Feedback enrichment analysis for transcription factor-target genes in signaling pathways

Feedback regulation plays an important role in the regulation of molecular processes. Although feedback regulatory mechanisms that generate potential-specific dynamic behavior, such as oscillation and switch-like activation, have been found, their significant contribution to the signal transduction system has not been fully explored. In this study, I focused on the feedback regulation of signal molecules like transcription factor (TF)-associated target genes controlled after transcription (named TF-target feedback genes). I statistically analyzed the static network of signal transduction pathways and TF-target feedbacks to investigate their presence in upstream signal molecules of TFs in 394 different cell types, including 146 primary cells, 111 tissues, and 137 cell lines. The directed network of signal transduction utilized pathways annotated in KEGG, and the TF-target genes estimated per individual cells were used. Feedback enrichment analysis of upstream signal molecules of TF was performed to investigate whether TF-target genes are upstream of their TF and form a feedback loop in signal transduction. The study revealed the difference in the number of TF-target feedbacks between cells, while each cell had at least 11 significant TF-target feedbacks and invariably involved the E2F transcription factor 4 feedback within the cell cycle. The findings suggest the possibility of the regulation of the TF-associated signal transduction by the TF itself at the transcription level.