What Makes a Functional Gene Regulatory Network? A Circuit Motif Analysis

One of the key questions in systems biology is to understand the roles of gene regulatory circuits in determining cellular states and their functions. In previous studies, some researchers have inferred large gene networks from genome wide genomics/transcriptomics data using the top-down approach, while others have modeled core gene circuits of small sizes using the bottom-up approach. Despite many existing systems biology studies, there is still no general rule on what sizes of gene networks and what types of circuit motifs a system would need to achieve robust biological functions. Here, we adopt a gene circuit motif analysis to discover four-node circuits responsible for multiplicity (rich in dynamical behavior), flexibility (versatile to alter gene expression), or both. We identify the most reoccurring two-node circuit motifs and the co-occurring motif pairs. Furthermore, we investigate the contributing factors of multiplicity and flexibility for large gene networks of different types and sizes. We find that gene networks of intermediate sizes tend to have combined high levels of multiplicity and flexibility. Our study will contribute to a better understanding of the dynamical mechanisms of gene regulatory circuits and provide insights into rational designs of robust gene circuits in synthetic and systems biology.