Discovering Feedback and Coupled Feedback Loops in KEGG Pathways through Cross-Map Identification

Each gene regulatory network (GRN) involves a set of DNA components and indirectly interacts each other to control gene expression rates. Especially, some sub-networks appear in a GRN holding feedback loop or coupled feedback loop mechanisms, which possess specific relationships and aim to maintain certain functional conditions. Many cases have been reported and experimentally verified the existence of feedback and coupled feedback loops in transcription regulatory networks. However, most feedback loops were not shown directly from the pathways reported by KEGG database. In this study, we integrated all possible cross-regulatory pathways within KEGG maps through examining the feedback relationship among all genes. A total of 427 biological pathway maps were verified individually and an on-line web based system was designed for identifying a specified gene for its possible feedback relationship. In addition, paralogous gene information was also considered for discovering potential coupled feedback loop relationships. There are 50 newly identified feedback loops and 124 coupled feedback loops were found in this study, of which 48 (96%) feedback loops were constructed from different KEGG maps. The built cross-linked pathways could facilitate biologists in understanding how the unveiled dynamic patterns of gene regulation maintain the balance of a specific biological function.