scholarly journals Novel generic models for differentiating stem cells reveal oscillatory mechanisms

2021 ◽  
Vol 18 (183) ◽  
Author(s):  
Saeed Farjami ◽  
Karen Camargo Sosa ◽  
Jonathan H. P. Dawes ◽  
Robert N. Kelsh ◽  
Andrea Rocco
Keyword(s):  
Cell Fate ◽  
Regulatory Networks ◽  
Oscillatory Process ◽  
Oscillatory Regime ◽  
Epigenetic Landscape ◽  
Generic Models ◽  
Gene Regulatory ◽  
Oscillatory Mechanisms ◽  
Gradual Variation ◽  
Standard Framework

Understanding cell fate selection remains a central challenge in developmental biology. We present a class of simple yet biologically motivated mathematical models for cell differentiation that generically generate oscillations and hence suggest alternatives to the standard framework based on Waddington’s epigenetic landscape. The models allow us to suggest two generic dynamical scenarios that describe the differentiation process. In the first scenario, gradual variation of a single control parameter is responsible for both entering and exiting the oscillatory regime. In the second scenario, two control parameters vary: one responsible for entering, and the other for exiting the oscillatory regime. We analyse the standard repressilator and four variants of it and show the dynamical behaviours associated with each scenario. We present a thorough analysis of the associated bifurcations and argue that gene regulatory networks with these repressilator-like characteristics are promising candidates to describe cell fate selection through an oscillatory process.

scholarly journals Novel Generic Models for Differentiating Stem Cells Reveal Oscillatory Mechanisms

2021 ◽  
Author(s):  
Saeed Farjami ◽  
Karen Camargo Sosa ◽  
Jonathan H.P. Dawes ◽  
Robert N. Kelsh ◽  
Andrea Rocco
Keyword(s):  
Cell Fate ◽  
Regulatory Networks ◽  
Oscillatory Process ◽  
Oscillatory Regime ◽  
Epigenetic Landscape ◽  
Generic Models ◽  
Gene Regulatory ◽  
Oscillatory Mechanisms ◽  
Gradual Variation ◽  
Standard Framework

Understanding cell fate selection remains a central challenge in developmental biology. We present a class of simple yet biologically-motivated mathematical models for cell differentiation that generically generate oscillations and hence suggest alternatives to the standard framework based on Waddington's epigenetic landscape. The models allow us to suggest two generic dynamical scenarios that describe the differentiation process. In the first scenario gradual variation of a single control parameter is responsible for both entering and exiting the oscillatory regime. In the second scenario two control parameters vary: one responsible for entering, and the other for exiting the oscillatory regime. We analyse the standard repressilator and four variants of it and show the dynamical behaviours associated with each scenario. We present a thorough analysis of the associated bifurcations and argue that gene regulatory networks with these repressilator-like characteristics are promising candidates to describe cell fate selection through an oscillatory process.

scholarly journals GATA-targeted compounds modulate cardiac subtype cell differentiation in dual reporter stem cell line

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Mika J. Välimäki ◽  
Robert S. Leigh ◽  
Sini M. Kinnunen ◽  
Alexander R. March ◽  
Ana Hernández de Sande ◽  
...  
Keyword(s):  
Gene Expression ◽  
Progenitor Cells ◽  
Cell Fate ◽  
Reporter Gene ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Cell Fate Decisions ◽  
Dual Reporter ◽  
Gene Regulatory ◽  
Reporter Gene Assays

AbstractBackgroundPharmacological modulation of cell fate decisions and developmental gene regulatory networks holds promise for the treatment of heart failure. Compounds that target tissue-specific transcription factors could overcome non-specific effects of small molecules and lead to the regeneration of heart muscle following myocardial infarction. Due to cellular heterogeneity in the heart, the activation of gene programs representing specific atrial and ventricular cardiomyocyte subtypes would be highly desirable. Chemical compounds that modulate atrial and ventricular cell fate could be used to improve subtype-specific differentiation of endogenous or exogenously delivered progenitor cells in order to promote cardiac regeneration.MethodsTranscription factor GATA4-targeted compounds that have previously shown in vivo efficacy in cardiac injury models were tested for stage-specific activation of atrial and ventricular reporter genes in differentiating pluripotent stem cells using a dual reporter assay. Chemically induced gene expression changes were characterized by qRT-PCR, global run-on sequencing (GRO-seq) and immunoblotting, and the network of cooperative proteins of GATA4 and NKX2-5 were further explored by the examination of the GATA4 and NKX2-5 interactome by BioID. Reporter gene assays were conducted to examine combinatorial effects of GATA-targeted compounds and bromodomain and extraterminal domain (BET) inhibition on chamber-specific gene expression.ResultsGATA4-targeted compounds 3i-1000 and 3i-1103 were identified as differential modulators of atrial and ventricular gene expression. More detailed structure-function analysis revealed a distinct subclass of GATA4/NKX2-5 inhibitory compounds with an acetyl lysine-like domain that contributed to ventricular cells (%Myl2-eGFP+). Additionally, BioID analysis indicated broad interaction between GATA4 and BET family of proteins, such as BRD4. This indicated the involvement of epigenetic modulators in the regulation of GATA-dependent transcription. In this line, reporter gene assays with combinatorial treatment of 3i-1000 and the BET bromodomain inhibitor (+)-JQ1 demonstrated the cooperative role of GATA4 and BRD4 in the modulation of chamber-specific cardiac gene expression.ConclusionsCollectively, these results indicate the potential for therapeutic alteration of cell fate decisions and pathological gene regulatory networks by GATA4-targeted compounds modulating chamber-specific transcriptional programs in multipotent cardiac progenitor cells and cardiomyocytes. The compound scaffolds described within this study could be used to develop regenerative strategies for myocardial regeneration.

scholarly journals Distinct and overlapping gene regulatory networks in BMP- and HDAC-controlled cell fate determination in the embryonic forebrain

BMC Genomics ◽  
2012 ◽  
Vol 13 (1) ◽  
pp. 298 ◽  
Author(s):  
Catharina Scholl ◽  
Kathrin Weiβmüller ◽  
Pavlo Holenya ◽  
Maya Shaked-Rabi ◽  
Kerry L Tucker ◽  
...  
Keyword(s):  
Cell Fate ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Cell Fate Determination ◽  
Fate Determination ◽  
Overlapping Gene ◽  
Gene Regulatory

scholarly journals Multiple morphogens and rapid elongation promote segmental patterning during development

2021 ◽  
Vol 17 (6) ◽  
pp. e1009077
Author(s):  
Yuchi Qiu ◽  
Lianna Fung ◽  
Thomas F. Schilling ◽  
Qing Nie
Keyword(s):  
Cell Fate ◽  
Gene Regulatory Networks ◽  
Cell Sorting ◽  
Short Range ◽  
Regulatory Networks ◽  
Neural Plate ◽  
Convergent Extension ◽  
Simultaneous Formation ◽  
Gene Regulatory ◽  
Rapid Elongation

The vertebrate hindbrain is segmented into rhombomeres (r) initially defined by distinct domains of gene expression. Previous studies have shown that noise-induced gene regulation and cell sorting are critical for the sharpening of rhombomere boundaries, which start out rough in the forming neural plate (NP) and sharpen over time. However, the mechanisms controlling simultaneous formation of multiple rhombomeres and accuracy in their sizes are unclear. We have developed a stochastic multiscale cell-based model that explicitly incorporates dynamic morphogenetic changes (i.e. convergent-extension of the NP), multiple morphogens, and gene regulatory networks to investigate the formation of rhombomeres and their corresponding boundaries in the zebrafish hindbrain. During pattern initiation, the short-range signal, fibroblast growth factor (FGF), works together with the longer-range morphogen, retinoic acid (RA), to specify all of these boundaries and maintain accurately sized segments with sharp boundaries. At later stages of patterning, we show a nonlinear change in the shape of rhombomeres with rapid left-right narrowing of the NP followed by slower dynamics. Rapid initial convergence improves boundary sharpness and segment size by regulating cell sorting and cell fate both independently and coordinately. Overall, multiple morphogens and tissue dynamics synergize to regulate the sizes and boundaries of multiple segments during development.

Dissecting Organismal Morphogenesis by Bridging Genetics and Biophysics

2021 ◽  
Vol 55 (1) ◽  
Author(s):  
Nikhil Mishra ◽  
Carl-Philipp Heisenberg
Keyword(s):  
Cell Fate ◽  
Regulatory Networks ◽  
Annual Review ◽  
Publication Date ◽  
Technological Advances ◽  
Complex Shapes ◽  
Gene Regulatory ◽  
And Mathematics ◽  
Multicellular Organisms ◽  
Shape Changes

Multicellular organisms develop complex shapes from much simpler, single-celled zygotes through a process commonly called morphogenesis. Morphogenesis involves an interplay between several factors, ranging from the gene regulatory networks determining cell fate and differentiation to the mechanical processes underlying cell and tissue shape changes. Thus, the study of morphogenesis has historically been based on multidisciplinary approaches at the interface of biology with physics and mathematics. Recent technological advances have further improved our ability to study morphogenesis by bridging the gap between the genetic and biophysical factors through the development of new tools for visualizing, analyzing, and perturbing these factors and their biochemical intermediaries. Here, we review how a combination of genetic, microscopic, biophysical, and biochemical approaches has aided our attempts to understand morphogenesis and discuss potential approaches that may be beneficial to such an inquiry in the future. Expected final online publication date for the Annual Review of Genetics, Volume 55 is November 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Modeling gene-regulatory networks to describe cell fate transitions and predict master regulators

2018 ◽  
Vol 4 (1) ◽  
Author(s):  
Pierre-Etienne Cholley ◽  
Julien Moehlin ◽  
Alexia Rohmer ◽  
Vincent Zilliox ◽  
Samuel Nicaise ◽  
...  
Keyword(s):  
Cell Fate ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Master Regulators ◽  
Gene Regulatory

COMPLEXITY OF THE SEARCH SPACE IN A MODEL OF ARTIFICIAL EVOLUTION OF GENE REGULATORY NETWORKS CONTROLLING 3D MULTICELLULAR MORPHOGENESIS

2009 ◽  
Vol 12 (03) ◽  
pp. 347-369 ◽  
Author(s):  
MICHAŁ JOACHIMCZAK ◽  
BORYS WRÓBEL
Keyword(s):  
Cell Fate ◽  
Evolutionary Biology ◽  
Regulatory Networks ◽  
Dimensional Space ◽  
Evolutionary Process ◽  
Search Space ◽  
Evolutionary Search ◽  
Genetic Operators ◽  
Genetic Elements ◽  
Gene Regulatory

The question of what properties of biological systems allow for efficient evolutionary search in complex fitness landscapes (evolvability) is one of the central interests both for the research in the field of evolutionary biology and artificial life. Here, we attempt to address this issue by using a model of 3D multicellular development in which cell fate is determined by differential gene expression in each cell. In our model, cells can vary in size and can move freely in 3D space, affected by forces of adhesion and repulsion. The development relies on an indirect mapping between the genotype and the morphology (the phenotype). Cell differentiation is allowed by positional information provided by diffusible factors. The state of the gene regulatory network (GRN) coded by the genome determines the cell fate (such as division, death, growth). The genetic elements in our systems define points in N-dimensional space. The connectivity in the GRN is determined by the proximity of these points; one can imagine the evolutionary process as their movement in space. Changing the number of dimensions of this space allows to ask directly the questions about the effect of the complexity of the search space on the efficiency of the evolutionary search. Higher dimensionality results in a larger search space, but in our model this search space can still be explored thanks to the action of genetic operators that allow for duplications of genetic elements, a mutational mechanism that allows for regulatory innovations in the network.

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