeutics. A.K.C. has financial interests in the above companies.

3. Phys. Rev. Res.

   

   Self-consistent sharp interface theory of active condensate dynamics

   Andriy Goychuk^=⊂, Leonardo Demarchi⁼, Ivan Maryshev, and 1 more author

   Physical Review Research, Jul 2024

   Abs arXiv URL

   Biomolecular condensates help organize the cell cytoplasm and nucleoplasm into spatial compartments with different chemical compositions. A key feature of such compositional patterning is the local enrichment of enzymatically active biomolecules which, after transient binding via molecular interactions, catalyze reactions among their substrates. Thereby, biomolecular condensates provide a spatial template for nonuniform concentration profiles of substrates. In turn, the concentration profiles of substrates, and their molecular interactions with enzymes, drive enzyme fluxes which can enable novel nonequilibrium dynamics. To analyze this generic class of systems, with a current focus on self-propelled droplet motion, we here develop a self-consistent sharp interface theory. In our theory, we diverge from the usual bottom-up approach, which involves calculating the dynamics of concentration profiles based on a given chemical potential gradient. Instead, reminiscent of control theory, we take the reverse approach by deriving the chemical potential profile and enzyme fluxes required to maintain a desired condensate form and dynamics. The chemical potential profile and currents of enzymes come with a corresponding power dissipation rate, which allows us to derive a thermodynamic consistency criterion for the passive part of the system (here, reciprocal enzyme-enzyme interactions). As a first-use case of our theory, we study the role of reciprocal interactions, where the transport of substrates due to reactions and diffusion is, in part, compensated by redistribution due to molecular interactions. More generally, our theory applies to mass-conserved active matter systems with moving phase boundaries.

4. Phys. Rev. Lett.

   Delayed Excitations Induce Polymer Looping and Coherent Motion

   Andriy Goychuk^⊂, Deepti Kannan, and Mehran Kardar^⊂

   Physical Review Letters, Aug 2024

   Abs arXiv URL

   We consider inhomogeneous polymers driven by energy-consuming active processes which encode temporal patterns of athermal kicks. We find that such temporal excitation programs, propagated by tension along the polymer, can effectively couple distinct polymer loci. Consequently, distant loci exhibit correlated motions that fold the polymer into specific conformations, as set by the local actions of the active processes and their distribution along the polymer. Interestingly, active kicks that are canceled out by a time-delayed echo can induce strong compaction of the active polymer.

2023

1. Phys. Rev. Lett.

   

   Enzyme-Enriched Condensates Show Self-Propulsion, Positioning, and Coexistence

   Leonardo Demarchi⁼, Andriy Goychuk^=⊂, Ivan Maryshev, and 1 more author

   Physical Review Letters, Mar 2023

   Abs arXiv URL

   Enzyme-enriched condensates can organize the spatial distribution of their substrates by catalyzing nonequilibrium reactions. Conversely, an inhomogeneous substrate distribution induces enzyme fluxes through substrate-enzyme interactions. We find that condensates move toward the center of a confining domain when this feedback is weak. Above a feedback threshold, they exhibit self-propulsion, leading to oscillatory dynamics. Moreover, catalysis-driven enzyme fluxes can lead to interrupted coarsening, resulting in equidistant condensate positioning, and to condensate division.

2. Proc. Natl. Acad. Sci.

   Polymer folding through active processes recreates features of genome organization

   Andriy Goychuk⁼, Deepti Kannan⁼, Arup K. Chakraborty^⊂, and 1 more author

   Proceedings of the National Academy of Sciences, May 2023

   Abs bioRxiv URL

   From proteins to chromosomes, polymers fold into specific conformations that control their biological function. Polymer folding has long been studied with equilibrium thermodynamics, yet intracellular organization and regulation involve energy-consuming, active processes. Signatures of activity have been measured in the context of chromatin motion, which shows spatial correlations and enhanced subdiffusion only in the presence of adenosine triphosphate. Moreover, chromatin motion varies with genomic coordinate, pointing toward a heterogeneous pattern of active processes along the sequence. How do such patterns of activity affect the conformation of a polymer such as chromatin? We address this question by combining analytical theory and simulations to study a polymer subjected to sequence-dependent correlated active forces. Our analysis shows that a local increase in activity (larger active forces) can cause the polymer backbone to bend and expand, while less active segments straighten out and condense. Our simulations further predict that modest activity differences can drive compartmentalization of the polymer consistent with the patterns observed in chromosome conformation capture experiments. Moreover, segments of the polymer that show correlated active (sub)diffusion attract each other through effective long-ranged harmonic interactions, whereas anticorrelations lead to effective repulsions. Thus, our theory offers nonequilibrium mechanisms for forming genomic compartments, which cannot be distinguished from affinity-based folding using structural data alone. As a first step toward exploring whether active mechanisms contribute to shaping genome conformations, we discuss a data-driven approach.

3. Phys. Rev. E

   

   Geometry-induced patterns through mechanochemical coupling

   Laeschkir Würthner⁼, Andriy Goychuk⁼, and Erwin Frey

   Physical Review E, Jul 2023

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   Intracellular protein patterns regulate a variety of vital cellular processes such as cell division and motility, which often involve dynamic cell-shape changes. These changes in cell shape may in turn affect the dynamics of pattern-forming proteins, hence leading to an intricate feedback loop between cell shape and chemical dynamics. While several computational studies have examined the rich resulting dynamics, the underlying mechanisms are not yet fully understood. To elucidate some of these mechanisms, we explore a conceptual model for cell polarity on a dynamic one-dimensional manifold. Using concepts from differential geometry, we derive the equations governing mass-conserving reaction–diffusion systems on time-evolving manifolds. Analyzing these equations mathematically, we show that dynamic shape changes of the membrane can induce pattern-forming instabilities in parts of the membrane, which we refer to as regional instabilities. Deformations of the local membrane geometry can also (regionally) suppress pattern formation and spatially shift already existing patterns. We explain our findings by applying and generalizing the local equilibria theory of mass-conserving reaction–diffusion systems. This allows us to determine a simple onset criterion for geometry-induced pattern-forming instabilities, which is linked to the phase-space structure of the reaction–diffusion system. The feedback loop between membrane shape deformations and reaction–diffusion dynamics then leads to a surprisingly rich phenomenology of patterns, including oscillations, traveling waves, and standing waves, even if these patterns do not occur in systems with a fixed membrane shape. Our paper reveals that the local conformation of the membrane geometry acts as an important dynamical control parameter for pattern formation in mass-conserving reaction-diffusion systems.

2021

1. J. Nanobiotechnology

   

   Optically transparent vertical silicon nanowire arrays for live-cell imaging

   Roey Elnathan, Andrew W. Holle, Jennifer Young, and 9 more authors

   Journal of Nanobiotechnology, Feb 2021

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   Programmable nano-bio interfaces driven by tuneable vertically configured nanostructures have recently emerged as a powerful tool for cellular manipulations and interrogations. Such interfaces have strong potential for ground-breaking advances, particularly in cellular nanobiotechnology and mechanobiology. However, the opaque nature of many nanostructured surfaces makes non-destructive, live-cell characterization of cellular behavior on vertically aligned nanostructures challenging to observe. Here, a new nanofabrication route is proposed that enables harvesting of vertically aligned silicon (Si) nanowires and their subsequent transfer onto an optically transparent substrate, with high efficiency and without artefacts. We demonstrate the potential of this route for efficient live-cell phase contrast imaging and subsequent characterization of cells growing on vertically aligned Si nanowires. This approach provides the first opportunity to understand dynamic cellular responses to a cell-nanowire interface, and thus has the potential to inform the design of future nanoscale cellular manipulation technologies.

2. Nat. Phys.

   

   Surface-tension-induced budding drives alveologenesis in human mammary gland organoids

   Pablo A. Fernández⁼, Benedikt Buchmann⁼, Andriy Goychuk⁼, and 5 more authors

   Nature Physics, Oct 2021

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   Organ development involves complex shape transformations driven by active mechanical stresses that sculpt the growing tissue. Epithelial gland morphogenesis is a prominent example where cylindrical branches transform into spherical alveoli during growth. Here we show that this shape transformation is induced by a local change from anisotropic to isotropic tension within the epithelial cell layer of developing human mammary gland organoids. By combining laser ablation with optical force inference and theoretical analysis, we demonstrate that circumferential tension increases at the expense of axial tension through a reorientation of cells that correlates with the onset of persistent collective rotation around the branch axis. This enables the tissue to locally control the onset of a generalized Rayleigh–Plateau instability, leading to spherical tissue buds. The interplay between cell motion, cell orientation and tissue tension is a generic principle that may turn out to drive shape transformations in other cell tissues.

3. Preprint

   Tissue flow through pores: a computational study

   Felix Kempf, Andriy Goychuk, and Erwin Frey

   bioRxiv, Oct 2021

   Abs bioRxiv

   Cell migration is of major importance for the understanding of phenomena such as morphogenesis, cancer metastasis, or wound healing. In many of these situations cells are under external confinement. In this work we show by means of computer simulations with a Cellular Potts Model (CPM) that the presence of a bottleneck in an otherwise straight channel has a major influence on the internal organisation of an invading cellular monolayer and the motion of individual cells therein. Comparable to a glass or viscoelastic material, the cell sheet is found to exhibit features of both classical solids and classical fluids. The local ordering on average corresponds to a regular hexagonal lattice, while the relative motion of cells is unbounded. Compared to an unconstricted channel, we observe that a bottleneck perturbs the formation of regular hexagonal arrangements in the epithelial sheet and leads to pile-ups and backflow of cells near the entrance to the constriction, which also affects the overall invasion speed. The scale of these various phenomena depends on the dimensions of the different channel parts, as well as the shape of the funnel domain that connects wider to narrower regions.

4. Nat. Phys.

   A diffusiophoretic mechanism for ATP-driven transport without motor proteins

   Beatrice Ramm⁼, Andriy Goychuk⁼, Alena Khmelinskaia, and 5 more authors

   Nature Physics, Jul 2021

   News&Views Abs bioRxiv URL

   The healthy growth and maintenance of a biological system depends on the precise spatial organization of molecules within the cell through the dissipation of energy. Reaction–diffusion mechanisms can facilitate this organization, as can directional cargo transport orchestrated by motor proteins, by relying on specific protein interactions. However, transport of material through the cell can also be achieved by active processes based on non-specific, purely physical mechanisms, a phenomenon that remains poorly explored. Here, using a combined experimental and theoretical approach, we discover and describe a hidden function of the Escherichia coli MinDE protein system: in addition to forming dynamic patterns, this system accomplishes the directional active transport of functionally unrelated cargo on membranes. Remarkably, this mechanism enables the sorting of diffusive objects according to their effective size, as evidenced using modular DNA origami–streptavidin nanostructures. We show that the diffusive fluxes of MinDE and non-specific cargo couple via density-dependent friction. This non-specific process constitutes a diffusiophoretic mechanism, as yet unknown in a cell biology setting. This nonlinear coupling between diffusive fluxes could represent a generic physical mechanism for establishing intracellular organization.

2020

1. Cell Rep.

   Cell-Based Strain Remodeling of a Nonfibrous Matrix as an Organizing Principle for Vasculogenesis

   Daniel Rüdiger, Kerstin Kick, Andriy Goychuk, and 3 more authors

   Cell Reports, Aug 2020

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   Endothelial tube formation on a reconstituted basement membrane (Matrigel) is a well-established in vitro model for studying the processes of angiogenesis and vasculogenesis. However, to date, the organizing principles that underlie the morphogenesis of this network and that shape the initial process of cells’ finding one another remain elusive. Here, we identify a mechanism that allows cells to form networks by mechanically reorganizing and stiffening their extracellular matrix, independent of chemical guidance cues. Interestingly, we find that this cellular self-organization strongly depends on the connectivity, plasticity, and topology of the surrounding matrix; cell contractility; and cell density. Cells rearrange the matrix and form bridges of matrix material that are stiffer than their surroundings, thus creating a durotactic track for the initiation of cell protrusions and cell-cell contacts. This contractility-based communication via strain stiffening and matrix rearrangement might be a general organizing principle during tissue development or regeneration.

2. PLOS ONE

   Quasi-periodic migration of single cells on short microlanes

   Fang Zhou, Sophia A. Schaffer, Christoph Schreiber, and 4 more authors

   PLOS ONE, Apr 2020

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   Cell migration on microlanes represents a suitable and simple platform for the exploration of the molecular mechanisms underlying cell cytoskeleton dynamics. Here, we report on the quasi-periodic movement of cells confined in stripe-shaped microlanes. We observe persistent polarized cell shapes and directed pole-to-pole motion within the microlanes. Cells depolarize at one end of a given microlane, followed by delayed repolarization towards the opposite end. We analyze cell motility via the spatial velocity distribution, the velocity frequency spectrum and the reversal time as a measure for depolarization and spontaneous repolarization of cells at the microlane ends. The frequent encounters of a boundary in the stripe geometry provides a robust framework for quantitative investigations of the cytoskeleton protrusion and repolarization dynamics. In a first advance to rigorously test physical models of cell migration, we find that the statistics of the cell migration is recapitulated by a Cellular Potts model with a minimal description of cytoskeleton dynamics. Using LifeAct-GFP transfected cells and microlanes with differently shaped ends, we show that the local deformation of the leading cell edge in response to the tip geometry can locally either amplify or quench actin polymerization, while leaving the average reversal times unaffected.

2019

1. Phys. Rev. Lett.

   Protein Recruitment through Indirect Mechanochemical Interactions

   Andriy Goychuk, and Erwin Frey

   Physical Review Letters, Oct 2019

   Abs arXiv URL

   Some of the key proteins essential for important cellular processes are capable of recruiting other proteins from the cytosol to phospholipid membranes. The physical basis for this cooperativity of binding is, surprisingly, still unclear. Here, we suggest a general feedback mechanism that explains cooperativity through mechanochemical coupling mediated by the mechanical properties of phospholipid membranes. Our theory predicts that protein recruitment, and therefore also protein pattern formation, involves membrane deformation, and is strongly affected by membrane composition.

2. eLife

   

   Bridging the gap between single-cell migration and collective dynamics

   Florian Thüroff⁼, Andriy Goychuk⁼, Matthias Reiter, and 1 more author

   eLife, Dec 2019

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   Motivated by the wealth of experimental data recently available, we present a cellular-automaton-based modeling framework focussing on high-level cell functions and their concerted effect on cellular migration patterns. Specifically, we formulate a coarse-grained description of cell polarity through self-regulated actin organization and its response to mechanical cues. Furthermore, we address the impact of cell adhesion on collective migration in cell cohorts. The model faithfully reproduces typical cell shapes and movements down to the level of single cells, yet allows for the efficient simulation of confluent tissues. In confined circular geometries, we find that specific properties of individual cells (polarizability; contractility) influence the emerging collective motion of small cell cohorts. Finally, we study the properties of expanding cellular monolayers (front morphology; stress and velocity distributions) at the level of extended tissues.

2018

1. Preprint

   

   Morphology and Motility of Cells on Soft Substrates

   Andriy Goychuk, David B. Brückner, Andrew W. Holle, and 3 more authors

   arXiv, Dec 2018

   Abs arXiv

   Recent experiments suggest that the interplay between cells and the mechanics of their substrate gives rise to a diversity of morphological and migrational behaviors. Here, we develop a Cellular Potts Model of polarizing cells on a visco-elastic substrate. We compare our model with experiments on endothelial cells plated on polyacrylamide hydrogels to constrain model parameters and test predictions. Our analysis reveals that morphology and migratory behavior are determined by an intricate interplay between cellular polarization and substrate strain gradients generated by traction forces exerted by cells (self-haptotaxis).

2015

1. New J. Phys.

   Stochastic Wilson–Cowan models of neuronal network dynamics with memory and delay

   Igor Goychuk, and Andriy Goychuk

   New Journal of Physics, Apr 2015

   Abs arXiv URL

   We consider a simple Markovian class of the stochastic Wilson–Cowan type models of neuronal network dynamics, which incorporates stochastic delay caused by the existence of a refractory period of neurons. From the point of view of the dynamics of the individual elements, we are dealing with a network of non-Markovian stochastic two-state oscillators with memory, which are coupled globally in a mean-field fashion. This interrelation of a higher-dimensional Markovian and lower-dimensional non-Markovian dynamics is discussed in its relevance to the general problem of the network dynamics of complex elements possessing memory. The simplest model of this class is provided by a three-state Markovian neuron with one refractory state, which causes firing delay with an exponentially decaying memory within the two-state reduced model. This basic model is used to study critical avalanche dynamics (the noise sustained criticality) in a balanced feedforward network consisting of the excitatory and inhibitory neurons. Such avalanches emerge due to the network size dependent noise (mesoscopic noise). Numerical simulations reveal an intermediate power law in the distribution of avalanche sizes with the critical exponent around −1.16. We show that this power law is robust upon a variation of the refractory time over several orders of magnitude. However, the avalanche time distribution is biexponential. It does not reflect any genuine power law dependence.