PT - JOURNAL ARTICLE AU - Sloas, D. Christopher AU - Ngo, John T. TI - Synthetic Mechanotransduction Using Engineered SynNotch Receptors AID - 10.1101/2022.05.01.490205 DP - 2022 Jan 01 TA - bioRxiv PG - 2022.05.01.490205 4099 - http://biorxiv.org/content/early/2022/05/01/2022.05.01.490205.short 4100 - http://biorxiv.org/content/early/2022/05/01/2022.05.01.490205.full AB - Cells can sense and interpret mechanical stimuli from their environment, but the ability to engineer customized mechanosensing capabilities has remained a synthetic biology challenge. Here, we introduce a set of synthetic Notch (SynNotch)-derived proteins that can be used to convert extracellular tensile forces into specifiable gene expression changes. By elevating the tension levels needed to induce SynNotch activation, in combination with structure-guided mutagenesis, we designed tunable mechanoreceptors with sensitivities in the physiologically relevant picoNewton (pN) range. Cells expressing these receptors could distinguish between varying levels of ligand-mediated tension and enact customizable transcriptional responses in turn. The utility of these tools was demonstrated by the design of a decision-making circuit, through which fibroblasts could be made to differentiate into myoblasts in response to mechanostimulation with tensile forces of distinct magnitudes. This work provides insight regarding how mechanically-induced structural alterations in proteins can be used to transduce physical forces into biochemical signals, and the system should facilitate further programming of force-related phenomena in biological systems.Competing Interest StatementThe authors are co-inventors on a patent relating to mechanically-regulated gene expression control.