Multistability in cellular differentiation enabled by a network of three mutually repressing master regulators

Duddu, Atchuta Srinivas; Sahoo, Sarthak; Hati, Souvadra; Jhunjhunwala, Siddharth; Jolly, Mohit Kumar

doi:10.1101/2020.05.14.089805

Cited by 6 publications

(8 citation statements)

References 72 publications

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“…Similarly, distribution within the bistable states is broadly conserved: for the 5-component network, all bistable phases (the combination of steady states) formed as a combination of any of the ten dominant monostable states together have a frequency of about 80% (Fig 6B). The dominance of these bistable states as a combination of any of the dominant monostable states continues for 7-component (Fig 6B ) and, 9-component (Fig S6A) toggle polygon as well, thus resonating with our previous observation for the toggle triad network [18].…”

Section: Figure 5: Odd-numbered Toggle Polygons Comparison Between the Most Frequent Solutions Of The Different Odd-element Toggle Polygosupporting

confidence: 88%

“…Next, we focused on odd-numbered toggle polygons. Our previous simulations showed that a toggle triad network could converge to one of the six dominant states: three 'single-positive' ones (only one of the nodes of the network is high, other two are low -(A, B, C) = (1, 0, 0), (0, 1, 0) or (0, 0, 1)) and the three 'double positive' ones (two of the nodes in the network are high -(A, B, C) = (1, 0, 1), (0, 1, 1), (1, 0, 1)) [18]. We next analyzed the steady states of higher order oddnumbered toggle polygon networks to find similarities and differences with trends seen for toggle triad.…”

Section: Design Principles Of Odd-numbered Toggle Polygonsmentioning

confidence: 99%

“…Such a toggle triad, i.e., a circular coupling of three toggle switches (between A and B, between B and C, and between A and C), can enable three dominant distinct stable steady states -(high A, low B, low C), (low A, high B, low C) and (low A, low B, high C), each corresponding to a differentiated cell type. Similar to a toggle switch, including self-activations on A, B and C can enrich for hybrid states -(high A, high B, low C), (high A, low B, high C) and (low A, high B, high C) (Th1/Th2, Th2/Th17 and Th1/Th17 in this case) [18]. However, the dynamics and design principles of higher-order circular coupling of toggle switches remains unclear.…”

Section: Introductionmentioning

confidence: 96%

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Operating principles of circular toggle polygons

Hati¹,

Duddu²,

Jolly³

2021

Phys. Biol.

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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 oddnumbered 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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Section: Figure 5: Odd-numbered Toggle Polygons Comparison Between the Most Frequent Solutions Of The Different Odd-element Toggle Polygosupporting

confidence: 88%

Section: Design Principles Of Odd-numbered Toggle Polygonsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

See 1 more Smart Citation

Operating principles of circular toggle polygons

Hati¹,

Duddu²,

Jolly³

2021

Phys. Biol.

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“…We define a link-strength metric similar to the one used earlier [95] to quantify the strength of each link independent of its activation at steady state. The link strength ( !…”

Section: Link Strength Metricsmentioning

confidence: 99%

Hybrid E/M phenotype(s) and stemness: a mechanistic connection embedded in network topology

Pasani

Sahoo

Jolly

2020

Preprint

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Metastasis remains an unsolved clinical challenge. Two crucial features of metastasizing cancer cells are a) their ability to dynamically move along the epithelial-hybrid-mesenchymal spectrum and b) their tumor-initiation potential or stemness. With increasing functional characterization of hybrid epithelial /mesenchymal (E/M) phenotypes along the spectrum, recent in vitro and in vivo studies have suggested an increasing association of hybrid E/M phenotypes with stemness. However, the mechanistic underpinnings enabling this association remain unclear. Here, we develop a mechanism-based mathematical modeling framework that interrogates the emergent nonlinear dynamics of the coupled network modules regulating E/M plasticity (miR-200/ZEB) and stemness (LIN28/let-7). Simulating the dynamics of this coupled network across a large ensemble of parameter sets, we observe that hybrid E/M phenotype(s) are more likely to acquire stemness relative to 'pure' epithelial or mesenchymal states. We also integrate multiple 'phenotypic stability factors' (PSFs) that have been shown to stabilize hybrid E/M phenotypes both in silico and in vitro - such as OVOL1/2, GRHL2, and NRF2 - with this network, and demonstrate that the enrichment of hybrid E/M phenotype(s) with stemness is largely conserved in the presence of these PSFs. Thus, our results offer mechanistic insights into recent experimental observations of hybrid E/M phenotype(s) being essential for tumor-initiation and highlight how this feature is embedded in the underlying topology of interconnected EMT and stemness networks.

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“…Next, we focused on odd-numbered toggle polygons. Our previous simulations showed that a toggle triad network could converge to one of the six dominant states: three ‘single-positive’ ones (only one of the nodes of the network is high, other two are low – (A, B, C) = (1, 0, 0), (0, 1, 0) or (0, 0, 1)) and the three ‘double positive’ ones (two of the nodes in the network are high – (A, B, C) = (1, 0, 1), (0, 1, 1), (1, 0, 1)) [18]. We next analyzed the steady states of higher order odd-numbered toggle polygon networks to find similarities and differences with trends seen for toggle triad.…”

Section: Resultsmentioning

confidence: 99%

Operating principles of circular toggle polygons

Hati

Duddu

Jolly

2020

Preprint

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Multistability in cellular differentiation enabled by a network of three mutually repressing master regulators

Cited by 6 publications

References 72 publications

Operating principles of circular toggle polygons

Operating principles of circular toggle polygons

Hybrid E/M phenotype(s) and stemness: a mechanistic connection embedded in network topology

Operating principles of circular toggle polygons

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