Departments of Chemistry andCenter for Theoretical Biological Physics, Rice University, Houston, TX 77005.
Departments of Chemistry andCenter for Theoretical Biological Physics, Rice University, Houston, TX 77005Physics and Astronomy, and
Proc Natl Acad Sci U S A. 2014 Jul 15;111(28):10185-90. doi: 10.1073/pnas.1408561111. Epub 2014 Jun 19.
Stem cell differentiation has been viewed as coming from transitions between attractors on an epigenetic landscape that governs the dynamics of a regulatory network involving many genes. Rigorous definition of such a landscape is made possible by the realization that gene regulation is stochastic, owing to the small copy number of the transcription factors that regulate gene expression and because of the single-molecule nature of the gene itself. We develop an approximation that allows the quantitative construction of the epigenetic landscape for large realistic model networks. Applying this approach to the network for embryonic stem cell development explains many experimental observations, including the heterogeneous distribution of the transcription factor Nanog and its role in safeguarding the stem cell pluripotency, which can be understood by finding stable steady-state attractors and the most probable transition paths between those attractors. We also demonstrate that the switching rate between attractors can be significantly influenced by the gene expression noise arising from the fluctuations of DNA occupancy when binding to a specific DNA site is slow.
干细胞分化被认为是来自于表观遗传景观上吸引子之间的转变，该景观控制着涉及许多基因的调控网络的动态。由于转录因子的拷贝数较少，基因表达受到调控，并且由于基因本身的单分子性质，因此可以通过实现基因调控的随机性来严格定义这样的景观。我们开发了一种近似方法，允许对大型现实模型网络进行表观遗传景观的定量构建。将这种方法应用于胚胎干细胞发育的网络，可以解释许多实验观察结果，包括转录因子 Nanog 的异质分布及其在保护干细胞多能性中的作用，通过找到稳定的稳态吸引子和这些吸引子之间最可能的转变路径，可以理解这一点。我们还证明，当结合到特定的 DNA 位点时，DNA 占有率的波动会导致基因表达噪声，从而显著影响吸引子之间的转换速率。
