Department of Computational Science and Engineering, Nagoya University, Nagoya, Japan ; Department of Applied Physics, Nagoya University, Nagoya, Japan ; School of Computational Sciences, Korea Institute for Advanced Study, Seoul, Korea ; Okazaki Institute for Integrative Bioscience, Okazaki, Japan.
Department of Applied Physics, Nagoya University, Nagoya, Japan.
PLoS Comput Biol. 2013;9(12):e1003380. doi: 10.1371/journal.pcbi.1003380. Epub 2013 Dec 12.
A remarkable feature of the self-renewing population of embryonic stem cells (ESCs) is their phenotypic heterogeneity: Nanog and other marker proteins of ESCs show large cell-to-cell variation in their expression level, which should significantly influence the differentiation process of individual cells. The molecular mechanism and biological implication of this heterogeneity, however, still remain elusive. We address this problem by constructing a model of the core gene-network of mouse ESCs. The model takes account of processes of binding/unbinding of transcription factors, formation/dissolution of transcription apparatus, and modification of histone code at each locus of genes in the network. These processes are hierarchically interrelated to each other forming the dynamical feedback loops. By simulating stochastic dynamics of this model, we show that the phenotypic heterogeneity of ESCs can be explained when the chromatin at the Nanog locus undergoes the large scale reorganization in formation/dissolution of transcription apparatus, which should have the timescale similar to the cell cycle period. With this slow transcriptional switching of Nanog, the simulated ESCs fluctuate among multiple transient states, which can trigger the differentiation into the lineage-specific cell states. From the simulated transitions among cell states, the epigenetic landscape underlying transitions is calculated. The slow Nanog switching gives rise to the wide basin of ESC states in the landscape. The bimodal Nanog distribution arising from the kinetic flow running through this ESC basin prevents transdifferentiation and promotes the definite decision of the cell fate. These results show that the distribution of timescales of the regulatory processes is decisively important to characterize the fluctuation of cells and their differentiation process. The analyses through the epigenetic landscape and the kinetic flow on the landscape should provide a guideline to engineer cell differentiation.
胚胎干细胞 (ESC) 自我更新群体的一个显著特征是其表型异质性：Nanog 和其他 ESC 标志物蛋白的表达水平存在很大的细胞间变异性，这应该会显著影响单个细胞的分化过程。然而，这种异质性的分子机制和生物学意义仍然难以捉摸。我们通过构建一个小鼠 ESC 核心基因网络模型来解决这个问题。该模型考虑了转录因子的结合/解吸、转录装置的形成/解体以及基因网络中每个基因位点组蛋白密码的修饰过程。这些过程相互关联，形成动态反馈环。通过模拟该模型的随机动力学，我们表明，当 Nanog 基因座的染色质经历转录装置形成/解体的大规模重组时，可以解释 ESC 的表型异质性，这应该具有与细胞周期周期相似的时间尺度。通过 Nanog 的这种缓慢转录开关，模拟的 ESC 在多个瞬态之间波动，这可以触发向谱系特异性细胞状态的分化。从模拟的细胞状态之间的转变中，计算了转变背后的表观遗传景观。缓慢的 Nanog 切换导致景观中 ESC 状态的宽基底。源于流经 ESC 基底的动力学流的 Nanog 双峰分布阻止了转分化并促进了细胞命运的明确决定。这些结果表明，调节过程的时间尺度分布对于描述细胞的波动及其分化过程至关重要。通过表观遗传景观和景观上的动力学流进行的分析应该为工程细胞分化提供指导。
