High-dimensional switches and the modelling of cellular differentiation
High-dimensional switches and the modelling of cellular differentiation
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DOI：
10.1016/j.jtbi.2004.10.027
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发表时间：
2005-04-07
影响因子：
2
通讯作者：
Demongeot, J
中科院分区：
文献类型：
--
作者：
Cinquin, O;Demongeot, J
许多基因已被确定为驱动细胞分化，但由于它们复杂的相互作用，理解它们的集体行为需要数学模型。有趣的是，在许多发育背景下，特别是在造血方面，已经观察到调控分化的基因最初在祖细胞中共表达，尽管它们存在拮抗作用，但在一个基因上调而另一些基因下调之前。我们描述了三类在实验观察到的相互作用(包括bHLH蛋白二聚化)后在分子水平上模拟的、包括任意数量的拮抗成分的通用“主调控网络”可以起到“多开关”的作用，以全有或全无的方式指导从两种以上可能的结果中选择的特定细胞类型的分化。BHLH二聚网络在竞争较弱时可以很容易地显示出许多拮抗因素共存(得出了一个简单的特征)。竞争的短暂增加可能会迫使做出决定，这可能对应于一些与ID蛋白质相关的无法解释的实验观察；响应速度因网络所受的初始条件而异，这可能解释重新编程时细胞行为的某些方面。在分化过程早期或在多能干细胞中，低水平的拮抗因子共存可能是这些因子之间相互作用的固有特性，不需要特定的调控系统。(C)2004爱思唯尔有限公司。保留所有权利。
Many genes have been identified as driving cellular differentiation, but because of their complex interactions, the understanding of their collective behaviour requires mathematical modelling. Intriguingly, it has been observed in numerous developmental contexts, and particularly haematopoiesis, that genes regulating differentiation are initially co-expressed in progenitors despite their antagonism, before one is upregulated and others downregulated. We characterise conditions under which three classes of generic "master regulatory networks", modelled at the molecular level after experimentally observed interactions (including bHLH protein dimerisation), and including an arbitrary number of antagonistic components, can behave as a "multi-switch", directing differentiation in an all-or-none fashion to a specific cell-type chosen among more than two possible outcomes. bHLH dimerisation networks can readily display coexistence of many antagonistic factors when competition is low (a simple characterisation is derived). Decision-making can be forced by a transient increase in competition, which could correspond to some unexplained experimental observations related to Id proteins; the speed of response varies with the initial conditions the network is subjected to, which could explain some aspects of cell behaviour upon reprogramming. The coexistence of antagonistic factors at low levels, early in the differentiation process or in pluripotent stem cells, could be an intrinsic property of the interaction between those factors, not requiring a specific regulatory system. (C) 2004 Elsevier Ltd. All rights reserved.