A stochastic and dynamical view of pluripotency in mouse embryonic stem cells

Lin, Yen Ting; Hufton, Peter G.; Lee, Esther J.; Potoyan, Davit A.

doi:10.1371/journal.pcbi.1006000

Cited by 39 publications

(37 citation statements)

References 86 publications

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“…Cooperativity and redundancies are not considered in the current WASABI 409 framework, so that a gene can only be regulated by one gene, except for negative 410 feedback or incoherent feedforward interactions. However, many experimentally curated 411 GRN show evidence for cooperations (2 genes are needed to activate a third gene) or 412 redundant interactions (2 genes independently activating a third gene) [47]. We 413 intentionally did not considered such multi-interactions because our current calibration 414 algorithm relies on the comparison of marginal distributions which are not sufficiently 415 informative for inferring cooperative effects.…”

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confidence: 99%

WASABI: a dynamic iterative framework for gene regulatory network inference

Bonnaffoux

Herbach

Angélique

et al. 2018

Preprint

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Inference of gene regulatory networks from gene expression data has been a long-standing and notoriously difficult task in systems biology. Recently, single-cell transcriptomic data have been massively used for gene regulatory network inference, with both successes and limitations. In the present work we propose an iterative algorithm called WASABI, dedicated to inferring a causal dynamical network from time-stamped single-cell data, which tackles some of the limitations associated with current approaches. We first introduce the concept of waves, which posits that the information provided by an external stimulus will affect genes one-by-one through a cascade, like waves spreading through a network. This concept allows us to infer the network one gene at a time, after genes have been ordered regarding their time of regulation. We then demonstrate the ability of WASABI to correctly infer small networks, which have been simulated in silico using a mechanistic model consisting of coupled piecewise-deterministic Markov processes for the proper description of gene expression at the single-cell level. We finally apply WASABI on in vitro generated data on an avian model of erythroid differentiation. The structure of the resulting gene regulatory network sheds a fascinating new light on the molecular mechanisms controlling this process. In particular, we find no evidence for hub genes and a much more distributed network structure than expected. Interestingly, we find that a majority of genes are under the direct control of the differentiation-inducing stimulus. In conclusion, WASABI is a versatile algorithm which should help biologists to fully exploit the power of time-stamped single-cell data. Author summaryAll cells have to make everyday decisions regarding their behavior in response to changing environment. Such decisions result from the dynamical behavior of an underlying gene regulatory network. Inferring the structure of such networks is an inverse problem which has occupied the systems biology community for decades. We 1/28 propose in the present work a divide-and-conquer strategy called WASABI, which splits the potentially untractable global problem into much simpler subproblems. We show that by adding one gene at a time, we can infer small networks, the behavior of which has been simulated in silico using a mechanistic model which incorporates the fundamentally probabilistic nature of the gene expression process. When applied to real-life data, our algorithm sheds a new fascinating light onto the molecular control of a differentiation process. It is our hope that WASABI will prove useful in helping biologists to fully exploit the power of time-stamped single-cell data. Introduction 1It is widely accepted that the process of cell decision making results from the behavior 2 of an underlying dynamic gene regulatory network (GRN) [1]. The GRN maintains a 3 stable state but can also respond to external perturbations to rearrange the gene 4 expression pattern in a new relevant stable state, such as during a differenti...

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confidence: 99%

WASABI: a dynamic iterative framework for gene regulatory network inference

Bonnaffoux

Herbach

Angélique

et al. 2018

Preprint

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“…The structural organization of chromosomes changes with the cell type and phase of life, chromosomal loci have been observed to move across genomic compartments during cell differentiation (4)(5)(6). As a consequence, chromatin compartmentalization is believed to play a role in gene regulation, stochastic cell fate determination (7,8) and the establishment of stable cellular phenotypes (9,10).…”

Section: Introductionmentioning

confidence: 99%

Mesoscale liquid model of chromatin recapitulates nuclear order of eukaryotes

Laghmach

Pierro

Potoyan

2019

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The nuclear envelope segregates the genome of Eukaryota from the cytoplasm. Within the nucleus, chromatin is further compartmentalized into architectures that change throughout the lifetime of the cell. Epigenetic patterns along the chromatin polymer strongly correlate with chromatin compartmentalization and, accordingly, also change during the cell life cycle and at differentiation. Recently, it has been suggested that sub-nuclear chromatin compartmentalization might result from a process of liquid-liquid phase separation orchestrated by the epigenetic marking and operated by proteins that bind to chromatin. Here, we translate these observations into a diffuse interface model of chromatin, which we named MEsoscale Liquid mOdel of Nucleus (MELON). Using this streamlined continuum model of the genome, we study the large-scale rearrangements of chromatin that happen at different stages of the growth and senescence of the cell, and during nuclear inversion events. Particularly, we investigate the role of droplet diffusion, fluctuations, and heterochromatin-lamina interactions during nuclear remodeling. Our results indicate that the physical process of liquid-liquid phase separation, together with surface effects is sufficient to recapitulate much of the large-scale morphology and dynamics of chromatin along the life cycle of cells. SIGNIFICANCE STATEMENTEukaryotic chromatin occupies a few micrometers of nuclear space while remaining dynamic and accessible for gene regulation. The physical state of nuclear chromatin is shaped by the juxtaposition of complex, out of equilibrium processes on one hand and intrinsic polymeric aspect of the genome on the other. Recent experiments have revealed a remarkable ability of disordered nuclear proteins to drive liquid-liquid phase separation of chromatin domains. We have built a mesoscale liquid model of nuclear chromatin which allows dissecting the contribution of liquid behavior of chromatin to nuclear order of eukaryotes. Our results show that liquid-liquid phase separation, together with surface effects is sufficient for recapitulating large-scale morphology and dynamics of chromatin at many stages of the nuclear cycle. Laghmach et alClear evidence of hierarchical compartmentalization in chromatin at multiple scales has emerged through studies employing DNA-DNA proximity ligation assays. First, two genomic compartments were observed (3), named A and B, which were then refined through higher resolution experiments to reveal the existence of even smaller sub-compartments (10). The A and B compartments appear to be enriched in epigenetic markings correlating with transcriptional activation and silencing respectively. Several studies have suggested that chromatin compartmentalization may result from a process of liquid-liquid phase separation orchestrated by the epigenetic markings which collectively act to remodel chromosomal loci (15)(16)(17)(18)(19). The epigenetically driven phase segregation events have shown to emerge right at the nucleosome resolution mediated by protein b...

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“…However, such 38 physiological (normal) cell reprogramming might have pathological consequences if the 39 acquisition of epigenetic and phenotypic plasticity is not transient. In response to 40 chronically permissive tissue environments for in vivo reprogramming, the occurrence of 41 unrestrained epigenetic plasticity might permanently lock cells into self-renewing (a) (b) Fig 2. Schematic reprentation of the ER-GRN model and its multiscale reduction. (a): Gene regulatory network (GRN) of two self-activating, mutually-inhibitory genes with epigenetic regulation.…”

Section: Introduction 25mentioning

confidence: 99%

“…Our deconstruction of epigenetic plasticity and phenotypic malleability 730 provides crucial insights into how pathological states of permanently acquired 731 pluripotency can be therapeutically unlocked by exploiting epigenetic heterogeneity. 732 We have added an ER layer to previous approaches in which cell phenotypes were 733 associated with the attractors of complex gene regulatory systems and their robustness, 734 with the resilience of such attractors tuned by the presence of intrinsic noise, 735 environmental fluctuations, and other disturbances [35][36][37][38][39][40][41][42][43]. Our approach is based on 736 two main pillars: namely, a framework for the generation of the ensemble of ER systems, 737 and a multiscale asymptotic analysis-based method for model reduction of the stochastic 738 ER-GRN model (see Section Multi-scale analysis and model reduction).…”

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confidence: 99%

A multiscale model of epigenetic heterogeneity reveals the kinetic routes of pathological cell fate reprogramming

Folguera-Blasco

Pérez-Carrasco

Cuyàs

et al. 2018

Preprint

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The inherent capacity of somatic cells to switch their phenotypic status in response to damage stimuli in vivo might have a pivotal role in ageing and cancer. However, how the entry-exit mechanisms of phenotype reprogramming are established remains poorly understood. In an attempt to elucidate such mechanisms, we herein introduce a stochastic model of combined epigenetic regulation (ER)-gene regulatory network (GRN) to study the plastic phenotypic behaviours driven by ER heterogeneity. Furthermore, based on the existence of multiple scales, we formulate a method for stochastic model reduction, from which we derive an efficient hybrid simulation scheme that allows us to deal with such complex systems. Our analysis of the coupled system reveals a regime of tristability in which pluripotent stem-like and differentiated steady-states coexist with a third indecisive state. Crucially, ER heterogeneity of differentiation genes is for the most part responsible for conferring abnormal robustness to pluripotent stem-like states. We then formulate epigenetic heterogeneity-based strategies capable of unlocking and facilitating the transit from differentiation-refractory (pluripotent stem-like) to differentiation-primed epistates. The application of the hybrid numerical method validated the likelihood of such switching involving solely kinetic changes in epigenetic factors. Our results suggest that epigenetic heterogeneity regulates the mechanisms and kinetics of phenotypic robustness of cell fate reprogramming. The occurrence of tunable switches capable of modifying the nature of cell fate reprogramming from pathological to physiological might pave the way for new therapeutic strategies to regulate reparative reprogramming in ageing and cancer. Author summaryCertain modifications of the structure and functioning of the protein/DNA complex 1 called chromatin can allow adult, fully differentiated cells to adopt a stem cell-like 2 pluripotent state in a purely epigenetic manner, not involving changes in the underlying 3 DNA sequence. Such reprogramming-like phenomena may constitute an innate 4 reparative route through which human tissues respond to injury and could also serve as 5 a novel regenerative strategy in human pathological situations in which tissue or organ 6 repair is impaired. However, it should be noted that in vivo reprogramming would be 7 capable of maintaining tissue homeostasis provided the acquisition of pluripotency 8 features is strictly transient and accompanied by an accurate replenishment of the 9 specific cell types being lost. Crucially, an excessive reprogramming to pluripotency in 10 the absence of controlled re-differentiation would impair the repair or the replacement of 11 damaged cells, thereby promoting pathological alterations of cell fate. A mechanistic 12 understanding of how the degree of chromatin plasticity dictates the reparative versus 13 pathological behaviour of in vivo reprogramming to rejuvenate aged tissues while 14 preventing tumorigenesis is urgently needed, including especially th...

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A stochastic and dynamical view of pluripotency in mouse embryonic stem cells

Cited by 39 publications

References 86 publications

WASABI: a dynamic iterative framework for gene regulatory network inference

WASABI: a dynamic iterative framework for gene regulatory network inference

Mesoscale liquid model of chromatin recapitulates nuclear order of eukaryotes

A multiscale model of epigenetic heterogeneity reveals the kinetic routes of pathological cell fate reprogramming

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