scholarly journals AnIn-SilicoMammalian Whole-Cell Model Reveals the Influence of Spatial Organization on RNA Splicing Efficiency

2018 ◽  
Author(s):  
Zhaleh Ghaemia ◽  
Joseph R. Peterson ◽  
Martin Gruebele ◽  
Zaida Luthey-Schulten
Keyword(s):  
Experimental Data ◽  
Hela Cell ◽  
Rna Splicing ◽  
Spatial Organization ◽  
Cell Model ◽  
Stochastic Simulations ◽  
Eukaryotic Cells ◽  
Nuclear Pore ◽  
Whole Cell ◽  
Membrane Bound

Spatial organization is a characteristic of eukaryotic cells, achieved by utilizing both membrane-bound and non-bound organelles. We model the effects of this organization and of organelle heterogeneity on RNA splicing (the process of making translationally-ready messenger RNA) and on splicing particles (the building blocks of splicing machinery) in mammalian cells. We constructed a spatially-resolved whole HeLa cell model from various experimental data and developed reaction networks to describe the RNA splicing processes. We incorporated these networks into our whole-cell model and performed stochastic simulations for up to 15 minutes of biological time. We find that the number of nuclear pore complexes affects the number of assembled splicing particles; that a slight increase of splicing particle localization in nuclear speckles (non-membrane-bound or- ganelles) leads to disproportionate enhancement in the mRNA splicing and reduction in the transcript noise; and that compartmentalization is critical for a correctly-assembled particle yield. Our model also predicts that the distance between genes and speckles has a considerable effect on effective mRNA production rate, further emphasizing the importance of genome organization around speckles. The HeLa cell model, including organelles and subcompartments, provides an adaptable foundation to study other cellular processes which are strongly modulated by spatio-temporal heterogeneity.Significance StatementThe spliceosome is one of the most complex cellular machineries that cuts and splices the RNA code in eukaryotic cells. It dynamically assembles, disassembles, and its components are formed in multiple compartments. The efficiency of splicing process depends on localization of its components in nuclear membrane-less organelles. Therefore, a computational model of spliceosomal function must contain a spatial model of the entire cell. However, building such a model is a challenging task, mainly due to the lack of homogeneous experimental data and a suitable computational framework. Here, we overcome these challenges and present a whole HeLa cell model, with nuclear, subnuclear, and extensive cytoplasmic structures. The three-dimensional model is supplemented by reaction-diffusion processes to shed light on the function of the spliceosome.

scholarly journals Whole-cell scale dynamic organization of lysosomes revealed by spatial statistical analysis

2017 ◽  
Author(s):  
Qinle Ba ◽  
Guruprasad Raghavan ◽  
Kirill Kiselyov ◽  
Ge Yang
Keyword(s):  
Collective Behavior ◽  
Spatial Organization ◽  
Cultured Cells ◽  
Single Cells ◽  
Eukaryotic Cells ◽  
Intracellular Space ◽  
Whole Cell ◽  
Spatial Statistical Analysis ◽  
Membrane Bound ◽  
Coordinated Effects

In eukaryotic cells, lysosomes are distributed in the cytoplasm as individual membrane-bound compartments to degrade macromolecules and to control cellular metabolism. A fundamental yet unanswered question is whether and, if so, how individual lysosomes are spatially organized so that their functions can be coordinated and integrated to meet changing needs of cells. To address this question, we analyze their collective behavior in cultured cells using spatial statistical techniques. We find that in single cells, lysosomes maintain nonrandom, stable, yet distinct spatial distributions, which are mediated by the coordinated effects of the cytoskeleton and lysosomal biogenesis on different lysosomal subpopulations. Furthermore, we find that throughout the intracellular space, lysosomes form dynamic clusters that substantially increase their interactions with endosomes. Together, our findings reveal the spatial organization of lysosomes at the whole-cell scale and provide new insights into how organelle interactions are mediated and regulated over the entire intracellular space.

scholarly journals An in-silico human cell model reveals the influence of spatial organization on RNA splicing

2020 ◽  
Vol 16 (3) ◽  
pp. e1007717 ◽  
Author(s):  
Zhaleh Ghaemi ◽  
Joseph R. Peterson ◽  
Martin Gruebele ◽  
Zaida Luthey-Schulten
Keyword(s):  
Human Cell ◽  
In Silico ◽  
Rna Splicing ◽  
Spatial Organization ◽  
Cell Model

scholarly journals Mitochondrial Protein Network: From Biogenesis to Bioenergetics in Health and Disease

2020 ◽  
Vol 22 (1) ◽  
pp. 1
Author(s):  
Alessandra Ferramosca
Keyword(s):  
Crucial Role ◽  
Mitochondrial Protein ◽  
Protein Network ◽  
Eukaryotic Cells ◽  
Double Membrane ◽  
Health And Disease ◽  
Membrane Bound

Mitochondria are double membrane-bound organelles which are essential for the viability of eukaryotic cells, because they play a crucial role in bioenergetics, metabolism and signaling [...]

Accurate Modeling of Complex Antitoxin Effect of Quercetin Based on Neural Networks

2019 ◽  
Vol 29 (01) ◽  
pp. 1950013 ◽  
Author(s):  
Changju Yang ◽  
Entaz Bahar ◽  
Hyonok Yoon ◽  
Hyongsuk Kim
Keyword(s):  
Experimental Data ◽  
Neural Networks ◽  
Artificial Neural Networks ◽  
Secondary Metabolites ◽  
Hela Cell ◽  
Protective Effect ◽  
Nonlinear Modeling ◽  
Inflammatory Activity ◽  
High Complexity ◽  
Anti Oxidant

A nonlinear modeling of the protective effect of Quercetin (QCT) against various Mycotoxins (MTXs) has a high complexity and is conducted using artificial neural networks (ANNs). QCT is known to possess strong anti-oxidant, anti-inflammatory activity that can prevent many diseases. MTXs are highly toxic secondary metabolites that are capable of causing disease and death in humans and animals. The protective model of QCT against various MTXs (Citrinin, Patulin and Zearalenol) on HeLa cell is built accurately via learning of sparsely measured experimental data by the ANNs. It has shown that the neuro-model can predict the nonlinear protective effect of QCT against MTX-induced cytotoxicity for the measurement of percentage of inhibition of MTXs.

scholarly journals Conserved Spatial Organization of FG Domains in the Nuclear Pore Complex

2013 ◽  
Vol 104 (1) ◽  
pp. 37-50 ◽  
Author(s):  
Claire E. Atkinson ◽  
Alexa L. Mattheyses ◽  
Martin Kampmann ◽  
Sanford M. Simon
Keyword(s):  
Nuclear Pore Complex ◽  
Spatial Organization ◽  
Nuclear Pore

scholarly journals Simple biophysics underpins collective conformations of the intrinsically disordered proteins of the Nuclear Pore Complex

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Andrei Vovk ◽  
Chad Gu ◽  
Michael G Opferman ◽  
Larisa E Kapinos ◽  
Roderick YH Lim ◽  
...  
Keyword(s):  
Spatial Organization ◽  
Intrinsically Disordered Proteins ◽  
Nucleocytoplasmic Transport ◽  
Transport Proteins ◽  
Disordered Proteins ◽  
Biophysical Model ◽  
Nuclear Pore ◽  
Intrinsically Disordered

Nuclear Pore Complexes (NPCs) are key cellular transporter that control nucleocytoplasmic transport in eukaryotic cells, but its transport mechanism is still not understood. The centerpiece of NPC transport is the assembly of intrinsically disordered polypeptides, known as FG nucleoporins, lining its passageway. Their conformations and collective dynamics during transport are difficult to assess in vivo. In vitro investigations provide partially conflicting results, lending support to different models of transport, which invoke various conformational transitions of the FG nucleoporins induced by the cargo-carrying transport proteins. We show that the spatial organization of FG nucleoporin assemblies with the transport proteins can be understood within a first principles biophysical model with a minimal number of key physical variables, such as the average protein interaction strengths and spatial densities. These results address some of the outstanding controversies and suggest how molecularly divergent NPCs in different species can perform essentially the same function.

scholarly journals Phosphorylation-dependent mitotic SUMOylation drives nuclear envelope–chromatin interactions

2021 ◽  
Vol 220 (12) ◽  
Author(s):  
Christopher Ptak ◽  
Natasha O. Saik ◽  
Ashwini Premashankar ◽  
Diego L. Lapetina ◽  
John D. Aitchison ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nuclear Envelope ◽  
Spatial Organization ◽  
G1 Phase ◽  
Nuclear Pore ◽  
Nuclear Pore Complexes ◽  
Chromatin Binding ◽  
Chromatin Interactions ◽  
Sumo Ligase ◽  
Pore Complexes

In eukaryotes, chromatin binding to the inner nuclear membrane (INM) and nuclear pore complexes (NPCs) contributes to spatial organization of the genome and epigenetic programs important for gene expression. In mitosis, chromatin–nuclear envelope (NE) interactions are lost and then formed again as sister chromosomes segregate to postmitotic nuclei. Investigating these processes in S. cerevisiae, we identified temporally and spatially controlled phosphorylation-dependent SUMOylation events that positively regulate postmetaphase chromatin association with the NE. Our work establishes a phosphorylation-mediated targeting mechanism of the SUMO ligase Siz2 to the INM during mitosis, where Siz2 binds to and SUMOylates the VAP protein Scs2. The recruitment of Siz2 through Scs2 is further responsible for a wave of SUMOylation along the INM that supports the assembly and anchorage of subtelomeric chromatin at the INM and localization of an active gene (INO1) to NPCs during the later stages of mitosis and into G1-phase.

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