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

Abstract

AbstractAntisense 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 transcriptPeriod2(Per2) and exhibits a rhythmic and antiphasic expression pattern compared toPer2in mouse. By assuming thatPer2ASandPer2mutually repress each other, our previous mathematical model predicted thatPer2ASregulates 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 betweenPer2andPer2ASvia 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 ofPer2AS-Per2interaction in the mammalian circadian clock. Our mechanistic description ofPer2AS-Per2interaction can also be extended to other mathematical models that involve sense-antisense RNA pairs that mutually repress each other.