Exploring intermediate cell states through the lens of single cells

MacLean, Adam L.; Hong, Tian; Nie, Qing

doi:10.1016/j.coisb.2018.02.009

Cited by 72 publications

(73 citation statements)

References 103 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…9A). From Figure 9A, the cell can either switch directly between the low and high level states, or indirectly through the intermediate state, which show similar dynamics as in the intermediate state of EMT [44]. Moreover, in the simulation, the nucleosome state shows bimodal distribution with two distinguish states (Fig.…”

Section: 5mentioning

confidence: 82%

“…Epigenetic regulation induced multistability. In many biological systems of cell-type switches, there are intermediate cell states that play important roles in mediating cell fate transitions [44]. Typical biological systems with intermediate cell states include the epithelial-to-mesenchymal transition (EMT) [63,45], hematopoietic progenitor cell differentiation [67], and CD4 + T cell lineage specification.…”

Section: 5mentioning

confidence: 99%

See 1 more Smart Citation

Cell-Type Switches Induced by Stochastic Histone Modification Inheritance

Huang

Lei

2018

Preprint

View full text Add to dashboard Cite

Cell plasticity is important for tissue developments during which somatic cells may switch between distinct states. Genetic networks to yield multistable states are usually required to yield multiple states, and either external stimuli or noise in gene expressions are trigger signals to induce cell-type switches between the states. In many biological systems, cells show highly plasticity and can switch between different state spontaneously, but maintaining the dynamic equilibrium of the cell population. Here, we considered a mechanism of spontaneous cell-type switches through the combination between gene regulation network and stochastic epigenetic state transitions. We presented a mathematical model that consists of a standard positive feedback loop with changes of histone modifications during with cell cycling. Based on the model, nucleosome state of an associated gene is a random process during cell cycling, and hence introduces an inherent noise to gene expression, which can automatically induce cell-type switches in cell cycling. Our model reveals a simple mechanism of spontaneous cell-type switches through a stochastic histone modification inheritance during cell cycle. This mechanism is inherent to the normal cell cycle process, and is independent to the external signals.2010 Mathematics Subject Classification. Primary: 92B05, 91B70; Secondary : 92D25. 1 2 RONGSHENG HUANG AND JINZHI LEI changes in the activities of regulators in the gene regulation network is one of the driving force to induce cell type switch, e.g., stem cell differentiation [10,23,24,42]. During development, cells undergo a unidirectional course of differentiation, which can be viewed as a dynamical process on the Waddington epigenetic landscape with multistable states, the input signals can change the landscape to guide the transition between different states [15,19,72].Chromatin regulators play crucial roles in establishing and maintaining gene expression states [4,30]. Histone modifications and DNA methylations are important epigenetic states that can regulate the chromatin state of a DNA sequence, and modulate the gene expression dynamics. These epigenetic modifications are modulated by intercellular enzyme activities, and hence dynamically change over time and during cell cycle [50]. The stochastic epigenetic inheritance during cell cycle can result in spontaneous alteration of epigenetic state during development; epigenetic changes in regulatory loci often correlate with expression changes during stem cell differentiation [3,8,27,58,73].Here, to investigate how stochastic epigenetic inheritance affect the dynamical process of cell fate decision, we studied a computational model that combines positive feedback regulation with histone modification of the gene promoter. Moreover, cell cycle was included in the model through the stochastic inheritance during cell cycle. We show that the dynamic behavior of histone modification in the cell division can induce spontaneous cell-type switches during normal development process, from which t...

show abstract

Section: 5mentioning

confidence: 82%

Section: 5mentioning

confidence: 99%

Cell-Type Switches Induced by Stochastic Histone Modification Inheritance

Huang

Lei

2018

Preprint

View full text Add to dashboard Cite

show abstract

“…Their success probably stems from the fact that it would be difficult to describe differentiation as the transition between only 2 states, as we highlighted in the context of in vitro erythropoiesis with our SB model. Actually, differentiation from one cell type to another is a continuous process, so its best description would probably be a continuum of states, which would punctuate the transition between the two cell types (19,46) . However, explicitly accounting for this continuum would require an infinity of intermediary states.…”

Section: Discussionmentioning

confidence: 99%

Calibration, Selection and Identifiability Analysis of a Mathematical Model of the in vitro Erythropoiesis in Normal and Perturbed Contexts

Duchesne

Guillemin

Gandrillon

et al. 2018

Preprint

View full text Add to dashboard Cite

The in vivo erythropoiesis, which is the generation of mature red blood cells in the bone marrow of whole organisms, has been described by a variety of mathematical models in the past decades. However, the in vitro erythropoiesis, which produces red blood cells in cultures, has received much less attention from the modelling community. In this paper, we propose the first mathematical model of in vitro erythropoiesis. We start by formulating different models and select the best one at fitting experimental data of in vitro erythropoietic differentiation. It is based on a set of linear ODE, describing 3 hypothetical populations of cells at different stages of differentiation. We then compute confidence intervals for all of its parameters estimates, and conclude that our model is fully identifiable. Finally, we use this model to compute the effect of a chemical drug called Rapamycin, which affects all states of differentiation in the culture, and relate these effects to specific parameter variations. We provide the first model for the kinetics of in vitro cellular differentiation which is proven to be identifiable. It will serve as a basis for a model which will better account for the variability which is inherent to experimental protocol used for the model calibration.vitro context, i.e. the process that takes place in cells grown in culture, is much simpler to characterize experimentally. Yet, to our knowledge, no modeling study has focused on it so far. Since the in vitro differentiation is an experimental tool of choice for the study of cellular decision-making (17,18,19) , we propose to develop a model for the dynamics of the in vitro erythropoiesis.Moreover, the current models of erythropoiesis suffer from one major drawback: the weakness of their parameterization, which can fall within three categories.A vast majority of the existing models of erythropoiesis are based on experimental parameter values from the litterature. In some cases these values are used in other contexts that those in which they were obtained (typically, in other species (12) ).In other cases, the parameter values of a model are chosen arbitrarily to reproduce a qualitative behaviour. Apart from this qualitative fit, such approaches do not provide any information regarding the validity of the values (16) .Finally, when the parameters of a model are estimated to reproduce a dataset, the precision of this estimation is seldom investigated (20) . By this, we mean that depending on the algorithmic details of the estimation, it is possible that several values of the parameters might render the same fit to the data. In this case the model is said to be unidentifiable.A model is said to be identifiable if and only if it is possible to infer a unique value for each of its parameter by comparing its output to experimental data. Otherwise it is unidentifiable. A model can be non-identifiable for several reasons (21,22) .Structural identifiability is related to the structure of the model, and the observed variables. A model is structurally unidentifi...

show abstract

“…Besides these stable pluripotent and differentiated cell states (SC, DA and DB), we found some other attractor states, which we define as the intermediate states (IA, IB and IO). The intermediate states have been suggested to play critical roles during cell lineage transitions [9,[39][40][41] and cancer progression [11].…”

Section: Epigenetic Landscape For Developmentmentioning

confidence: 99%

Quantifying the interplay between genetic and epigenetic regulations in stem cell development

et al. 2019

View full text Add to dashboard Cite

Waddington epigenetic landscape, as a classic metaphor, has been used to explain cellular development and differentiation. However, it remains challenging to quantify the epigenetic landscape. Especially, a key issue arises as what are the underlying mechanisms for the interplay between genetic and epigenetic regulations to govern cell fate decisions in development. Based on a developmental epigenetic model combining histone modifications and gene regulations, we studied state switching mechanisms of histone modifications for stem cell development, and uncovered corresponding epigenetic landscape. The topography of landscape provides a quantitative measure for the relative stability of different attractors or phenotypes. We showed that histone regulations facilitate the occurrence of intermediate states or multistability. From the epigenetic landscape of stem cell differentiation, we identified key cellular states characterized by attractors, including pluripotent stem cell state, differentiated state and intermediate states. We also quantified representative kinetic transition paths for differentiation, reprogramming and transdifferentiation, which agree well with previous experimental observations. Specifically, previous experiments indicate that transdifferentiation can go through a mixed, unspecific intermediate or progenitor-like state. By calculating the kinetic transition paths, our developmental epigenetic models are able to replicate all these three experimental results, and therefore provide theoretical explanations for these experimental observations. We propose that epigenetic regulations play critical roles on the kinetic transitions for differentiation, reprogramming and transdifferentiation, which also provide a source for the heterogeneity of gene expressions observed in developmental process. Our work provides new insights into the roles of epigenetic modifications on controlling gene expression and stem cell differentiation, and facilitates our mechanistic understanding for the cell fate determinations regarding the interplay between genetic and epigenetic regulations.The Waddington landscapes for gene regulatory networks have been quantified to investigate the stochastic dynamics of cell fate decisions and phenotypic stability [6][7][8][9][10][11][12][13][14]. From the landscape perspective, different phenotypes are delineated as the basins of attraction on a potential surface, and the cell fate determination process is viewed as a ball rolling from one basin to the other on the landscape surface by surmounting certain barriers. The potential barrier heights separating the attractors or basins quantify the degrees of feasibility for cells to switch from one cell type to the other. Therefore, the landscape provides a way to quantify the stochastic dynamics of cell fate decisions in development based on underlying gene regulatory networks.On the other hand, epigenetic regulations (such as histone modifications) are associated with active and repressed chromatin states, and therefore control gene ...

show abstract

Exploring intermediate cell states through the lens of single cells

Cited by 72 publications

References 103 publications

Cell-Type Switches Induced by Stochastic Histone Modification Inheritance

Cell-Type Switches Induced by Stochastic Histone Modification Inheritance

Calibration, Selection and Identifiability Analysis of a Mathematical Model of the in vitro Erythropoiesis in Normal and Perturbed Contexts

Quantifying the interplay between genetic and epigenetic regulations in stem cell development

Contact Info

Product

Resources

About