TANGO-Light - optogenetic control of transcriptional modulators

Cell signalling pathways, in particular downstream receptor activation, frequently converge in the activation of transcriptional modulators. Yet, cells are able to differentiate the stimulation of each receptor. It has become clear that transcriptional modulators, such as transcription factors, do not work in on or off states but rather in patterns of active/inactivate conformations. Thus, it is the intensity and duration of such fluctuating activity that result in differential cellular and genes expression changes, and this is challenging to replicate using traditional methods such as inhibitors or genetic constructs. Optogenetics, which is based on the use of light-responsive proteins, offers precise control over biological processes, in a spatio-temporal manner, allowing targeted fine-tuned modulation of specific proteins or signalling pathways. Here, we engineered an optogenetic system to control transcriptional modulators, by fusing a photoactivatable receptor and the TANGO system. By this mean we show that we are able to control a plethora of transcriptional modulators by light. And by doing so, changing cells fate - inducing cells to acquire a more mesenchymal or epithelial phenotype. This optogenetic system was also adapted to mimic signalling pathways such as Notch and Wnt in a light-dose dependent manner. Finally, we show that this light-responsive system can be induced by natural light sources upon cell-cell contact/proximity.