Impacts of the feedback loop between sense-antisense RNAs in regulating circadian rhythms

Abstract

Antisense transcripts are a unique group of non-coding RNAs that are transcribed from the opposite strand of a sense coding gene in an antisense orientation. Even though they do not encode a protein, these transcripts play a regulatory role in a variety of biological processes, including circadian rhythms. We and others found an antisense transcript, Per2AS, that is transcribed from the strand opposite the sense transcript Period2 (Per2) and exhibits a rhythmic and antiphasic expression pattern compared to Per2 in mouse. By assuming that Per2AS and Per2 mutually repress each other, our previous mathematical model predicted that Per2AS regulates the robustness and the amplitude of circadian rhythms. In this study, we revised our previous model and developed a new mathematical model that mechanistically described the mutually repressive relationship between Per2 and Per2AS via transcriptional interference. We found that the simulation results are largely consistent with experimental observations including the counterintuitive ones that could not be fully explained by our previous model. These results indicate that our revised model serves as a foundation to build more detailed models in the future to better understand the impact of Per2AS-Per2 interaction in the mammalian circadian clock. Our mechanistic description of Per2AS-Per2 interaction can also be extended to other mathematical models that involve sense-antisense RNA pairs that mutually repress each other.