Limit-cycle oscillatory coexpression of cross-inhibitory transcription factors: a model mechanism for lineage promiscuity

Bokes, Pavol; King, John R.

Abstract

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.

Citation

Bokes, P., & King, J. R. (in press). Limit-cycle oscillatory coexpression of cross-inhibitory transcription factors: a model mechanism for lineage promiscuity. Mathematical Medicine and Biology, https://doi.org/10.1093/imammb/dqy003

• Journal Article Type: Article
• Acceptance Date: Jan 29, 2018
• Online Publication Date: Feb 23, 2018
• Deposit Date: Mar 7, 2018
• Publicly Available Date: Feb 24, 2019
• Journal: Mathematical Medicine and Biology
• Print ISSN: 1477-8599
• Electronic ISSN: 1477-8602
• Publisher: Oxford University Press
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1093/imammb/dqy003
• Public URL: https://nottingham-repository.worktribe.com/output/916213
• Publisher URL: https://doi.org/10.1093/imammb/dqy003
• Additional Information: This is a pre-copyedited, author-produced version of an article accepted for publication in Mathematical Medicine and Biology following peer review. The version of record Pavol Bokes, John R King; Limit-cycle oscillatory coexpression of cross-inhibitory transcription factors: a model mechanism for lineage promiscuity, Mathematical Medicine and Biology: A Journal of the IMA, , dqy003, https://doi.org/10.1093/imammb/dqy003 is available online at: https://doi.org/10.1093/imammb/dqy003
• Contract Date: Mar 7, 2018