Multistability and transitions between spatiotemporal patterns through versatile Notch-Hes signaling

Pfeuty, Benjamin

doi:10.1016/j.jtbi.2022.111060

Cited by 4 publications

(2 citation statements)

References 81 publications

(83 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Multistability is a hallmark of diverse cell-fate decision regulatory networks [2], and synthetic multistable circuits are being increasingly integrated in E. coli, yeast and mammalian cells [9,[36][37][38]. It is not observed only at an intracellular level, but also in spatial tissue-level patterning through the emergent dynamics of cell-cell communication networks such as Notch-Delta-Jagged signaling [39,40]. Thus, decoding the dynamical traits of multistable networks is critical to better understand cellular development and reprogramming and has attracted extensive theoretical attention too [41].…”

Section: Discussionmentioning

confidence: 99%

Multistability and predominant double-positive states in a four node mutually repressive network: a case study of Th1/Th2/Th17/T-reg differentiation

Duddu,

Andreas,

Harshavardhan

et al. 2024

Preprint

View full text Add to dashboard Cite

Elucidating the emergent dynamics of complex regulatory networks enabling cellular differentiation is crucial to understand embryonic development and suggest strategies for synthetic circuit design. A well-studied network motif often driving cellular decisions is a toggle switch - a set of two mutually inhibitory lineage-specific transcription factors A and B. A toggle switch often enables two possible mutually exclusive states - (high A, low B) and (low A, high B) - from a common progenitor cell. However, the dynamics of networks enabling differentiation of more than two cell types from a progenitor cell is not well-studied. Here, we investigate the dynamics of four master regulators A, B, C and D inhibiting each other, thus forming a toggle tetrahedron. Our simulations show that a toggle tetrahedron predominantly allows for co-existence of six ‘double positive’ or hybrid states where two of the nodes are expressed relatively high as compared to the remaining two - (high A, high B, low C, low D), (high A, low B, high C, low D), (high A, low B, low C, high D), (low A, high B, high C, low D), (low A, low B, high C, high D) and (low A, high B, low C, high D). Stochastic simulations showed state-switching among these phenotypes, indicating phenotypic plasticity. Finally, we apply our results to understand the differentiation of naive CD4+T cells into Th1, Th2, Th17 and Treg subsets, suggesting Th1/Th2/Th17/Treg decision-making to be a two-step process. Our results reveal multistable dynamics and establish the stable co-existence of hybrid cell-states, offering a potential explanation for simultaneous differentiation of multipotent naïve CD4+ T cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Multistability and predominant double-positive states in a four node mutually repressive network: a case study of Th1/Th2/Th17/T-reg differentiation

Duddu,

Andreas,

Harshavardhan

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…This paper aims to shed light on these questions. Mathematics, and particularly dynamical systems theory, has had an impact on understanding gene expression dynamics [33][34][35] (specifically Hes1 dynamics [36][37][38][39]), the cell cycle [40][41][42][43][44][45] and their links to cell fate [46][47][48]. Although the relationship between Hes1 and cell cycle has previously been investigated in large, multiple parameter models (in [49], for example), thus far, no two-component (Hes1/cell cycle) model exists.…”

Section: Introductionmentioning

confidence: 99%

Bilateral Feedback in Oscillator Model Is Required to Explain the Coupling Dynamics of Hes1 with the Cell Cycle

Rowntree

Sabherwal²,

Papalopulu

2022

Mathematics

View full text Add to dashboard Cite

Biological processes are governed by the expression of proteins, and for some proteins, their level of expression can fluctuate periodically over time (i.e., they oscillate). Many oscillatory proteins (e.g., cell cycle proteins and those from the HES family of transcription factors) are connected in complex ways, often within large networks. This complexity can be elucidated by developing intuitive mathematical models that describe the underlying critical aspects of the relationships between these processes. Here, we provide a mathematical explanation of a recently discovered biological phenomenon: the phasic position of the gene Hes1’s oscillatory expression at the beginning of the cell cycle of an individual human breast cancer stem cell can have a predictive value on how long that cell will take to complete a cell cycle. We use a two-component model of coupled oscillators to represent Hes1 and the cell cycle in the same cell with minimal assumptions. Inputting only the initial phase angles, we show that this model is capable of predicting the dynamic mitosis to mitosis behaviour of Hes1 and predicting cell cycle length patterns as found in real-world experimental data. Moreover, we discover that bidirectional coupling between Hes1 and the cell cycle is critical within the system for the data to be reproduced and that nonfixed asymmetry in the interactions between the oscillators is required. The phase dynamics we present here capture the complex interplay between Hes1 and the cell cycle, helping to explain nongenetic cell cycle variability, which has critical implications in cancer treatment contexts.

show abstract

Modulating Th1/Th2 drift in asthma-related immune inflammation by enhancing bone mesenchymal stem cell homing through targeted inhibition of the Notch1/Jagged1 signaling pathway

Kun,

Xiaomei,

Lei

et al. 2024

International Immunopharmacology

View full text Add to dashboard Cite

Multistability and transitions between spatiotemporal patterns through versatile Notch-Hes signaling

Cited by 4 publications

References 81 publications

Multistability and predominant double-positive states in a four node mutually repressive network: a case study of Th1/Th2/Th17/T-reg differentiation

Multistability and predominant double-positive states in a four node mutually repressive network: a case study of Th1/Th2/Th17/T-reg differentiation

Bilateral Feedback in Oscillator Model Is Required to Explain the Coupling Dynamics of Hes1 with the Cell Cycle

Modulating Th1/Th2 drift in asthma-related immune inflammation by enhancing bone mesenchymal stem cell homing through targeted inhibition of the Notch1/Jagged1 signaling pathway

Contact Info

Product

Resources

About