Department of Chemical Engineering, Technion, Haifa, Israel.
Network Biology Research Laboratories, Lorry Lokey Center for Life Sciences and Engineering, Technion, Haifa, Israel.
PLoS One. 2020 Sep 3;15(9):e0238433. doi: 10.1371/journal.pone.0238433. eCollection 2020.
Phenotypic switches are associated with alterations in the cell's gene expression profile and are vital to many aspects of biology. Previous studies have identified local motifs of the genetic regulatory network that could underlie such switches. Recent advancements allowed the study of networks at the global, many-gene, level; however, the relationship between the local and global scales in giving rise to phenotypic switches remains elusive. In this work, we studied the epithelial-mesenchymal transition (EMT) using a gene regulatory network model. This model supports two clusters of stable steady-states identified with the epithelial and mesenchymal phenotypes, and a range of intermediate less stable hybrid states, whose importance in cancer has been recently highlighted. Using an array of network perturbations and quantifying the resulting landscape, we investigated how features of the network at different levels give rise to these landscape properties. We found that local connectivity patterns affect the landscape in a mostly incremental manner; in particular, a specific previously identified double-negative feedback motif is not required when embedded in the full network, because the landscape is maintained at a global level. Nevertheless, despite the distributed nature of the switch, it is possible to find combinations of a few local changes that disrupt it. At the level of network architecture, we identified a crucial role for peripheral genes that act as incoming signals to the network in creating clusters of states. Such incoming signals are a signature of modularity and are expected to appear also in other biological networks. Hybrid states between epithelial and mesenchymal arise in the model due to barriers in the interaction between genes, causing hysteresis at all connections. Our results suggest emergent switches can neither be pinpointed to local motifs, nor do they arise as typical properties of random network ensembles. Rather, they arise through an interplay between the nature of local interactions, and the core-periphery structure induced by the modularity of the cell.
表型转换与细胞基因表达谱的改变有关，对生物学的许多方面都至关重要。先前的研究已经确定了遗传调控网络的局部基序，这些基序可能是这种转换的基础。最近的进展允许在全局、多基因水平上研究网络；然而，在产生表型转换方面，局部和全局尺度之间的关系仍然难以捉摸。在这项工作中，我们使用基因调控网络模型研究了上皮-间充质转化（EMT）。该模型支持两种稳定的稳态簇，分别是上皮表型和间充质表型，以及一系列中间不稳定的混合状态，这些状态在癌症中的重要性最近得到了强调。我们使用一系列网络扰动并量化了由此产生的景观，研究了不同层次的网络特征如何产生这些景观特性。我们发现，局部连接模式以增量方式影响景观；特别是，在全网络中嵌入时，不需要特定的先前确定的双负反馈基序，因为景观在全局水平上得以维持。然而，尽管转换具有分布式性质，但有可能找到少数局部变化的组合来破坏它。在网络架构层面，我们确定了外围基因作为网络的输入信号在创建状态簇方面的关键作用。这种输入信号是模块性的特征，预计也会出现在其他生物网络中。由于基因之间相互作用的障碍，上皮和间充质之间的混合状态出现在模型中，导致所有连接的滞后。我们的结果表明，涌现的转换既不能精确定位到局部基序，也不能作为随机网络集合的典型特性出现。相反，它们是通过局部相互作用的性质与细胞模块性引起的核心-外围结构之间的相互作用而产生的。
