Polarization of regulatory inputs reveals structural constraints in reconstructed pathway-associated regulatory networks
Year: 2026
Type: preprint
Abstract: Activating and inhibitory interactions jointly shape cellular regulation, yet it remains unclear whether their allocation among individual targets exhibits systematic organization beyond basic structural constraints. Here we introduce antagonistic–cooperative polarization, a target-wise principle in which the sign of each regulatory interaction is determined by the class of its target. This formulation yields a node-separable graph polarization index and decomposes departures from perfect polarization exactly into localized conflicts at targets receiving both activating and inhibitory inputs. We applied the framework to 98 pathway-associated regulatory subnetworks reconstructed from a unified signed regulatory network. Target-wise sign consistency was generally high, but the key evidence for non-random organization came from constrained null models: mixed-input targets were depleted relative to both global sign shuffling and degree-preserving directed rewiring, with depletion increasing systematically with pathway size. This association was robust to rewiring-mobility and pathway-overlap analyses, and indegree-stratified analysis identified the clearest statistically supported depletion among targets receiving exactly two signed inputs. Mixed-input organization was pathway-specific but recurrent across genes; recurrent mixed-input targets remained enriched for Cancer Gene Census genes after accounting for pathway opportunity. Mixed-input occurrences were also preferentially associated with signed feedback motifs, particularly negative feedback, whereas downstream reach was not increased. Together, these results reveal a prevalent polarized backbone punctuated by localized sites of opposing regulation whose abundance departs from expectations under complementary null models controlling for network topology, sign composition, degree structure, and source-specific regulatory output.
Institutions: Magna Graecia University, University of Naples Federico II
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7222828836