Delayed self-regulation and time-dependent chemical drive leads to novel states in epigenetic landscapes.
Delayed self-regulation and time-dependent chemical drive leads to novel states in epigenetic landscapes.
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DOI：
10.1098/rsif.2014.0706
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发表时间：
2014-11-06
期刊：
影响因子：
--
通讯作者：
Chakrabarti B
中科院分区：
文献类型：
--
作者：
Mitra MK;Taylor PR;Hutchison CJ;McLeish TC;Chakrabarti B
细胞从干细胞状态分化为成熟的谱系定型状态时的表观遗传途径历史上一直根据由丘陵和山谷组成的沃丁顿景观来理解。光滑的山顶和山谷布满的山底分别代表了它们的未分化和分化状态。尽管植根于非线性动力学和分岔理论的数学思想已被用来量化这一图景，但迄今为止，由多步化学反应或细胞形状转变引起的时间延迟的重要性被忽视。我们认为，这一特征对于理解细胞分化和探索单基因调控电路模型中时间延迟的作用至关重要。我们表明，时间相关的驱动和延迟的相互作用引入了一种新的机制，其中系统在两个允许的稳态之间显示出持续的振荡。我们根据最近在小鼠体细胞中诱导多能状态的令人困惑的实验来解释这些结果。我们还评论了这种振荡状态如何为理解细胞发育中更一般的反馈电路提供一个框架。
The epigenetic pathway of a cell as it differentiates from a stem cell state to a mature lineage-committed one has been historically understood in terms of Waddington's landscape, consisting of hills and valleys. The smooth top and valley-strewn bottom of the hill represent their undifferentiated and differentiated states, respectively. Although mathematical ideas rooted in nonlinear dynamics and bifurcation theory have been used to quantify this picture, the importance of time delays arising from multistep chemical reactions or cellular shape transformations have been ignored so far. We argue that this feature is crucial in understanding cell differentiation and explore the role of time delay in a model of a single-gene regulatory circuit. We show that the interplay of time-dependent drive and delay introduces a new regime where the system shows sustained oscillations between the two admissible steady states. We interpret these results in the light of recent perplexing experiments on inducing the pluripotent state in mouse somatic cells. We also comment on how such an oscillatory state can provide a framework for understanding more general feedback circuits in cell development.
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