交叉抑制转录因子的极限环振荡共表达:谱系混杂的模式机制。

IF 0.8 4区 数学 Q4 BIOLOGY Mathematical Medicine and Biology-A Journal of the Ima Pub Date : 2019-03-14 DOI:10.1093/imammb/dqy003
Pavol Bokes, John R King
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引用次数: 2

摘要

谱系开关是控制和维持发育细胞对特定细胞命运的承诺的遗传调控基序。谱系开关的典型例子是一对转录因子PU.1和GATA-1,其中前者与造血系统中的髓系有关,后者与红系有关。在分子水平上,PU.1和GATA-1通过直接的蛋白-蛋白相互作用进行正向调节并相互拮抗。在这里,我们使用数学模型来确定一种新型的动态行为,可以由这样的监管架构支持。根据PU.1-GATA-1相互作用的特点,我们利用质量作用定律,建立了一个关键分子浓度的微分方程系统。经过一系列的系统近似后,系统被简化为一个更简单的系统,该系统易于处理相平面和线性化方法。简化的系统在形式上类似并推广了数学生态学中一个著名的竞争物种模型。然而,除了一对竞争物种所表现出的定性机制(独占性、双稳态独占性、稳定节点共表达)之外,它还允许振荡极限环共表达。该模型的一个关键结果是,在细胞命运选择的背景下,这种振荡可以被分化细胞利用,以交替地产生相反的结果;采用分岔理论的方法来描述这种可能性。
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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 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.

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来源期刊
CiteScore
2.20
自引率
0.00%
发文量
15
审稿时长
>12 weeks
期刊介绍: Formerly the IMA Journal of Mathematics Applied in Medicine and Biology. Mathematical Medicine and Biology publishes original articles with a significant mathematical content addressing topics in medicine and biology. Papers exploiting modern developments in applied mathematics are particularly welcome. The biomedical relevance of mathematical models should be demonstrated clearly and validation by comparison against experiment is strongly encouraged. The journal welcomes contributions relevant to any area of the life sciences including: -biomechanics- biophysics- cell biology- developmental biology- ecology and the environment- epidemiology- immunology- infectious diseases- neuroscience- pharmacology- physiology- population biology
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