Pairing competitive and topologically distinct regulatory modules enhances patterned gene expression

Biological networks are inherently modular, yet little is known about how modules are assembled to enable coordinated and complex functions. We used RNAi and time-series, whole-genome microarray analyses to systematically perturb and characterize components of a C. elegans lineage-specific transcriptional regulatory network. These data are supported by select reporter gene analyses and comprehensive yeast-one-hybrid and promoter sequence analyses. Based on these results we define and characterize two modules composed of muscle- and epidermal-specifying transcription factors that function together within a single cell lineage to robustly specify multiple cell types. The expression of these two modules, although positively regulated by a common factor, is reliably segregated among daughter cells. Our analyses indicate that these modules repress each other, and we propose that this cross-inhibition coupled with their relative time of induction function to enhance the initial asymmetry in their expression patterns, thus leading to the observed invariant gene expression patterns and cell lineage. The coupling of asynchronous and topologically distinct modules may be a general principle of module assembly that functions to potentiate genetic switches. Keywords: Gene expression response of RNAi knockdowns生物网络本质上具有模块化特性，但目前对于模块如何组装以实现协同且复杂的生物学功能仍知之甚少。我们通过RNA干扰（RNA interference, RNAi）与全基因组时间序列微阵列分析，对秀丽隐杆线虫（Caenorhabditis elegans）谱系特异性转录调控网络的组分进行系统性扰动与表征。本数据集辅以筛选后的报告基因分析、全面的酵母单杂交（yeast one-hybrid）与启动子序列分析结果作为验证支撑。基于上述结果，我们定义并表征了由肌肉特异性与表皮特异性转录因子组成的两个模块，二者在同一细胞谱系中协同发挥功能，可稳定特化多种细胞类型。尽管这两个模块的表达均受同一转录因子的正向调控，但其表达模式会在子代细胞中稳定分离。我们的分析显示，这两个模块彼此相互抑制；据此我们提出，这种交叉抑制结合二者的相对诱导时序，可强化其表达模式的初始不对称性，进而形成已观测到的恒定基因表达模式与细胞谱系。异步且拓扑结构迥异的模块间的耦合，或许是模块组装的通用原则，该原则可增强遗传开关的调控效能。关键词：RNA干扰敲低后的基因表达响应