scholarly journals Theory of active chromatin remodeling

2019 ◽  
Author(s):  
Zhongling Jiang ◽  
Bin Zhang
Keyword(s):  
Chromatin Remodeling ◽  
Computational Models ◽  
Energy Landscape ◽  
Nucleosome Positioning ◽  
Active Chromatin ◽  
Intrinsic Signals ◽  
Biologically Relevant ◽  
The Impact ◽  
Prediction In Silico

Nucleosome positioning controls the accessible regions of chromatin and plays essential roles in DNA-templated processes. ATP driven remodeling enzymes are known to be crucial for its establishment in vivo, but their non-equilibrium nature has hindered the development of a unified theoretical framework for nucleosome positioning. Using a perturbation theory, we show that the effect of these enzymes can be well approximated by effective equilibrium models with rescaled temperatures and interactions. Numerical simulations support the accuracy of the theory in predicting both kinetic and steady-state quantities, including the effective temperature and the radial distribution function, in biologically relevant regimes. The energy landscape view emerging from our study provides an intuitive understanding for the impact of remodeling enzymes in either reinforcing or overwriting intrinsic signals for nucleosome positioning, and may help improve the accuracy of computational models for its prediction in silico.

scholarly journals PalaCell2D: A framework for detailed tissue morphogenesis

2021 ◽  
Author(s):  
Raphaël Conradin ◽  
Christophe Coreixas ◽  
Jonas Latt ◽  
Bastien Chopard
Keyword(s):  
Internal Pressure ◽  
Tissue Growth ◽  
Cellular Mechanisms ◽  
Simple Description ◽  
Biologically Relevant ◽  
In Vivo Experiments ◽  
Cell Shapes ◽  
And Migration ◽  
The Impact

AbstractIn silico, cell based approaches for modeling biological morphogenesis are used to test and validate our understanding of the biological and mechanical process that are at work during the growth and the organization of multi-cell tissues. As compared to in vivo experiments, computer based frameworks dedicated to tissue modeling allow us to easily test different hypotheses, and to quantify the impact of various biophysically relevant parameters.Here, we propose a formalism based on a detailed, yet simple, description of cells that accounts for intra-, inter- and extra-cellular mechanisms. More precisely, the cell growth and division is described through the space and time evolution of the membrane vertices. These vertices follow a Newtonian dynamics, meaning that their evolution is controlled by different types of forces: a membrane force (spring and bending), an adherence force (inter-cellular spring), external and internal pressure forces. Different evolution laws can be applied on the internal pressure, depending on the intra-cellular mechanism of interest. In addition to the cells dynamics, our formalism further relies on a lattice Boltzmann method, using the Palabos library, to simulate the diffusion of chemical signals. The latter aims at driving the growth and migration of a tissue by simply changing the state of the cells.All of this leads to an accurate description of the growth and division of cells, with realistic cell shapes and where membranes can have different properties. While this work is mainly of methodological nature, we also propose to validate our framework through simple, yet biologically relevant benchmark tests at both single-cell and full tissue scales. This includes free and chemically controlled cell tissue growth in an unbounded domain. The ability of our framework to simulate cell migration, cell compression and morphogenesis under external constraints is also investigated in a qualitative manner.

scholarly journals Erythrocytes: Oxygen Sensors and Modulators of Vascular Tone

Physiology ◽  
2009 ◽  
Vol 24 (2) ◽  
pp. 107-116 ◽  
Author(s):  
Mary L. Ellsworth ◽  
Christopher G. Ellis ◽  
Daniel Goldman ◽  
Alan H. Stephenson ◽  
Hans H. Dietrich ◽  
...  
Keyword(s):  
Vascular Tone ◽  
Computational Models ◽  
Control Mechanism ◽  
Atp Release ◽  
Oxygen Demand ◽  
Oxygen Sensors ◽  
Feedback Mechanisms ◽  
In Vivo Experiments ◽  
The Impact

Through oxygen-dependent release of the vasodilator ATP, the mobile erythrocyte plays a fundamental role in matching microvascular oxygen supply with local tissue oxygen demand. Signal transduction within the erythrocyte and microvessels as well as feedback mechanisms controlling ATP release have been described. Our understanding of the impact of this novel control mechanism will rely on the integration of in vivo experiments and computational models.

scholarly journals Beyond Plug and Pray: Context Sensitivity and in silico Design of Artificial Neomycin Riboswitches

2020 ◽  
Author(s):  
Christian Günzel ◽  
Felix Kühnl ◽  
Katharina Arnold ◽  
Sven Findeiß ◽  
Christina Weinberg ◽  
...  
Keyword(s):  
In Silico ◽  
Rna Structure ◽  
Computational Models ◽  
Switching Behavior ◽  
Genetic Circuits ◽  
Sequence Context ◽  
Translational Initiation ◽  
Structural Responses ◽  
The Impact

AbstractGene regulation in prokaryotes often depends on RNA elements such as riboswitches or RNA thermometers located in the 5’ untranslated region of mRNA. Rearrangements of the RNA structure in response, e. g., to the binding of small molecules or ions control translational initiation or premature termination of transcription and thus mRNA expression. Such structural responses are amenable to computational modeling, making it possible to rationally design synthetic riboswitches for a given aptamer. Starting from an artificial aptamer, we construct the first synthetic transcriptional riboswitches that respond to the antibiotic neomycin. We show that the switching behavior in vivo critically depends not only on the sequence of the riboswitch itself, but also on its sequence context. We therefore developed in silico methods to predict the impact of the context, making it possible to adapt the design and to rescue non-functional riboswitches. We furthermore analyze the influence of 5’ hairpins with varying stability on neomycin riboswitch activity. Our data highlight the limitations of a simple plug-and-play approach in the design of complex genetic circuits and demonstrate that detailed computational models significantly simplify, improve, and automate the design of transcriptional circuits. Our design software is available under a free license on Github.1

scholarly journals A Novel Mechanism of Antagonism between ATP-Dependent Chromatin Remodeling Complexes Regulates RNR3 Expression

2009 ◽  
Vol 29 (12) ◽  
pp. 3255-3265 ◽  
Author(s):  
Raghuvir S. Tomar ◽  
James N. Psathas ◽  
Hesheng Zhang ◽  
Zhengjian Zhang ◽  
Joseph C. Reese
Keyword(s):  
Gene Expression ◽  
Chromatin Remodeling ◽  
Chromatin Structure ◽  
Large Subunit ◽  
Nucleosome Positioning ◽  
Gene Encoding ◽  
Control Of Gene Expression ◽  
Dna Binding Factors ◽  
Chromatin Remodeling Complexes

ABSTRACT Gene expression depends upon the antagonistic actions of chromatin remodeling complexes. While this has been studied extensively for the enzymes that covalently modify the tails of histones, the mechanism of how ATP-dependent remodeling complexes antagonize each other to maintain the proper level of gene activity is not known. The gene encoding a large subunit of ribonucleotide reductase, RNR3, is regulated by ISW2 and SWI/SNF, complexes that repress and activate transcription, respectively. Here, we studied the functional interactions of these two complexes at RNR3. Deletion of ISW2 causes constitutive recruitment of SWI/SNF, and conditional reexpression of ISW2 causes the repositioning of nucleosomes and reduced SWI/SNF occupancy at RNR3. Thus, ISW2 is required for restriction of access of SWI/SNF to the RNR3 promoter under the uninduced condition. Interestingly, the binding of sequence-specific DNA binding factors and the general transcription machinery are unaffected by the status of ISW2, suggesting that disruption of nucleosome positioning does not cause a nonspecific increase in cross-linking of all factors to RNR3. We provide evidence that ISW2 does not act on SWI/SNF directly but excludes its occupancy by positioning nucleosomes over the promoter. Genetic disruption of nucleosome positioning by other means led to a similar phenotype, linking repressed chromatin structure to SWI/SNF exclusion. Thus, incorporation of promoters into a repressive chromatin structure is essential for prevention of the opportunistic actions of nucleosome-disrupting activities in vivo, providing a novel mechanism for maintaining tight control of gene expression.

scholarly journals Emergence of robust nucleosome patterns from an interplay of positioning mechanisms

2018 ◽  
Author(s):  
Johannes Nuebler ◽  
Michael Wolff ◽  
Benedikt Obermayer ◽  
Wolfram Möbius ◽  
Ulrich Gerland
Keyword(s):  
Dna Sequence ◽  
Chromatin Remodeling ◽  
Nucleosome Positioning ◽  
Eukaryotic Cells ◽  
Active Chromatin ◽  
Complex Interplay ◽  
Quantitative Characteristics ◽  
Characteristic Features ◽  
Species Specific ◽  
Effective Description

AbstractProper positioning of nucleosomes in eukaryotic cells is determined by a complex interplay of factors, including nucleosome-nucleosome interactions, DNA sequence, and active chromatin remodeling. Yet, characteristic features of nucleosome positioning, such as gene-averaged nucleosome patterns, are surprisingly robust across perturbations, conditions, and species. Here, we explore how this robustness arises despite the underlying complexity. We leverage mathematical models to show that a large class of positioning mechanisms merely affects the quantitative characteristics of qualitatively robust positioning patterns. We demonstrate how statistical positioning emerges as an effective description from the complex interplay of different positioning mechanisms, which ultimately only renormalize the model parameter quantifying the effective softness of nucleosomes. This renormalization can be species-specific, rationalizing a puzzling discrepancy between the effective nucleosome softness of S. pombe and S. cerevisiae. More generally, we establish a quantitative framework for dissecting the interplay of different nucleosome positioning determinants.

scholarly journals E-ChRPs: Engineered Chromatin Remodeling Proteins for Precise Nucleosome Positioning

2018 ◽  
Author(s):  
DA Donovan ◽  
JG Crandall ◽  
OGB Banks ◽  
ZD Jensvold ◽  
LE McKnight ◽  
...  
Keyword(s):  
Chromatin Remodeling ◽  
Dna Sequences ◽  
Structural Changes ◽  
Nucleosome Positioning ◽  
Dna Binding Proteins ◽  
Chromatin Structural ◽  
Development And Validation ◽  
Dependent Processes

SummaryRegulation of chromatin structure is essential for controlling the access of DNA to factors that require association with specific DNA sequences. The ability to alter chromatin organization in a targeted manner would provide a mechanism for directly manipulating DNA-dependent processes and should provide a means to study direct consequences of chromatin structural changes. Here we describe the development and validation of engineered chromatin remodeling proteins (E-ChRPs) for inducing programmable changes in nucleosome positioning by design. We demonstrate that E-ChRPs function both in vivo and in vitro to specifically reposition target nucleosomes and entire nucleosomal arrays, and possess the ability to evict native DNA-binding proteins through their action. E-ChRPs can be designed with a range of targeting modalities, including the SpyCatcher and dCas9 moieties, resulting in high versatility and enabling diverse future applications. Thus, engineered chromatin remodeling proteins represent a simple and robust means to probe regulation of DNA-dependent processes in different chromatin contexts.

Computational exploration of mechanistic determinants of antibody drug-conjugate pharmacokinetics using quantitative systems pharmacology modeling strategies.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14000-e14000
Author(s):  
John M Burke ◽  
Anna Katharina Wilkins ◽  
Andrew Matteson ◽  
Lore Gruenbaum ◽  
Josh F Apgar
Keyword(s):  
Half Life ◽  
Computational Models ◽  
Systems Pharmacology ◽  
Antibody Drug Conjugate ◽  
Quantitative Systems Pharmacology ◽  
Drug Conjugate ◽  
Drug Antibody Ratio ◽  
The Impact ◽  
Antibody Drug

e14000 Background: The pharmacokinetics of antibody drug conjugate (ADC) therapeutics typically show a discrepancy between the PK of total antibody (conjugated and unconjugated antibody) and that of conjugated antibody, carrying one or more payload molecules This discrepancy is often attributed to deconjugation (Kamath, 2014), however recent evidence suggests that the underlying mechanisms may be more complex. Methods: This work employs a computational quantitative systems pharmacology (QSP) approach to understand the impact of drug antibody ratio (DAR) and the resulting changes in molecular properties on overall PK and relative payload disposition as observed in preclinical and clinical studies. Results: Using QSP approaches, the model (1) describes the kinetics of individual DAR species and agrees well with typical ADC PK, individual DAR PK, and average DAR measurements in vivo; (2), quantitatively describes the trade-off between higher DAR and lower exposure; consequently, we predict that ADC2 is half as potent as ADC4 and ADC8, which are equipotent; (3) longer mAb half-life reduces payload delivery after multiple doses; and (4) ADC half-life affects the percent of payload delivered through different mechanisms. Conclusions: A QSP model describing mechanism is a useful tool to translate and understand PK from preclinical species to human, by acting as a central repository of data, knowledge, and hypotheses. It provided a rational basis to generate testable hypotheses and provide early insights into complex ADC PK data and established the benefit of using computational models to design novel ADCs and to optimize the discovery and development of existing ADCs.

scholarly journals NucPosDB: a database of nucleosome positioning in vivo and nucleosomics of cell-free DNA

2021 ◽  
Author(s):  
Mariya Shtumpf ◽  
Kristan V Piroeva ◽  
Shivam P Agrawal ◽  
Divya R Jacob ◽  
Vladimir B. Teif
Keyword(s):  
Computational Models ◽  
Nucleosome Occupancy ◽  
Nucleosome Positioning ◽  
Liquid Biopsies ◽  
Cell Free Dna ◽  
Regulatory Processes ◽  
Free Dna ◽  
Cells Of Origin

Nucleosome positioning is involved in many gene regulatory processes happening in the cell and it may change as cells differentiate or respond to the changing microenvironment in a healthy or diseased organism. One important implication of nucleosome positioning in clinical epigenetics is its use in the "nucleosomics" analysis of cell-free DNA (cfDNA) for the purpose of patient diagnostics in liquid biopsies. The rationale for this is that the apoptotic nucleases that digest chromatin of the dying cells mostly cut DNA between nucleosomes. Thus, the short pieces of DNA in body fluids reflect the positions of nucleosomes in the cells of origin. Here we report a systematic nucleosomics database - NucPosDB, curating published nucleosome positioning datasets in vivo as well as datasets of sequenced cell-free DNA (cfDNA) that reflect nucleosome positioning in situ in the cells of origin. Users can select subsets of the database by a number of criteria and then obtain raw or processed data. NucPosDB also reports the originally determined regions with stable nucleosome occupancy across several individuals with a given condition. An additional section provides a catalogue of computational tools for the analysis of nucleosome positioning or cfDNA experiments and theoretical algorithms for the prediction of nucleosome positioning from DNA sequence. We provide an overview of the field, describe the structure of the database in this context and demonstrate data variability using examples of different medical conditions. NucPosDB is useful both for analysis of fundamental gene regulation processes and training computational models for patient diagnostics based on cfDNA. The database currently curates ~400 publications on nucleosome positioning in cell lines and in situ as well as cfDNA from >10,000 patients and healthy volunteers. For open-access cfDNA datasets as well as key MNase-seq datasets in human cells, NucPosDB allows downloading processed mapped data in addition to the stable-nucleosome regions. NucPosDB is available at https://generegulation.org/nucposdb/.

scholarly journals Thermodynamic modeling of genome-wide nucleosome depleted regions in yeast

2021 ◽  
Vol 17 (1) ◽  
pp. e1008560
Author(s):  
Hungyo Kharerin ◽  
Lu Bai
Keyword(s):  
Thermodynamic Modeling ◽  
Thermodynamic Model ◽  
Nucleosome Positioning ◽  
Nucleosome Remodeling ◽  
Genetic Components ◽  
Genome Wide ◽  
Specific Factors ◽  
The Impact ◽  
Nuclear Processes

Nucleosome positioning in the genome is essential for the regulation of many nuclear processes. We currently have limited capability to predict nucleosome positioning in vivo, especially the locations and sizes of nucleosome depleted regions (NDRs). Here, we present a thermodynamic model that incorporates the intrinsic affinity of histones, competitive binding of sequence-specific factors, and nucleosome remodeling to predict nucleosome positioning in budding yeast. The model shows that the intrinsic affinity of histones, at near-saturating histone concentration, is not sufficient in generating NDRs in the genome. However, the binding of a few factors, especially RSC towards GC-rich and poly(A/T) sequences, allows us to predict ~ 66% of genome-wide NDRs. The model also shows that nucleosome remodeling activity is required to predict the correct NDR sizes. The validity of the model was further supported by the agreement between the predicted and the measured nucleosome positioning upon factor deletion or on exogenous sequences introduced into yeast. Overall, our model quantitatively evaluated the impact of different genetic components on NDR formation and illustrated the vital roles of sequence-specific factors and nucleosome remodeling in this process.

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