scholarly journals Modular HUWE1 architecture serves as hub for degradation of cell-fate decision factors

2020 ◽  
Author(s):  
Moritz Hunkeler ◽  
Cyrus Y. Jin ◽  
Michelle W. Ma ◽  
Daan Overwijn ◽  
Julie K. Monda ◽  
...  
Keyword(s):  
Cell Fate ◽  
Three Dimensional ◽  
Cellular Stress Response ◽  
Cell Fate Decision ◽  
Decision Factors ◽  
Link Functions ◽  
Wide Range ◽  
Essential Enzyme ◽  
Fate Decision ◽  
Molecular Picture

SummaryHECT ubiquitin ligases play essential roles in metazoan development and physiology. The HECT ligase HUWE1 is central to the cellular stress response by mediating degradation of key death or survival factors including Mcl1, p53, DDIT4, and Myc. As a step toward understanding regulation of HUWE1 engagement with its diverse substrates, we present here the cryo-EM structure of HUWE1, offering a first complete molecular picture of a HECT ubiquitin ligase. The ~4400 amino acid residue polypeptide forms an alpha solenoid-shaped assembly with a central pore decorated with protein interaction modules. This modularity enables HUWE1 to target a wide range of substrates for destruction. The locations of human mutations associated with severe neurodevelopmental disorders link functions of this essential enzyme with its three-dimensional organization.

scholarly journals A single-cell resolved cell-cell communication model explains lineage commitment in hematopoiesis

Development ◽  
2021 ◽  
Vol 148 (24) ◽  
Author(s):  
Megan K. Rommelfanger ◽  
Adam L. MacLean
Keyword(s):  
Cell Fate ◽  
Cell Communication ◽  
Communication Model ◽  
Cell Fate Decision ◽  
Cell Coupling ◽  
Environmental Signals ◽  
Cell Fate Decisions ◽  
Wide Range ◽  
Fate Decision ◽  
Cell Cell

ABSTRACT Cells do not make fate decisions independently. Arguably, every cell-fate decision occurs in response to environmental signals. In many cases, cell-cell communication alters the dynamics of the internal gene regulatory network of a cell to initiate cell-fate transitions, yet models rarely take this into account. Here, we have developed a multiscale perspective to study the granulocyte-monocyte versus megakaryocyte-erythrocyte fate decisions. This transition is dictated by the GATA1-PU.1 network: a classical example of a bistable cell-fate system. We show that, for a wide range of cell communication topologies, even subtle changes in signaling can have pronounced effects on cell-fate decisions. We go on to show how cell-cell coupling through signaling can spontaneously break the symmetry of a homogenous cell population. Noise, both intrinsic and extrinsic, shapes the decision landscape profoundly, and affects the transcriptional dynamics underlying this important hematopoietic cell-fate decision-making system. This article has an associated ‘The people behind the papers’ interview.

scholarly journals A single-cell resolved cell-cell communication model explains lineage commitment in hematopoiesis

2021 ◽  
Author(s):  
Megan K. Franke ◽  
Adam L. MacLean
Keyword(s):  
Decision Making ◽  
Cell Fate ◽  
Single Cells ◽  
System Modeling ◽  
Cell Communication ◽  
Internal Dynamic ◽  
Cell Fate Decision ◽  
Wide Range ◽  
Fate Decision ◽  
Cell Cell

The role of cell-cell communication in cell fate decision-making has not been well-characterized through a dynamical systems perspective. To do so, here we develop multiscale models that couple cell-cell communication with cell-internal gene regulatory network dynamics. This allows us to study the influence of external signaling on cell fate decision-making at the resolution of single cells. We study the granulocyte-monocyte vs. megakaryocyte-erythrocyte fate decision, dictated by the GATA1-PU.1 network, as an exemplary bistable cell fate system, modeling the cell-internal dynamic with ordinary differential equations and the cell-cell communication via a Poisson process. We show that, for a wide range of cell communication topologies, subtle changes in signaling can lead to dramatic changes in cell fate. We find that cell-cell coupling can explain how populations of heterogeneous cell types can arise. Analysis of intrinsic and extrinsic cell-cell communication noise demonstrates that noise alone can alter the cell fate decision-making boundaries. These results illustrate how external signals alter transcriptional dynamics, and provide insight into hematopoietic cell fate decision-making.

scholarly journals insideOutside: an accessible algorithm for classifying interior and exterior points, with applications in embryology

2021 ◽  
Author(s):  
Stanley E. Strawbridge ◽  
Agata Kurowski ◽  
Elena Corujo-Simon ◽  
Alexander G. Fletcher ◽  
Jennifer Nichols
Keyword(s):  
Cell Fate ◽  
Spatial Information ◽  
Inner Cell Mass ◽  
Cell Mass ◽  
Three Dimensional ◽  
Mathematical Framework ◽  
Cell Fate Decision ◽  
Machine Learning Approach ◽  
Quantitative Immunofluorescence ◽  
Fate Decision

AbstractA crucial aspect of embryology is relating the position of individual cells to the broader geometry of the embryo. A classic example can be seen in the first cell-fate decision of the mouse embryo, where interior cells become inner cell mass and exterior cells become trophectoderm. Advances in image acquisition and processing technology used by quantitative immunofluorescence have resulted in the production of embryo images with increasingly rich spatial information that demand accessible analytical methods. Here, we describe a simple mathematical framework and an unsupervised machine learning approach for classifying interior and exterior points of a three-dimensional point-cloud. We benchmark our method to demonstrate that it yields higher classification rates for pre-implantation mouse embryos and greater accuracy when challenged with local surface concavities. This method should prove useful to experimentalists within and beyond embryology, with broader applications in the biological and life sciences.

scholarly journals Cell fate clusters in ICM organoids arise from cell fate heredity and division: a modelling approach

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Tim Liebisch ◽  
Armin Drusko ◽  
Biena Mathew ◽  
Ernst H. K. Stelzer ◽  
Sabine C. Fischer ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Division ◽  
Cell Fate ◽  
Inner Cell Mass ◽  
Cell Mass ◽  
Cell Lineage ◽  
Cell Fate Decision ◽  
Cell Fate Decisions ◽  
Chemical Signalling ◽  
Fate Decision

AbstractDuring the mammalian preimplantation phase, cells undergo two subsequent cell fate decisions. During the first decision, the trophectoderm and the inner cell mass are formed. Subsequently, the inner cell mass segregates into the epiblast and the primitive endoderm. Inner cell mass organoids represent an experimental model system, mimicking the second cell fate decision. It has been shown that cells of the same fate tend to cluster stronger than expected for random cell fate decisions. Three major processes are hypothesised to contribute to the cell fate arrangements: (1) chemical signalling; (2) cell sorting; and (3) cell proliferation. In order to quantify the influence of cell proliferation on the observed cell lineage type clustering, we developed an agent-based model accounting for mechanical cell–cell interaction, i.e. adhesion and repulsion, cell division, stochastic cell fate decision and cell fate heredity. The model supports the hypothesis that initial cell fate acquisition is a stochastically driven process, taking place in the early development of inner cell mass organoids. Further, we show that the observed neighbourhood structures can emerge solely due to cell fate heredity during cell division.

scholarly journals Inflammation, epigenetics, and metabolism converge to cell senescence and ageing: the regulation and intervention

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Xudong Zhu ◽  
Zhiyang Chen ◽  
Weiyan Shen ◽  
Gang Huang ◽  
John M. Sedivy ◽  
...  
Keyword(s):  
Cell Fate ◽  
Cellular Response ◽  
State Of The Art ◽  
Cell Senescence ◽  
Therapeutic Interventions ◽  
Cell Fate Decision ◽  
The Past ◽  
Fate Decision ◽  
The Individual ◽  
Remarkable Progress

AbstractRemarkable progress in ageing research has been achieved over the past decades. General perceptions and experimental evidence pinpoint that the decline of physical function often initiates by cell senescence and organ ageing. Epigenetic dynamics and immunometabolic reprogramming link to the alterations of cellular response to intrinsic and extrinsic stimuli, representing current hotspots as they not only (re-)shape the individual cell identity, but also involve in cell fate decision. This review focuses on the present findings and emerging concepts in epigenetic, inflammatory, and metabolic regulations and the consequences of the ageing process. Potential therapeutic interventions targeting cell senescence and regulatory mechanisms, using state-of-the-art techniques are also discussed.

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