Dataset Information

Stochastically modeling multiscale stationary biological processes.

ABSTRACT: Large scale biological responses are inherently uncertain, in part as a consequence of noisy systems that do not respond deterministically to perturbations and measurement errors inherent to technological limitations. As a result, they are computationally difficult to model and current approaches are notoriously slow and computationally intensive (multiscale stochastic models), fail to capture the effects of noise across a system (chemical kinetic models), or fail to provide sufficient biological fidelity because of broad simplifying assumptions (stochastic differential equations). We use a new approach to modeling multiscale stationary biological processes that embraces the noise found in experimental data to provide estimates of the parameter uncertainties and the potential mis-specification of models. Our approach models the mean stationary response at each biological level given a particular expected response relationship, capturing variation around this mean using conditional Monte Carlo sampling that is statistically consistent with training data. A conditional probability distribution associated with a biological response can be reconstructed using this method for a subset of input values, which overcomes the parameter identification problem. Our approach could be applied in addition to dynamical modeling methods (see above) to predict uncertain biological responses over experimental time scales. To illustrate this point, we apply the approach to a test case in which we model the variation associated with measurements at multiple scales of organization across a reproduction-related Adverse Outcome Pathway described for teleosts.

SUBMITTER: Rowland MA

PROVIDER: S-EPMC6932771 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Stochastically modeling multiscale stationary biological processes.

Rowland Michael A MA Mayo Michael L ML Perkins Edward J EJ Garcia-Reyero Natàlia N

PloS one 20191226 12

Large scale biological responses are inherently uncertain, in part as a consequence of noisy systems that do not respond deterministically to perturbations and measurement errors inherent to technological limitations. As a result, they are computationally difficult to model and current approaches are notoriously slow and computationally intensive (multiscale stochastic models), fail to capture the effects of noise across a system (chemical kinetic models), or fail to provide sufficient biologica ...[more]

PMID: 31877201

Similar Datasets

Project description:Nucleosomes form the fundamental building blocks of chromatin. Subtle modifications of the constituent histone tails mediate chromatin stability and regulate gene expression. For this reason, it is important to understand structural dynamics of nucleosomes at atomic levels. We report a novel multiscale model of the fundamental chromatin unit, a nucleosome, using a simplified model for rapid discrete molecular dynamics simulations and an all-atom model for detailed structural investigation. Using a simplified structural model, we perform equilibrium simulations of a single nucleosome at various temperatures. We further reconstruct all-atom nucleosome structures from simulation trajectories. We find that histone tails bind to nucleosomal DNA via strong salt-bridge interactions over a wide range of temperatures, suggesting a mechanism of chromatin structural organization whereby histone tails regulate inter- and intranucleosomal assemblies via binding with nucleosomal DNA. We identify specific regions of the histone core H2A/H2B-H4/H3-H3/H4-H2B/H2A, termed "cold sites", which retain a significant fraction of contacts with adjoining residues throughout the simulation, indicating their functional role in nucleosome organization. Cold sites are clustered around H3-H3, H2A-H4 and H4-H2A interhistone interfaces, indicating the necessity of these contacts for nucleosome stability. Essential dynamics analysis of simulation trajectories shows that bending across the H3-H3 is a prominent mode of intranucleosomal dynamics. We postulate that effects of salts on mononucleosomes can be modeled in discrete molecular dynamics by modulating histone-DNA interaction potentials. Local fluctuations in nucleosomal DNA vary significantly along the DNA sequence, suggesting that only a fraction of histone-DNA contacts make strong interactions dominating mononucleosomal dynamics. Our findings suggest that histone tails have a direct functional role in stabilizing higher-order chromatin structure, mediated by salt-bridge interactions with adjacent DNA.

Project description:The mammalian skin epidermis is a stratified epithelium composed of multiple layers of epithelial cells that exist in appropriate sizes and proportions, and with distinct boundaries separating each other. How the epidermis develops from a single layer of committed precursor cells to form a complex multilayered structure of multiple cell types remains elusive. Here, we construct stochastic, three-dimensional, and multiscale models consisting of a lineage of multiple cell types to study the control of epidermal development. Symmetric and asymmetric cell divisions, stochastic cell fate transitions within the lineage, extracellular morphogens, cell-to-cell adhesion forces, and cell signaling are included in model. A GPU algorithm was developed and implemented to accelerate the simulations. These simulations show that a balance between cell proliferation and differentiation during lineage progression is crucial for the development and maintenance of the epidermal tissue. We also find that selective intercellular adhesion is critical to sharpening the boundary between layers and to the formation of a highly ordered structure. The long-range action of a morphogen provides additional feedback regulations, enhancing the robustness of overall layer formation. Our model is built upon previous experimental findings revealing the role of Ovol transcription factors in regulating epidermal development. Direct comparisons of experimental and simulation perturbations show remarkable consistency. Taken together, our results highlight the major determinants of a well-stratified epidermis: balanced proliferation and differentiation, and a combination of both short- (symmetric/asymmetric division and selective cell adhesion) and long-range (morphogen) regulations. These underlying principles have broad implications for other developmental or regenerative processes leading to the formation of multilayered tissue structures, as well as for pathological processes such as epidermal wound healing.

Dataset Information

Stochastically modeling multiscale stationary biological processes.

Publications

Stochastically modeling multiscale stationary biological processes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets