Limit-cycle oscillatory coexpression of cross-inhibitory transcription factors: a model mechanism for lineage promiscuity
Lineage switches are genetic regulatory motifs that govern and maintain the commitment of a developing cell to a particular cell fate. A canonical example of a lineage switch is the pair of transcription factors PU.1 and GATA-1, of which the former is affiliated with the myeloid and the latter with...
| Main Authors: | , |
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| Format: | Article |
| Language: | English |
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Oxford University Press
2018
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| Online Access: | https://eprints.nottingham.ac.uk/50280/ |
| _version_ | 1848798208137887744 |
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| author | Bokes, Pavol King, John R. |
| author_facet | Bokes, Pavol King, John R. |
| author_sort | Bokes, Pavol |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Lineage switches are genetic regulatory motifs that govern and maintain the commitment of a developing cell to a particular cell fate. A canonical example of a lineage switch is the pair of transcription factors PU.1 and GATA-1, of which the former is affiliated with the myeloid and the latter with the erythroid lineage within the haematopoietic system. On a molecular level, PU.1 and GATA-1 positively regulate themselves and antagonize each other via direct protein–protein interactions. Here we use mathematical modelling to identify a novel type of dynamic behaviour that can be supported by such a regulatory architecture. Guided by the specifics of the PU.1–GATA-1 interaction, we formulate, using the law of mass action, a system of differential equations for the key molecular concentrations. After a series of systematic approximations, the system is reduced to a simpler one, which is tractable to phase-plane and linearization methods. The reduced system formally resembles, and generalizes, a well-known model for competitive species from mathematical ecology. However, in addition to the qualitative regimes exhibited by a pair of competitive species (exclusivity, bistable exclusivity, stable-node coexpression) it also allows for oscillatory limit-cycle coexpression. A key outcome of the model is that, in the context of cell-fate choice, such oscillations could be harnessed by a differentiating cell to prime alternately for opposite outcomes; a bifurcation-theory approach is adopted to characterize this possibility. |
| first_indexed | 2025-11-14T20:16:07Z |
| format | Article |
| id | nottingham-50280 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T20:16:07Z |
| publishDate | 2018 |
| publisher | Oxford University Press |
| recordtype | eprints |
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| spelling | nottingham-502802019-02-23T04:30:14Z https://eprints.nottingham.ac.uk/50280/ Limit-cycle oscillatory coexpression of cross-inhibitory transcription factors: a model mechanism for lineage promiscuity Bokes, Pavol King, John R. Lineage switches are genetic regulatory motifs that govern and maintain the commitment of a developing cell to a particular cell fate. A canonical example of a lineage switch is the pair of transcription factors PU.1 and GATA-1, of which the former is affiliated with the myeloid and the latter with the erythroid lineage within the haematopoietic system. On a molecular level, PU.1 and GATA-1 positively regulate themselves and antagonize each other via direct protein–protein interactions. Here we use mathematical modelling to identify a novel type of dynamic behaviour that can be supported by such a regulatory architecture. Guided by the specifics of the PU.1–GATA-1 interaction, we formulate, using the law of mass action, a system of differential equations for the key molecular concentrations. After a series of systematic approximations, the system is reduced to a simpler one, which is tractable to phase-plane and linearization methods. The reduced system formally resembles, and generalizes, a well-known model for competitive species from mathematical ecology. However, in addition to the qualitative regimes exhibited by a pair of competitive species (exclusivity, bistable exclusivity, stable-node coexpression) it also allows for oscillatory limit-cycle coexpression. A key outcome of the model is that, in the context of cell-fate choice, such oscillations could be harnessed by a differentiating cell to prime alternately for opposite outcomes; a bifurcation-theory approach is adopted to characterize this possibility. Oxford University Press 2018-02-23 Article PeerReviewed application/pdf en https://eprints.nottingham.ac.uk/50280/1/Limit%20cycle.pdf Bokes, Pavol and King, John R. (2018) Limit-cycle oscillatory coexpression of cross-inhibitory transcription factors: a model mechanism for lineage promiscuity. Mathematical Medicine and Biology . ISSN 1477-8602 https://doi.org/10.1093/imammb/dqy003 doi:10.1093/imammb/dqy003 doi:10.1093/imammb/dqy003 |
| spellingShingle | Bokes, Pavol King, John R. Limit-cycle oscillatory coexpression of cross-inhibitory transcription factors: a model mechanism for lineage promiscuity |
| title | Limit-cycle oscillatory coexpression of cross-inhibitory transcription factors: a model mechanism for lineage promiscuity |
| title_full | Limit-cycle oscillatory coexpression of cross-inhibitory transcription factors: a model mechanism for lineage promiscuity |
| title_fullStr | Limit-cycle oscillatory coexpression of cross-inhibitory transcription factors: a model mechanism for lineage promiscuity |
| title_full_unstemmed | Limit-cycle oscillatory coexpression of cross-inhibitory transcription factors: a model mechanism for lineage promiscuity |
| title_short | Limit-cycle oscillatory coexpression of cross-inhibitory transcription factors: a model mechanism for lineage promiscuity |
| title_sort | limit-cycle oscillatory coexpression of cross-inhibitory transcription factors: a model mechanism for lineage promiscuity |
| url | https://eprints.nottingham.ac.uk/50280/ https://eprints.nottingham.ac.uk/50280/ https://eprints.nottingham.ac.uk/50280/ |