Multiscale Modeling of Cellular Epigenetic States: Stochasticity in Molecular Networks, Chromatin Folding in Cell Nuclei, and Tissue Pattern Formation of Cells

Liang, Jie; Cao, Youfang; Gürsoy, Gamze; Naveed, Hammad; Terebus, Anna; Zhao, Jieling

doi:10.1615/critrevbiomedeng.2016016559

“…Recently, computational work has also focused on developing mechanistic models of cellfate decisions [31][32][33], especially the formation of patterns in time and space [34,35]. Multiscale approaches that combine probabilistic and deterministic models of tissues at the scale of individual cells have shown promise in helping to elucidate the details of tissue patterning [36][37][38][39][40].…”

Section: Introductionmentioning

confidence: 99%

Modeling binary and graded cone cell fate patterning in the mouse retina

Eldred

¹

,

Avelis

²

,

Johnston

³

et al. 2020

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Nervous systems are incredibly diverse, with myriad neuronal subtypes defined by gene expression. How binary and graded fate characteristics are patterned across tissues is poorly understood. Expression of opsin photopigments in the cone photoreceptors of the mouse retina provides an excellent model to address this question. Individual cones express S-opsin only, M-opsin only, or both S-opsin and M-opsin. These cell populations are patterned along the dorsal-ventral axis, with greater M-opsin expression in the dorsal region and greater S-opsin expression in the ventral region. Thyroid hormone signaling plays a critical role in activating M-opsin and repressing S-opsin. Here, we developed an image analysis approach to identify individual cone cells and evaluate their opsin expression from immunofluorescence imaging tiles spanning roughly 6 mm along the D-V axis of the mouse retina. From analyzing the opsin expression of~250,000 cells, we found that cones make a binary decision between S-opsin only and co-expression competent fates. Co-expression competent cells express graded levels of Sand M-opsins, depending nonlinearly on their position in the dorsal-ventral axis. M-and S-opsin expression display differential, inverse patterns. Using these single-cell data, we developed a quantitative, probabilistic model of cone cell decisions in the retinal tissue based on thyroid hormone signaling activity. The model recovers the probability distribution for cone fate patterning in the mouse retina and describes a minimal set of interactions that are necessary to reproduce the observed cell fates. Our study provides a paradigm describing how differential responses to regulatory inputs generate complex patterns of binary and graded cell fates.

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“…Such networks typically involve small copy numbers of the molecular species and large differences in the species reaction rates. Because of these factors, the network interactions have a stochastic nature [ 1 – 3 ], i.e. they are unpredictable through the influence of a random variable.…”

Section: Introductionmentioning

confidence: 99%

PRODIGEN: visualizing the probability landscape of stochastic gene regulatory networks in state and time space

Ma

¹

,

Luciani

²

,

Terebus

³

et al. 2017

Self Cite

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BackgroundVisualizing the complex probability landscape of stochastic gene regulatory networks can further biologists’ understanding of phenotypic behavior associated with specific genes.ResultsWe present PRODIGEN (PRObability DIstribution of GEne Networks), a web-based visual analysis tool for the systematic exploration of probability distributions over simulation time and state space in such networks. PRODIGEN was designed in collaboration with bioinformaticians who research stochastic gene networks. The analysis tool combines in a novel way existing, expanded, and new visual encodings to capture the time-varying characteristics of probability distributions: spaghetti plots over one dimensional projection, heatmaps of distributions over 2D projections, enhanced with overlaid time curves to display temporal changes, and novel individual glyphs of state information corresponding to particular peaks.ConclusionsWe demonstrate the effectiveness of the tool through two case studies on the computed probabilistic landscape of a gene regulatory network and of a toggle-switch network. Domain expert feedback indicates that our visual approach can help biologists: 1) visualize probabilities of stable states, 2) explore the temporal probability distributions, and 3) discover small peaks in the probability landscape that have potential relation to specific diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-016-1447-1) contains supplementary material, which is available to authorized users.

show abstract

Modeling binary and graded cone cell fate patterning in the mouse retina

Eldred

¹

,

Avelis

²

,

Johnston

³

et al. 2019

Preprint

0

View full text Add to dashboard Cite

Nervous systems are incredibly diverse, with myriad neuronal subtypes defined by gene expression. How binary and graded fate characteristics are patterned across tissues is poorly understood. Expression of opsin photopigments in the cone photoreceptors of the mouse retina provides an excellent model to address this question. Individual cones express S-opsin only, Mopsin, or both S-opsin and M-opsin. These cell populations are patterned along the dorsalventral axis, with greater M-opsin expression in the dorsal region and greater S-opsin expression in the ventral region. Thyroid hormone signaling plays a critical role in activating Mopsin and repressing S-opsin. Here, we developed an image analysis approach to identify individual cone cells and evaluate their opsin expression from immunofluorescence imaging tiles spanning roughly 6 mm along the D-V axis of the mouse retina. From analyzing the opsin expression of ~250,000 cells, we found that cones make a binary decision between S-opsin only and co-expression competent fates. Co-expression competent cells express graded levels of S-and M-opsins, depending nonlinearly on their position in the dorsal-ventral axis. M-and Sopsin expression display differential, inverse patterns. Using these single-cell data we developed a quantitative, stochastic model of cone cell decisions in the retinal tissue based on thyroid hormone signaling activity. The model recovers the probability distribution for cone fate patterning in the mouse retina and describes a minimal set of interactions that are necessary to reproduce the observed cell fates. Our study provides a paradigm describing how differential responses to regulatory inputs generate complex patterns of binary and graded cell fates. Author SummaryThe development of a cell in a mammalian tissue is governed by a complex regulatory network that responds to many input signals to give the cell a distinct identity, a process referred to as cell-fate specification. Some of these cell fates have binary on-or-off gene expression patterns, while others have graded gene expression that changes across the tissue. Differentiation of the photoreceptor cells that sense light in the mouse retina provides a good example of this process. Here, we explore how complex patterns of cell fates are specified in the mouse retina by building a computational model based on analysis of a large number of photoreceptor cells from microscopy images of whole retinas. We use the data and the model to study what exactly it means for a cell to have a binary or graded cell fate and how these cell fates can be distinguished from each other. Our study shows how tens-of-thousands of individual photoreceptor cells can be patterned across a complex tissue by a regulatory network, creating a different outcome depending upon the received inputs. How the numerous neuronal subtypes of the vertebrate nervous system are patterned is an ongoing puzzle in developmental neurobiology. Are neuronal subtypes distinct states generated by binary gene expression decisions? Or are ...

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Multiscale Modeling of Cellular Epigenetic States: Stochasticity in Molecular Networks, Chromatin Folding in Cell Nuclei, and Tissue Pattern Formation of Cells

Cited by 3 publications

References 113 publications

Modeling binary and graded cone cell fate patterning in the mouse retina

Modeling binary and graded cone cell fate patterning in the mouse retina

PRODIGEN: visualizing the probability landscape of stochastic gene regulatory networks in state and time space

Modeling binary and graded cone cell fate patterning in the mouse retina

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