Zhang Shuo, Zhao Juan, Lv Xiangdong, Fan Jialin, Lu Yi, Zeng Tao, Wu Hailong, Chen Luonan, Zhao Yun
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 200031 Shanghai, China.
University of Chinese Academy of Sciences, 100049 Beijing, China.
Cell Discov. 2020 Jun 30;6:43. doi: 10.1038/s41421-020-0173-z. eCollection 2020.
Genetic robustness is an important characteristic to tolerate genetic or nongenetic perturbations and ensure phenotypic stability. Morphogens, a type of evolutionarily conserved diffusible molecules, govern tissue patterns in a direction-dependent or concentration-dependent manner by differentially regulating downstream gene expression. However, whether the morphogen-directed gene regulatory network possesses genetic robustness remains elusive. In the present study, we collected 4217 morphogen-responsive genes along A-P axis of wing discs from the RNA-seq data, and clustered them into 12 modules. By applying mathematical model to the measured data, we constructed a gene modular network (GMN) to decipher the module regulatory interactions and robustness in morphogen-directed development. The computational analyses on asymptotical dynamics of this GMN demonstrated that this morphogen-directed GMN is robust to tolerate a majority of genetic perturbations, which has been further validated by biological experiments. Furthermore, besides the genetic alterations, we further demonstrated that this morphogen-directed GMN can well tolerate nongenetic perturbations (Hh production changes) via computational analyses and experimental validation. Therefore, these findings clearly indicate that the morphogen-directed GMN is robust in response to perturbations and is important for to ensure the proper tissue patterning in wing disc.
遗传稳健性是耐受遗传或非遗传扰动并确保表型稳定性的重要特征。形态发生素是一类进化上保守的可扩散分子，通过差异调节下游基因表达，以方向依赖或浓度依赖的方式控制组织模式。然而，形态发生素导向的基因调控网络是否具有遗传稳健性仍不清楚。在本研究中，我们从RNA测序数据中收集了沿翅盘前后轴的4217个形态发生素响应基因，并将它们聚类为12个模块。通过将数学模型应用于测量数据，我们构建了一个基因模块网络（GMN）来解读形态发生素导向发育中的模块调控相互作用和稳健性。对该GMN渐近动力学的计算分析表明，这种形态发生素导向的GMN对耐受大多数遗传扰动具有稳健性，这已通过生物学实验得到进一步验证。此外，除了基因改变，我们还通过计算分析和实验验证进一步证明，这种形态发生素导向的GMN能够很好地耐受非遗传扰动（Hh产生变化）。因此，这些发现清楚地表明，形态发生素导向的GMN对扰动具有稳健性，并且对于确保翅盘中适当的组织模式很重要。
