Rothenberg Ellen V
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California.
J Comput Biol. 2019 Jul;26(7):703-718. doi: 10.1089/cmb.2019.0098. Epub 2019 May 7.
Gene regulatory network modeling has played a major role in advancing the understanding of developmental systems, by crystallizing structures of relevant extant information, by formally posing hypothetical functional relationships between network elements, and by offering clear predictive tests to improve understanding of the mechanisms driving developmental progression. Both ordinary differential equation (ODE)-based and Boolean models have also been highly successful in explaining dynamics within subcircuits of more complex processes. In a very small number of cases, gene regulatory network models of much more global scope have been proposed that successfully predict the dynamics of the processes establishing most of an embryonic body plan. Can such successes be expanded to very different developmental systems, including post-embryonic mammalian systems? This perspective discusses several problems that must be solved in more quantitative and predictive theoretical terms, to make this possible. These problems include: the effects of cellular history on chromatin state and how these affect gene accessibility; the dose dependence of activities of many transcription factors (a problem for Boolean models); stochasticity of some transcriptional outputs (a problem for simple ODE models); response timing delays due to epigenetic remodeling requirements; functionally different kinds of repression; and the regulatory syntax that governs responses of genes with multiple enhancers.
基因调控网络建模在推动对发育系统的理解方面发挥了重要作用，它通过梳理相关现有信息的结构，通过正式提出网络元件之间的假设功能关系，以及通过提供明确的预测性测试来增进对驱动发育进程机制的理解。基于常微分方程（ODE）的模型和布尔模型在解释更复杂过程的子回路中的动态方面也都非常成功。在极少数情况下，已经提出了范围更广的基因调控网络模型，这些模型成功地预测了建立大部分胚胎体轴的过程的动态。这样的成功能否扩展到非常不同的发育系统，包括胚胎后哺乳动物系统？本文观点讨论了为实现这一目标必须从更定量和预测性的理论角度解决的几个问题。这些问题包括：细胞历史对染色质状态的影响以及这些影响如何影响基因可及性；许多转录因子活性的剂量依赖性（这是布尔模型面临的一个问题）；一些转录输出的随机性（这是简单ODE模型面临的一个问题）；由于表观遗传重塑需求导致的反应时间延迟；功能不同类型的抑制；以及控制具有多个增强子的基因反应的调控语法。
