Stochastic models coupling gene expression and partitioning in cell division in Escherichia coli

Baptista, Ines S C; Ribeiro, André S.

doi:10.1016/j.biosystems.2020.104154

“…Our results indicate that error-free epigenetic inheritance may not be critical in determing EMT population balance. This does not necessarily imply that cell division is not necessary, as cell division also introduces noise in all TF and microRNA concentrations (28). In fact, recent experiments (29) seem to indicate that suppressing division does interfere with EMT, albeit without demonstrating a specific causal connection.…”

Section: Discussionmentioning

confidence: 96%

NRF2-dependent epigenetic regulation can promote the hybrid epithelial/mesenchymal phenotype

Jia

¹

,

Jolly

²

,

Levine

³

2021

Preprint

0

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The epithelial-mesenchymal transition (EMT) is a cellular process critical for wound healing, cancer metastasis and embryonic development. Recent efforts have identified the role of hybrid epithelial/mesenchymal states, having both epithelial and mesehncymal traits, in enabling cancer metastasis and resistance to various therapies. Also, previous work has suggested that NRF2 can act as phenotypic stability factor to help stablize such hybrid states. Here, we incorporate a phenomenological epigenetic feedback effect into our previous computational model for EMT signaling. We show that this type of feedback can stabilize the hybrid state as compared to the fully mesenchymal phenotype if NRF2 can influence SNAIL at an epigenetic level, as this link makes transitions out of hybrid state more difficult. However, epigenetic regulation on other NRF2-related links do not significantly change the EMT dynamics. Finally, we considered possible cell division effects in our epigenetic regulation model, and our results indicate that the degree of epigenetic inheritance does not appear to be a critical factor for the hybrid E/M state stabilizing behavior of NRF2.

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“…Our results indicate that error-free epigenetic inheritance may not be critical in determing EMT population balance. This does not necessarily imply that cell division is not necessary, as cell division also introduces noise in all TF and microRNA concentrations ( Baptista and Ribeiro, 2020 ). In fact, recent experiments ( den Hollander et al, 2021 ) seem to indicate that suppressing division does interfere with EMT, albeit without demonstrating a specific causal connection.…”

Section: Discussionmentioning

confidence: 99%

NRF2-dependent Epigenetic Regulation can Promote the Hybrid Epithelial/Mesenchymal Phenotype

Jia

¹

,

Jolly

²

,

Levine

³

2022

Front. Cell Dev. Biol.

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The epithelial-mesenchymal transition (EMT) is a cellular process critical for wound healing, cancer metastasis and embryonic development. Recent efforts have identified the role of hybrid epithelial/mesenchymal states, having both epithelial and mesehncymal traits, in enabling cancer metastasis and resistance to various therapies. Also, previous work has suggested that NRF2 can act as phenotypic stability factor to help stablize such hybrid states. Here, we incorporate a phenomenological epigenetic feedback effect into our previous computational model for EMT signaling. We show that this type of feedback can stabilize the hybrid state as compared to the fully mesenchymal phenotype if NRF2 can influence SNAIL at an epigenetic level, as this link makes transitions out of hybrid state more difficult. However, epigenetic regulation on other NRF2-related links do not significantly change the EMT dynamics. Finally, we considered possible cell division effects in our epigenetic regulation model, and our results indicate that the degree of epigenetic inheritance does not appear to be a critical factor for the hybrid E/M state stabilizing behavior of NRF2.

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“…One canonical example is Notch-Delta signaling [35][36][37] that can drive tissue patterning outcomes across biological contexts [38]. The dynamics of a toggle switch can be influenced by gene expression noise [39], epigenetic changes [40], partitioning errors during cell division [41][42][43][44], and conformational noise in intrinsically disordered regions of a component in a switch [45]. Thus, the deterministic and stochastic dynamics of toggle switches and coupling of many positive and negative feedback loops have been well-explored in many biological systems [19,20,[46][47][48][49][50][51], including spatially extended realizations such as diffusion of mutually inhibiting molecules [52], and synthetic design of circuits to achieve a set of desired functions [53,54].…”

Section: Discussionmentioning

confidence: 99%

Operating principles of circular toggle polygons

Hati

¹

,

Duddu

²

,

Jolly

³

2020

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0

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Decoding the dynamics of cellular decision-making and cell differentiation is a central question in cell and developmental biology. A common network motif involved in many cell-fate decisions is a mutually inhibitory feedback loop between two self-activating ‘master regulators’ A and B, also called as toggle switch. Typically, it can allow for three stable states – (high A, low B), (low A, high B) and (medium A, medium B). A toggle triad – three mutually repressing regulators A, B and C, i.e. three toggle switches arranged circularly (between A and B, between B and C, and between A and C) – can allow for six stable states: three ‘single positive’ and three ‘double positive’ ones. However, the operating principles of larger toggle polygons, i.e. toggle switches arranged circularly to form a polygon, remain unclear. Here, we simulate using both discrete and continuous methods the dynamics of different sized toggle polygons. We observed a pattern in their steady state frequency depending on whether the polygon was an even or odd numbered one. The even-numbered toggle polygons result in two dominant states with consecutive components of the network expressing alternating high and low levels. The odd-numbered toggle polygons, on the other hand, enable more number of states, usually twice the number of components with the states that follow ‘circular permutation’ patterns in their composition. Incorporating self-activations preserved these trends while increasing the frequency of multistability in the corresponding network. Our results offer insights into design principles of circular arrangement of regulatory units involved in cell-fate decision making, and can offer design strategies for synthesizing genetic circuits.

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Stochastic models coupling gene expression and partitioning in cell division in Escherichia coli

Cited by 12 publications

References 121 publications

NRF2-dependent epigenetic regulation can promote the hybrid epithelial/mesenchymal phenotype

NRF2-dependent epigenetic regulation can promote the hybrid epithelial/mesenchymal phenotype

NRF2-dependent Epigenetic Regulation can Promote the Hybrid Epithelial/Mesenchymal Phenotype

Operating principles of circular toggle polygons

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