scholarly journals Engineering of a synthetic quadrastable gene network to approach Waddington landscape and cell fate determination

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Fuqing Wu ◽  
Ri-Qi Su ◽  
Ying-Cheng Lai ◽  
Xiao Wang
Keyword(s):  
Cell Fate ◽  
Regulatory Networks ◽  
Cell Fate Determination ◽  
Final States ◽  
Cell Fates ◽  
Fate Determination ◽  
Cellular Decision Making ◽  
Distinct Cell ◽  
Model Predictions ◽  
Gene Regulatory

The process of cell fate determination has been depicted intuitively as cells travelling and resting on a rugged landscape, which has been probed by various theoretical studies. However, few studies have experimentally demonstrated how underlying gene regulatory networks shape the landscape and hence orchestrate cellular decision-making in the presence of both signal and noise. Here we tested different topologies and verified a synthetic gene circuit with mutual inhibition and auto-activations to be quadrastable, which enables direct study of quadruple cell fate determination on an engineered landscape. We show that cells indeed gravitate towards local minima and signal inductions dictate cell fates through modulating the shape of the multistable landscape. Experiments, guided by model predictions, reveal that sequential inductions generate distinct cell fates by changing landscape in sequence and hence navigating cells to different final states. This work provides a synthetic biology framework to approach cell fate determination and suggests a landscape-based explanation of fixed induction sequences for targeted differentiation.

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 ANANSE: An enhancer network-based computational approach for predicting key transcription factors in cell fate determination

2020 ◽  
Author(s):  
Quan Xu ◽  
Georgios Georgiou ◽  
Gert Jan C. Veenstra ◽  
Huiqing Zhou ◽  
Simon J. van Heeringen
Keyword(s):  
Transcription Factors ◽  
Cell Fate ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Cell Types ◽  
Cell Fate Determination ◽  
Cell Type ◽  
Fate Determination ◽  
Cell Type Specific ◽  
Gene Regulatory

AbstractProper cell fate determination is largely orchestrated by complex gene regulatory networks centered around transcription factors. However, experimental elucidation of key transcription factors that drive cellular identity is currently often intractable. Here, we present ANANSE (ANalysis Algorithm for Networks Specified by Enhancers), a network-based method that exploits enhancer-encoded regulatory information to identify the key transcription factors in cell fate determination. As cell type-specific transcription factors predominantly bind to enhancers, we use regulatory networks based on enhancer properties to prioritize transcription factors. First, we predict genome-wide binding profiles of transcription factors in various cell types using enhancer activity and transcription factor binding motifs. Subsequently, applying these inferred binding profiles, we construct cell type-specific gene regulatory networks, and then predict key transcription factors controlling cell fate conversions using differential gene networks between cell types. This method outperforms existing approaches in correctly predicting major transcription factors previously identified to be sufficient for trans-differentiation. Finally, we apply ANANSE to define an atlas of key transcription factors in 18 normal human tissues. In conclusion, we present a ready-to-implement computational tool for efficient prediction of transcription factors in cell fate determination and to study transcription factor-mediated regulatory mechanisms. ANANSE is freely available at https://github.com/vanheeringen-lab/ANANSE.

scholarly journals Transient hysteresis and inherent stochasticity in gene regulatory networks

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
M. Pájaro ◽  
I. Otero-Muras ◽  
C. Vázquez ◽  
A. A. Alonso
Keyword(s):  
Cell Fate ◽  
Gene Regulatory Networks ◽  
Cellular Response ◽  
Regulatory Networks ◽  
Initial Conditions ◽  
Quantitative Description ◽  
Hysteresis Phenomenon ◽  
Cell Fate Determination ◽  
Fate Determination ◽  
Gene Regulatory

Abstract Cell fate determination, the process through which cells commit to differentiated states is commonly mediated by gene regulatory motifs with mutually exclusive expression states. The classical deterministic picture for cell fate determination includes bistability and hysteresis, which enables the persistence of the acquired cellular state after withdrawal of the stimulus, ensuring a robust cellular response. However, stochasticity inherent to gene expression dynamics is not compatible with hysteresis, since the stationary solution of the governing Chemical Master Equation does not depend on the initial conditions. We provide a quantitative description of a transient hysteresis phenomenon reconciling experimental evidence of hysteretic behaviour in gene regulatory networks with inherent stochasticity: under sufficiently slow dynamics hysteresis is transient. We quantify this with an estimate of the convergence rate to the equilibrium and introduce a natural landscape capturing system’s evolution that, unlike traditional cell fate potential landscapes, is compatible with coexistence at the microscopic level.

scholarly journals Role of aggregate size, multistability and communication in determining cell fate and patterning in M. xanthus

2019 ◽  
Author(s):  
Juan A. Arias Del Angel ◽  
Natsuko Rivera-Yoshida ◽  
Ana E. Escalante ◽  
León Patricio Martínez-Castilla ◽  
Mariana Benítez
Keyword(s):  
Cell Fate ◽  
Regulatory Networks ◽  
Cell Communication ◽  
Aggregate Size ◽  
Multiscale Model ◽  
Cellular Adhesion ◽  
Minimum Size ◽  
Cell Fate Determination ◽  
Fate Determination ◽  
Major Transitions

1.AbstractThe emergence of multicellular organisms that exhibit cell differentiation and stereotypic spatial arrangements has been recognized as one of the major transitions in evolution. Myxobacteria have emerged as a useful study model to investigate multicellular evolution and development. Here, we propose a multiscale model that considers cellular adhesion and movement, molecular regulatory networks (MRNs), and cell-to-cell communication to study the emergence of cell fate determination and spatial patterning of Myxococcus xanthus fruiting bodies. The model provides a dynamic accounting of the roles of MRN multistability, intercellular communication and conglomerate size in determining cell fate and patterning during M. xanthus development. It also suggests that for cell fate determination and patterning to occur, the cell aggregate must surpass a minimum size. The model also allows us to contrast alternative scenarios for the C-signal mechanism and provides stronger support for an indirect effect (as a diffusible molecule) than a direct one (as a membrane protein).

Signaling by the TGF-beta homolog decapentaplegic functions reiteratively within the network of genes controlling retinal cell fate determination in Drosophila

Development ◽  
1999 ◽  
Vol 126 (5) ◽  
pp. 935-943 ◽  
Author(s):  
R. Chen ◽  
G. Halder ◽  
Z. Zhang ◽  
G. Mardon
Keyword(s):  
Cell Fate ◽  
Retinal Cell ◽  
Cell Fate Determination ◽  
Tgf Beta ◽  
Eyes Absent ◽  
Fate Determination ◽  
Sine Oculis ◽  
Retinal Determination ◽  
Interactive Network ◽  
Distinct Cell

Retinal cell fate determination in Drosophila is controlled by an interactive network of genes, including eyeless, eyes absent, sine oculis and dachshund. We have investigated the role of the TGF-beta homolog decapentaplegic in this pathway. We demonstrate that, during eye development, while eyeless transcription does not depend on decapentaplegic activity, the expression of eyes absent, sine oculis and dachshund are greatly reduced in a decapentaplegic mutant background. We also show that decapentaplegic signaling acts synergistically with and at multiple levels of the retinal determination network to induce eyes absent, sine oculis and dachshund expression and ectopic eye formation. These results suggest a mechanism by which a general patterning signal such as Decapentaplegic cooperates reiteratively with tissue-specific factors to determine distinct cell fates during development.

scholarly journals Calpain DEK1 acts as a developmental switch gatekeeping cell fate transitions

2021 ◽  
Author(s):  
Viktor Demko ◽  
Tatiana Belova ◽  
Maxim Messerer ◽  
Torgeir R. Hvidsten ◽  
Pierre-François Perroud ◽  
...  
Keyword(s):  
Cell Fate ◽  
Regulatory Networks ◽  
Data Science ◽  
Control Cell ◽  
Cysteine Proteases ◽  
Regulatory Role ◽  
Phenotypic Traits ◽  
Cell Fates ◽  
Gene Regulatory ◽  
Developmental Switch

SummaryCalpains are cysteine proteases that control cell fate transitions. Although calpains are viewed as modulatory proteases displaying severe, pleiotropic phenotypes in eukaryotes, human calpain targets are also directed to the N-end rule degradatory pathway. Several of these destabilized targets are transcription factors, hinting at a gene regulatory role. Here, we analyze the gene regulatory networks of Physcomitrium patens and characterize the regulons that are deregulated in DEK1 calpain mutants. Predicted cleavage patterns of regulatory hierarchies in the five DEK1-controlled subnetworks are consistent with the gene’s pleiotropy and the regulatory role in cell fate transitions targeting a broad spectrum of functions. Network structure suggests DEK1-gated sequential transition between cell fates in 2D to 3D development. We anticipate that both our method combining phenotyping, transcriptomics and data science to dissect phenotypic traits and our model explaining the calpain’s role as a switch gatekeeping cell fate transitions will inform biology beyond plant development.

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