Cellular Lineages and Development: from single cells to landscapes - Poster Abstracts
Poster 1 - Minimum complexity drives regulatory logic in Boolean models of living systems
The properties of random Boolean networks have been investigated extensively as models of gene regulation in biological systems. However, the Boolean functions (BFs) specifying the associated logical update rules should not be expected to be random. In this talk, I will discuss the various biologically meaningful types of BFs and provide a systematic study of their preponderance in a compilation of 2,687 regulatory rules extracted from published, reconstructed Boolean models in a wide range of species, spanning a diverse biological processes. A surprising feature is that most of these BFs have odd ‘bias’, that is, they produce ‘on’ outputs for an odd number of input combinations. Upon further analysis, we can explain this observation, along with the enrichment of read-once functions (RoFs) and its nested canalyzing functions (NCFs) subset, in terms of two complexity measures: Boolean complexity based on string lengths in formal logic, which is yet unexplored in biological contexts, and the so-called average sensitivity. RoFs minimize Boolean complexity and the NCFs, in addition to minimizing the Boolean complexity, also minimize the average sensitivity. These results reveal the importance of minimum complexity in the Boolean regulatory logic of biological networks.
Poster 2 - Role of heterogeneous nuclear ribonucleoproteins(hnRNPs) in maintenance and differentiation of pluripotent Stem Cells
Stem cells are defined by high pluripotent plasticity, continuous self-renewal, and the ability to generate multilineage cell populations. The perpetuation of pluripotency is governed by intrinsic gene regulatory networks, metabolic pathways, epigenetic control mechanisms, alternative splicing machinery as well as non-coding transcripts. A diverse repertoire of protein isoforms from alternative splicing (AS) is expressed in ES cells and has distinct biological roles. Alternative splicing(AS) is a two-step trans-esterification process which, apart from the inclusion of the constitutively spliced exons and exclusion of introns, regulate alteration of exon inclusion and intron deletion, causing diversity in protein production. AS is played by various cis-regulatory elements as well as trans-acting factors including small and heterogenenous ribonuclear complexes(snRNPs and hnRNPs), Arginine and Serine rich SR and related proteins, Muscleblind Like Splicing Regulators, CG binding proteins and RNA Binding Fox-1 Homolog proteins. The inclusion and exclusion efficiency of exons and introns depend on their proportional participation as well as splice site signal strength.Reports from previous studies suggest that AS is intricately involved in cell fate decisions and embryonic development. In this study we report that, a group of hnRNPs express at a high level in pluripotent mouse embryonic stem cells when compared with mouse embryonic fibroblasts for their expression by RT-PCR analysis. To find the inter-association of these hnRNPs and how they are regulated, promoter regions of these hnRNPs were analyzed by in silico approach. Using high stringency cutoffs, we short listed klf6, PRDM1, SP2 as probable common transcription factors binding to the promoter regions of these hnRNPs. The association between different hnRNPs was also explored, which suggested high interconnectivity between them. Knockdown analysis by siRNAs and validation of the in silico findings are currently underway to further understand the regulatory roles of these hnRNPs in pluripotent stem cells.
Poster 3 - Circadian clock mediated control of cell cycle progression correlate cell cycle times in cellular lineages
The origin of lineage correlations in the Inter-mitotic time (IMT) of single cells is incompletely understood. Phenomenological model of circadian gating of cell cycle has been to shown to recapitulate experimentally observed cousin-mother inequality, wherein the cousin cells show higher cell cycle time correlations than the mother-daughter pairs. However, whether the known molecular links between the two gene networks are sufficient to account for cousin-mother inequality or not, remains an open question. We developed a computational algorithm that creates cellular lineages based on a stochastic biochemical model of the coupled circadian clock-cell cycle gene network. Our model demonstrated that circadian control of the cell cycle or forward coupling successfully recapitulated the cousin-mother inequality. We also simulated the effect of circadian inhibitor KL001 in order to suggest an experimental test to determine circadian gating. Our model predicted a 50% decrease in the difference between cousins and mother-daughter correlations, in contrast to a 5% change in population growth rate upon KL001 addition. We thus, propose the presence of IMT correlation in related cells as a potential way to detect circadian clock - cell cycle forward coupling in various cell types.
Poster 4 - Population scale cancer cell dynamics in the presence of chemotherapeutic agents
Anton S. Iyer
Isogenic cancer cells develop heterogeneity via a variety of factors like epigenetics, gene expression fluctuations, etc. These differences amongst genetically identical cells lead to divergent cell fate outcomes when subjected to drugs such as chemotherapies. It is well established that only a fraction of these cells die depending on the concentration of the drug administered, a phenomenon known as 'fractional killing'. However, how this fractional killing effect translates to population growth dynamics of cancer cells is poorly understood. Exponential growth models of cancer cell populations relate the net growth rate of a population to the single cell division and death times. Such models have been used widely in quantifying cell proliferation in response to drugs and have also been used to design improved clinical strategies for cancer treatment. With the improvement in single cell time-lapse imaging techniques, it has become possible to try and predict the population dynamics from single cell data. For U2OS cells proliferating in the absence of any drug, the deviations between theoretical predictions of growth rate and regression fits to the data could be minimized significantly provided the model incorporated a factor of synchronicity in cell age at time of seeding. Surprisingly however, the same theories failed to predict the observed growth rates after administration of the chemotherapeutic agent cisplatin. The underlying distributions of cell death and division times, inferred using a likelihood-based approach to account for competing fates, were found to vary insignificantly on increasing the concentration of the drug even though the net population growth dramatically changed. These surprising results could not be explained using the traditional theories connecting single cell data to population dynamics, revealing a lacuna in the current understanding of how drug resistant cancer cells contribute to cancer cell proliferation. My current work focusses on identifying other essential single cell parameters that are required for developing a quantitative understanding of the population dynamics of drug-treated cancer cells.
Poster 5 - Junctional Heterogeneity patterns sensory epithelium
Morphogenesis during development results from molecular events that cause cell specification and the developmental mechanics that shapes them into distinct organization. In the multicellular organism, the organization of different cell types establishes patterned tissue arrays that ultimately permits functions. The organization of this epithelium is poorly understood. We investigated this question in auditory epithelium of birds which has two cell types: the mechanosensory Hair cells intercalated by supporting cells. Here, each hair cell through HC-intrinsic LGN-Gαi signaling generates a polarized hair bundle on its apical surface. The Planar cell polarity cues further aligns this hair bundle polarity across epithelium. We observed that the development of this planar polarized epithelium is a bi-phasic process, where an initial local polarity of hair bundles are re-oriented to the tissue wide global polarity. Along with the generation of global polarity, the two cell types also attains a distinct geometry. We investigated the underlying mechanism and molecular players in generation of global polarity. We found that the junctions of this two cell types have asymmetric enrichment of differentially phosphorylated NMII, leading to differential line tension. This This asymmetry is patterned by crosstalk of planar cell polarity and LGN-Gαi signaling and can generates multicellular arrays. Together with experiments and theoretical modelling we elucidate how the junctional asymmetry patterns bird auditory epithelium and possibly other tissues.
Poster 6 - Neural stem cell-specific transcription factors specify lineage identity via modulating chromatin accessibility
The diversity of neurons in the brain is generated by neural stem cells (NSC), which divide asymmetrically during development to generate numerous lineally related neurons. In Drosophila, each such lineage is unique and identifiable. It has long been held that NSCs acquire unique combinations of transcription factors as they form on the neuroectoderm, allowing them to generate these unique neural lineages. While such spatial patterning generates diverse lineages, NSCs are also patterned in time to generate further diversity within lineages. This is brought about by a series of genes expressed sequentially in the NSC. For example, in the embryo this cascade consists of Hb>Kr>Pdm>Cas and it allows an NSC to generate a different neuron in each temporal window. Interestingly, while the spatial transcription factors (sTF) are unique to each NSC, the temporal transcription factor series (tTF) are shared by many NSC. Yet each NSC generates different neurons in a given time window. This suggests that spatial cues shape the temporal output of an NSC.
In this work we use two identified NSC and show that they have distinct open chromatin landscapes. By determining the genomic occupancy of candidate sTFs for each of these NSCs, we propose a possible role for them in modulating the chromatin landscape in an NSC-specific way. Our data also suggest that sTFs might mediate the differential activity of the tTF, Hb, by creating different accessible regions in the chromatin that Hb can bind to and regulate. Finally, we assess the role of one of these candidate sTFs in determining lineage identity and find that it is indeed important for its development.
In summary, our work supports a model where sTFs determine NSC identity by establishing unique chromatin landscapes. This in turn allows the same tTFs to regulate different targets in different NSCs. This model provides a mechanism by which spatial and temporal cues are integrated within NSCs to generate lineage-appropriate, time-specific neurons.
Poster 7 - Role of Cyclooxygenase-2 in migration of neural crest cells and patterning of heart and eye
Embryonic development is an elegant process that drives the formation of an organism from a single celled zygote, yet, many molecular details for one of the most brilliantly designed and regulated events of life remain unknown. One such family of enzymes, whose function in development remains unknown is of Cyclooxygenases (COX). The aim of this study is to investigate the role of its inducible isoform, COX-2 in development via inhibition, by using a pharmacological inhibitor, Etoricoxib. COX family of genes is known for its roles in housekeeping activities and inflammation. In order to understand the functions, it governs, the anatomical changes were observed in absence of the molecule. One such process, found to be ameliorated is the migration of neural crest cells (NCC). NCCs give rise to craniofacial structures, smooth muscles and components of neural system. To analyze the observations further, markers of migration were studied along with expression of COX-2.
For this study, the dose was inserted by air sac method and developmental stages were uniformly divided, viz., HH8 to HH20 and temporal protein and gene expressions of COX-2 and other migratory mediators, were being studied through western blot and qRT-PCR. Appropriate statistical analysis was carried out for the results. Expression of COX-2 altered in temporal fashion during early embryogenesis, while other migratory mediators viz., FGF8, FGF10, Sox9, Sox10 showed elevated expression. In peak migratory phase of neural crest cells i.e. at day 2, the levels of COX-2 were elevated as compared to the rest. Sox9, N-cadherin, Msx1 also showed increased protein and gene expression which is crucial for migration of neural crest cells.
Inhibition of COX-2 by Etoricoxib leads to the downregulation of the migration markers, hindering neural crest cell migration.
Poster 8 - Cellular adaptations of yeast to freeze-thaw
We study the survival of Saccharomyces cerevisiae when exposed to cycles of freeze (77K) and thaw (298 K), followed by growth. A "wild-type" population of cells has a ~2% survival rate upon exposure to a single cycle. However, under experimental evolution, we found that the population survival fraction increased to ~70% within ~25 cycles. Compared to the initial wild-type cells, we found that these "evolved" cell types displayed increased mass density, lower cellular volumes and lower cytoplasmic fluidity, together with increased basal levels of a glass-forming sugar, trehalose. Our measurements of the cellular growth rates and associated thermal fluxes using calorimetry indicate different nutrient utilization characteristics for the evolved cells. Further, when subjected to a stronger selection i.e. exposure to multiple (3) consecutive cycles of freeze-thaw before growth, we found that the cells evolved to exhibit significantly lower cytoplasmic fluidity compared to the weaker selection regime while achieving similar survival rates. Altogether, these point to an underlying mechanical adaptation of yeast to these extreme environmental perturbations.
Poster 9 - Control of Organ size and shape during differential development of wing and haltere in Drosophila
How genes and mechanical properties of individual cells combine and determine an organ's shape and size remains a mystery. Drosophila wing-a flat structure and the globular haltere are two homologous flight appendages emerging from a similar group of progenitor cells. The differential development of wing and haltere, which differ in cell size, number, and morphology, is dependent on the function of Hox gene Ultrabithorax (Ubx), which is only expressed in developing halteres and not the wings. Ubx modulates multiple growth regulatory and patterning gene pathways to fine-tune the specification of haltere shape. However, for determining the final shape of an organ, the various signalling networks and cues from the external environment have to converge at the level of altering the individual cell behaviours such as cell shape, size and its mechanical properties- thus dictating the overall tissue geometry. Our studies on differential development of wing and haltere shapes suggest that the localization and abundance of actomyosin complexes, apical contractility, properties of extracellular matrix, cell size and shape, which is a resultant of various cell intrinsic and extrinsic forces, can influence the flat vs globular geometry of these two organs. Some of the mutants of major growth regulatory pathways showing partial homeotic haltere to wing transformation exhibit respective cellular level transformation. This links growth regulatory pathways and cellular biophysical properties in determining tissue and organ morphology.
Poster 10 - Genetic interactions between point mutations and copy number alterations in cancer driver genes
The two-hit hypothesis (Knudson, 1971), that posited a two-step genetic alteration mechanism (later found out to be inactivating mutations in the two alleles of the same gene) to explain neoplastic transformation, has significantly guided identification and understanding of tumor suppressor genes (TSGs) over the following decades. However, tumour syndromes being rarely Mendelian, the hypothesis has also subsequently evolved to accommodate concepts of haploinsufficiency, dominant negative mutations, neomorphic mutation, non-genetic/epigenetic inactivation, epistatic interactions, etc. Yet, we still lack a comprehensive model that links these concepts to the heterogeneity that we observe in the allelic inactivation status (‘2-hits’ vs ‘1-hits’) of TSGs across cancer genomes. Towards this effort, we leverage TCGA cohort data to study the association of TSG mutations with copy number deletions of the other allele. We find differences in the prevalence of 2-hits across different mutation categories at a pan-cancer level and aim to dissect their mechanistic etiologies. We further want to investigate how the 2-hit prevalence changes with tissues of origin, genetic backgrounds and accompanying epigenetic landscapes, something that hints at the context dependence of such mechanisms. This forces us to think beyond classical Mendelism and the two-hit hypothesis when linking TSG genotypes to cancer cell phenotypes along the course of tumour development. Studying this will enable us to assess the differential impacts of specific mutation-copy number combinations on tumour initiation and clonal evolution as a function of prevailing contexts.
Poster 11 - Functional resilience of decision making motifs embedded in larger networks
Elucidating the design principles of regulatory networks driving cellular decision-making has important implications in understanding cell differentiation and guiding the design of synthetic circuits. Mutually repressing feedback loops between ‘master regulators’ of cell-fates can exhibit multistable dynamics, thus enabling multiple “single-positive” phenotypes: (high A, low B) and (low A, high B) for a toggle switch, and (high A, low B, low C), (low A, high B, low C) and (low A, low B, high C) for a toggle triad. However, the dynamics of these two network motifs has been interrogated in isolation in silico, but in vitro and in vivo, they often operate while embedded in larger regulatory networks. Here, we embed these network motifs in complex larger networks of varying sizes and connectivity and identify conditions under which these motifs maintain their canonical dynamical behavior, thus identifying hallmarks of their functional resilience. We show that the in-degree of a motif - defined as the number of incoming edges onto a motif - determines its functional properties. For a smaller in-degree, the functional traits for both these motifs (bimodality, pairwise correlation coefficient(s), and the frequency of “single-positive” phenotypes) are largely conserved, but increasing the in-degree can lead to a divergence from their stand-alone behaviors. These observations offer insights into design principles of biological networks containing these network motifs, as well as help devise optimal strategies for integration of these motifs into larger synthetic networks.
Poster 12 - Partially duplicated endothecial cell layer of the HD-ZIP IV transcription factor mutant ocl4 of maize: Trans-generational epigenetic-like inheritance and impact of phasiRNAs in cell fate specification
Plants are useful models to understand cell fate specification and developmental plasticity: a central question in biology. The HD-ZIP IV transcription factor mutant outer cell layer 4 (ocl4) of maize is normally male sterile, due to the partially duplicated endothecial layer in the anther. During multi-year propagation of this ocl4-1 allele mutant, we came across an individual that was male fertile. The subsequent lineages of this individual, maintained through self-pollinations, were fertile, although we show by confocal microscopy analysis that these anthers retained canonical cell fate features of sterile ocl4, i.e. the partially duplicated endothecium. Further, there were no genotypic changes in ocl4-1 allele as revealed by genotyping assays and RNASeq. Next, we examined the role of phased, small interfering RNA molecules (phasiRNAs) in this unusual phenomenon, as this newly discovered class of RNA molecules have been implicated in male fertility in grasses, just like their mammalian counterparts, i.e piRNAs. We found that conditioned fertile anthers accumulated significantly higher 21-nt phasiRNAs; and three key steps in the phasiRNA biogenesis pathway were impacted by Ocl4. Our differential expression analysis uncovered a distinct profile of genes for heat stress response, further strengthening the link between environmental and phenotype conditioning. Genes for plastid differentiation, especially those involved in metabolic processes, were also significantly differentially expressed, given that presence of chloroplasts is a key feature of normal endothecial cells. Thus, conditioned fertile ocl4 presents an unexpected complication in developmental cell fate specification leading to meiosis in male germline and opens up new questions in cellular lineages and development.
Poster 13 - Resource competition & emergent responses in gene regulatory dynamics'
Biological systems are majorly dependent on their property of bistability for switching on/off pathways. Along with the naturally occurring bistabilities, a new type of bistability, regulated by the resource competition, occurring as a consequence of limited presence of essential cellular resources and several genes are competing for the resource for its respective expression, is theoretically and experimentally verified in synthetic circuits. This emergent bistability produces a spatio-temporal pattern in diffusible cellular environment. In study of gene expression systems, transient pattern formation is generally ignored; however, considering phenotypic heterogeneity and its importance in phenomena like bacterial persistence, the dynamical patterns seem to be quite important along with the final state. We are interested in the emergent pattern formation by the host-circuit interaction in a diffusible cellular environment, considering different initial conditions to incorporate the effects of various signal cues that prepatterns the system. We report a study of frame-to-frame pattern formation with respect to time, effects of diffusion coefficient on pattern formation by analytical process, and evolution of potential valley landscape that will help us understanding the dynamics of cellular heterogeneity in contexts like persistence, embryogenesis and development."
Poster 14 - Modeling of cellular Involvement in Disease Onset and Progression
Understanding the onset and progression of a disease from the mild to the severe stage is key to finding the best treatment for that. Using computational and mathematical modeling techniques the disease progression could be quantitatively depicted. Such models could include observational data for some disease biomarkers or more direct measures of disease severity in order to characterise the natural development of the disease. A systems biology approach to disease modeling takes into account various biological, pathophysiological, and pharmacological processes to identify transitions between different disease states. Recently, we have developed a couple of mathematical models to understand the onset and disease progression of two common Inflammatory skin diseases Psoriasis and Atopic Dermatitis (AD). We have shown that the underlying mechanism for the onset of Psoriasis and the transition of AD disease from the acute to the chronic stage could be due to a bistable behaviour of the system. In addition, how to use bistable behaviour in developing a new treatment option for the above-mentioned disease has been demonstrated. We are also exploring the molecular mechanisms underlying the transition of another disease, Chronic Myeloid Leukaemia, from chronic to blast crisis state along with the modelling of the transition process.
Poster 15 - Emergent dynamics of gene regulatory network governing Hepatocyte-Cholangiocyte Plasticity during Liver Development and Regeneration
The liver is one of the few organs that has an immense regenerative potential even at adulthood in mammals. The liver tissue is composed of primarily two types of cells: the hepatocytes (forming the bulk of the liver parenchyma) and the cholangiocytes (forming the bulk of the intrahepatic bile ducts). The remarkable regenerative ability of the liver is in part due to the plasticity of hepatocytes and cholangiocytes to transdifferentiate to each other either directly or through intermediate cell states. In this study, we identify a core gene regulatory network (GRN) that underlies both the developmental and the trans-differentiation abilities of the hepatocytes and the cholangiocytes as evidenced by the dynamical properties of the GRN. Using mathematical modelling we uncover the plasticity enabled by the GRN with potential applications in cellular reprogramming of such cell types. Furthermore, we show the spatial organization of the hepatocytes/cholangiocytes in the liver parenchyma can be explained in part by the dynamics of the same GRN. Finally, we supplement all the simulated results with bulk and single-cell gene expression data.
Poster 16 - Detecting circadian oscillations in lineage trajectories with Gaussian Processes
Quantitative inference of the presence of oscillations in time-series datasets is a challenging problem. This is particularly the case for detection of circadian clock rhythms in dividing cells, both at the single cell as well as the population level. In single cells, oscillations can be observed in lineage trajectories when the dividing cells contain reporters for circadian clock proteins. However, they have very low amplitude, are noisy, and often peak-to-peak distances vary with time (non-stationary), influenced by the heterogeneity in cell division times. Population level measurements such as qPCR also exhibit these complex noisy patterns, thus making the oscillation detection problem a complex one. To address these challenges, we developed a non-parametric approach to detecting oscillations using Gaussian Processes (GPs), which is readily applicable to both single cell as well as population datasets after discretization. GPs can model noisy and non-stationary data, and overcome the challenges faced by existing parametric approaches by requiring only the definition of a kernel to describe the 'kind' of functions that might best describe the given data. By choosing kernels that represent prior beliefs of oscillation and non-oscillation, followed by Bayesian model selection to identify the more appropriate kernel, we developed a quantitative method for oscillation detection. We demonstrated that our method consistently outperformed existing methods on synthetic datasets, and finally used it to uncover cell-density dependent emergence of circadian clock oscillations in mouse embryonic stem cells.
Despite recent advances in the development of novel targeted chemotherapies, the prognosis of malignant glioma remains dismal. The chemo-resistance of this tumor is attributed to tumor heterogeneity. To explain this unique chemo- resistance, the concept of cancer stem cells has been evoked. Cancer stem cells, a subpopulation of whole tumor cells, are now regarded as candidate therapeutic targets. Regardless of the types of surface markers that best represent brain cancer stem cells, brain tumorigenic cells similar to normal neural stem cells be regulated or dysregulated by normal signaling pathways. Understanding the normal cellular hierarchy from stem cells, that is, from committed progenitor cells to more differentiated cells, is essential for the identification of cancer cells. Furthermore highly tumorigenic cellular subpopulations in adult primary tumors share some similarities with normal stem cells and progenitor cells within the same lineage The prospective isolation of cancer stem cells provides better targets for the development of new therapies and of new ways of measuring treatment efficacy. In addition, more carefully designed experiments are required on the lineage tracing of neural stem cells to clarify the role played by cancer stem cells in brain tumors.
Poster 18 - Geometry of Turing patterns
During vertebrate limb development, digits emerge as spots, which then elongate into rodlike shapes by recruiting new cells near these spots. Experimental evidence suggests a self-organised mechanism for the emergence of spots. A recent proposal suggests that patterning takes place through a Turing mechanism with a network of Bmp-Sox9-Wnt forming digit-interdigit patterns but the characterisation of the exact molecular mechanism remains unclear. Here, we study the geometry of these three-component Turing networks. The underlying geometry gives the simplest description of the given dynamics with few parameters and thus serves as a phenomenological model which constitutes a principled fit to the dynamics of chosen markers. Furthermore, the geometric model, which happens to be potential, gives the Waddington landscape for digit patterning. The final pattern corresponds to minima of the potential and transitions between them takes place through saddles. Turing patterning is noise-driven and framing it as a potential allows us to study the nonlinear robustness of the final pattern. We study the volume of parameter space in the original model which gives deep potential minima for the final pattern in the geometric model.
Poster 19 - Origin, robustness and interoperability of heterogeneous atypical switches in bistable network motifs with dual signalling
A number of cell fate decision making pathways involve positive feedback loop that generate bistable expression of genes leading to all-or-none cellular response against an external signal. Although positive feedback loops, originated either from mutual activation or mutual inhibition, under a single input signal is widely studied and well understood, however the fate of such motifs under dual signalling acting on both the genes are unknown. Using our in-house pseudo-potential energy based high-throughput bifurcation analysis method, we uncovered that these motifs generate various types of fused bistable switches depending on the synergistic or antagonistic nature of the signalling. A variety of previously unknown heterogeneous emergent bistable responses are possible due to the orientation of the two fusing bistable switches. Automated bifurcation analysis with random parameter searching and network perturbation analysis revealed the design principles of these emergent switches. We determined the phase diagrams of atypical bistable switches that uncover the conditions of interchangeability from one emergent behaviour to another. Our work opens a new avenue of exploring an unknown class of bistable switches which can have great potential in synthetic biology and also in stem cell differentiation.
Correlations in gene expression between multiple cells can be a valuable tool in understanding the dynamics of complex gene regulatory networks. However, there are often major challenges associated with analyzing cell-cell correlations from high-dimensional single-cell RNA sequencing data due to noise, entangled correlations, etc. In this poster, we primarily aim to better understand and interpret such data by simulating an artificial gene network. A cell-cell covariance matrix (C) reflects correlations between the vectors representing the gene expression profiles for each cell. From the analytical framework of C for an N-dimensional Gaussian process, we study its dependence on cell division time, intrinsic noise, and bifurcation parameters. Our simulations show a loss of correlations as one progresses through the cell lineage and power-law-like behavior from the eigenspectra. One of our objectives is to identify a subset of genes or combinations of genes that can control correlations in the system. In our simulations, since we work with a finite number of genes, one obtains continuous eigenspectra. Eventually, we would like to investigate the relationship between such eigenspectra and the 'true’ eigenspectra of the system, which would have degenerate eigenvalues.
Poster 21 - Smed-ETS-1 is essential for the function of subset of cathepsin+ cell population and regulates epidermal lineage landscape via basement membrane remodelling
Vinay Kumar Dubey
Extracellular matrix (ECM) is an important component of stem cell niche. Remodelling of ECM, mediated by ECM regulators such as MMPs plays a vital role in stem cell function. However, the mechanisms that modulate the function of ECM regulators in the stem cell niche is understudied. Here, we explored the role of the transcription factor (TF), ETS-1 in cathepsin+ cell population (a recently found population) regulating the expression of the ECM regulator, mt-mmpA, thereby modulating basement membrane (BM) thickness. In planarians, the basement membrane around the gut/inner parenchyma is thought to act as a niche for pluripotent stem cells. It has been shown that the early epidermal progenitors migrate outward from this region and progressively differentiate to maintain the terminal epidermis. Our data shows thickening of BM in the absence of ets-1 results in defective migration of stem cells progeny. Furthermore, the absence of ets-1 led to a defective epidermal progenitor landscape, in spite of its lack of expression in those cell types. Together, our results demonstrate the active role of ECM remodelling in regulating migration and differentiation during homeostasis and regeneration in planaria.
An important transition in the origin of life was the first emergence of self-reproducing entities capable of Darwinian evolution, exhibiting differential reproduction, phenotypic variation, and inheritance of phenotypic traits. The simplest system we can imagine to have these properties would consist of a compartmentalized autocatalytic reaction system that exhibits two growth states with different chemical compositions. Here we ask, how can one test whether such a system will exhibit inheritance of the compositional states upon growth and division of the compartment? We study deterministic dynamical models of a general class of autocatalytic chemical systems that exhibit two exponential growth states and show that subjecting such a system to a serial dilution protocol mimics the effects of general growth and division cycles. Next, we show that the inheritance of compositional information only occurs when the time interval between dilutions is below a critical threshold that depends on the efficiency of the catalytic reactions. Further, we show that these thresholds provide rigorous bounds on the properties of the growth and division cycles, enabling the inheritance of the chemical compositional state. Our result suggests that a serial dilution experiment, which is much easier to set up in a laboratory than a growing and dividing compartment, can be used to test whether a given autocatalytic chemical system can exhibit heredity. Lastly, we apply our results to a realistic autocatalytic system based on the Azoarcus ribozyme and suggest a protocol to test whether this system can exhibit heredity.