Duddu, AS and Sahoo, S and Hati, S and Jhunjhunwala, S and Jolly, MK (2020) Multi-stability in cellular differentiation enabled by a network of three mutually repressing master regulators: Multi-stability in cellular differentiation enabled by a network of three mutually repressing master regulators. In: Journal of the Royal Society Interface, 17 (170).
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Abstract
Identifying the design principles of complex regulatory networks driving cellular decision-making remains essential to decode embryonic development as well as enhance cellular reprogramming. A well-studied network motif involved in cellular decision-making is a toggle switch - a set of two opposing transcription factors A and B, each of which is a master regulator of a specific cell fate and can inhibit the activity of the other. A toggle switch can lead to two possible states - (high A, low B) and (low A, high B) - and drives the 'either-or' choice between these two cell fates for a common progenitor cell. However, the principles of coupled toggle switches remain unclear. Here, we investigate the dynamics of three master regulators A, B and C inhibiting each other, thus forming three-coupled toggle switches to form a toggle triad. Our simulations show that this toggle triad can lead to co-existence of cells into three differentiated 'single positive' phenotypes - (high A, low B, low C), (low A, high B, low C) and (low A, low B, high C). Moreover, the hybrid or 'double positive' phenotypes - (high A, high B, low C), (low A, high B, high C) and (high A, low B, high C) - can coexist together with 'single positive' phenotypes. Including self-activation loops on A, B and C can increase the frequency of 'double positive' states. Finally, we apply our results to understand cellular decision-making in terms of differentiation of naive CD4 + T cells into Th1, Th2 and Th17 states, where hybrid Th1/Th2 and hybrid Th1/Th17 cells have been reported in addition to the Th1, Th2 and Th17 ones. Our results offer novel insights into the design principles of a multi-stable network topology and provide a framework for synthetic biology to design tristable systems. © 2020 The Author(s).
| Item Type: | Journal Article |
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| Publication: | Journal of the Royal Society Interface |
| Publisher: | Royal Society Publishing |
| Additional Information: | The copyright for this article belongs to the Author(s). |
| Keywords: | Cytology; Decision making; Synthetic biology; Transcription, Cellular differentiation; Cellular reprogramming; Complex regulatory network; Design Principles; Embryonic development; Master regulators; Multi stabilities; Progenitor cell, T-cells, article; CD4+ T lymphocyte; cell differentiation; decision making; human cell; phenotypic plasticity; simulation; synthetic biology; Th1 cell; Th17 cell |
| Department/Centre: | Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering |
| Date Deposited: | 13 Jan 2023 05:23 |
| Last Modified: | 13 Jan 2023 05:23 |
| URI: | https://eprints.iisc.ac.in/id/eprint/79086 |
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