Theoretical study on the regulation of circadian rhythms by RNA methylation

Abstract Messenger RNAs are often destabilized by methylation, suggesting that RNA methylation alters mRNA and protein dynamics. This may indicate that the gene regulatory system is reflected by the metabolic system through RNA methylation because methylation substrates are components of the metabolic system. Elucidating the mechanisms by which RNA methylation regulates gene regulatory systems has posed considerable challenges due to the numerous targets of mRNA methylation. Recent studies have demonstrated that inhibition of RNA N6-methyladenosine methylation elongates circadian periods. The aim of this study was to understand the mechanisms by which RNA methylation regulates circadian rhythms. Using a detailed realistic model and a simple model, we demonstrated that period elongation of circadian rhythms by decreasing RNA methylation can be achieved by two possibilities, i.e., decreasing RNA methylation stabilizes nonoscillatory mRNAs such as Ck1δ and/or stabilizes oscillatory mRNAs of clock genes such as Per and Cry. In addition, we predicted that period elongation by stabilizing nonoscillatory mRNA (Ck1δ) should always be accompanied by the distortion of the circadian waveform. Finally, we discuss the validity of the two possible mechanisms on the regulation of circadian rhythms by RNA methylation by quantifying waveform distortion of circadian gene activity data with or without RNA methylation inhibitors.