Detecting and dissecting signaling crosstalk via the multilayer network integration of signaling and regulatory interactions [article]

Arda Halu, Seung Han Baek, Ian Lo, Leonardo Martini, Edwin K. Silverman, Scott T. Weiss, Kimberly R. Glass
2022 bioRxiv   pre-print
AbstractThe versatility of cellular response arises from the communication, or crosstalk, of signaling pathways in a complex network of signaling and transcriptional regulatory interactions. Understanding the various mechanisms underlying crosstalk on a global scale requires untargeted computational approaches. We present a network-based statistical approach, MuXTalk, that uses high-dimensional edges called multilinks to model the unique ways in which signaling and regulatory interactions can
more » ... terface. We demonstrate that the signaling-regulatory interface is located primarily in the intermediary region between signaling pathways where crosstalk occurs, and that multilinks can differentiate between distinct signaling-transcriptional mechanisms. Using statistically over-represented multilinks as proxies of crosstalk, we predict crosstalk among 60 signaling pathways, expanding currently available crosstalk databases by more than five-fold. MuXTalk surpasses existing methods in terms of prediction performance, identifies additions to manual curation efforts, and pinpoints potential mediators of crosstalk for each prediction. Moreover, it accommodates the inherent context-dependence of crosstalk, allowing future applications to cell type- and disease-specific crosstalk.
doi:10.1101/2022.09.29.510183 fatcat:n2gczqw7hfc7xjgaudhwppdawe