An oxo-mechanical coupling determines cell state

Across myriad habitats and diverse lifeforms, oxygen and mechanics are the most ubiquitously varying and profoundly influential environmental regulators. While physiological niches feature both varying oxygen levels and heterogeneous mechanics, laboratory experiments typically interrogate these as independent variables. Here, we show that combinatorial regimes defined by varying oxygen partial pressures and environmental mechanics--an oxo-mechanical cue--induce functionally-distinct cellular states in 3D ECM-like contexts. Single-cell morphometrics combined with multi-omics reveal that cellular response to oxygen deprivation depends on external mechanical milieus, whereas, cellular engagement with different mechanical microenvironments depends on oxygen availability. Independently perturbing both hypoxic signaling and cytoskeletal activity further reveals a reciprocal oxo-mechanical regulatory coupling, which operates by differentially altering the global chromatin accessibility for transcriptional regulation in response to specific combinations of oxygen partial pressures and external mechanical milieus. Together, our findings establish that a coupling between oxygen and mechanics drives the emergence of microenvironmentally-defined cell states.