Epigenetic regulator Stuxnet modulates octopamine effect on sleep through a Stuxnet-Polycomb-OctB2R cascade

Sleep homeostasis is crucial for sleep regulation. The role of epigenetic regulation in sleep homeostasis is unestablished. Previous studies showed that octopamine is important for sleep homeostasis. However, the regulatory mechanism of octopamine reception in sleep is unknown. In this study, we identify an epigenetic regulatory cascade (Stuxnet-Polycomb-Oct?2R) that modulates the octopamine receptor in Drosophila. We demonstrate that stuxnet positively regulates Oct?2R through repression of Polycomb in the ellipsoid body of the adult fly brain, and that Oct?2R is one of the major receptors mediating octopamine function in sleep homeostasis. In response to octopamine, Oct?2R transcription is inhibited as a result of stuxnet downregulation. This feedback through the Stuxnet-Polycomb-Oct?2R cascade is crucial for sleep homeostasis regulation. This study demonstrates a Stuxnet-Polycomb-Oct?2R-mediated epigenetic regulatory mechanism for octopamine reception, thus providing an example of epigenetic regulation of sleep homeostasis.