{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Duddu AS"],"funding":["Science and Engineering Research Board"],"pagination":["20200631"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC7536062"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["17(170)"],"pubmed_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<sup>+</sup> 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."],"journal":["Journal of the Royal Society, Interface"],"pubmed_title":["Multi-stability in cellular differentiation enabled by a network of three mutually repressing master regulators."],"pmcid":["PMC7536062"],"funding_grant_id":["SB/S2/RJN-049/2018"],"pubmed_authors":["Jhunjhunwala S","Sahoo S","Jolly MK","Duddu AS","Hati S"],"additional_accession":[]},"is_claimable":false,"name":"Multi-stability in cellular differentiation enabled by a network of three mutually repressing master regulators.","description":"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<sup>+</sup> 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.","dates":{"release":"2020-01-01T00:00:00Z","publication":"2020 Sep","modification":"2025-04-04T13:57:29.152Z","creation":"2025-04-04T13:57:29.152Z"},"accession":"S-EPMC7536062","cross_references":{"pubmed":["32993428"],"doi":["10.1098/rsif.2020.0631"]}}