RNA-Methylation-Dependent RNA Processing Controls the Speed of the Circadian Clock

Circadian rhythms are the physiological changes that follow a roughly 24-hour cycle, such as the sleep-wake cycle. They are found in most living things including animals, plants and fungi. The mammalian circadian biological clock regulates metabolism via a negative transcription-translation feedback loop of clock genes. Histone protein methylation is an epigenetic modification which has been suggested to be involved in circadian clock regulation; however, the role of RNA methylation in this process is still unknown.

The most common and abundant methylated nucleoside in eukaryotic RNA is N⁶-methyladenosine (m⁶A), which accounts for more than 80% of all RNA base methylations and is present in various species (1). The methyltransferase enzyme METTL3 is part of the complex involved in catalyzing m⁶A formation. The biological significance of this RNA modification has been unclear, possibly due to limited detection methods.

Scientists at the Graduate School of Pharmaceutical Science, Kyoto University in Japan hypothesized that regulation of RNA splicing and processing may potentially be involved in circadian clock metabolism since it was recently observed that a small percentage of rhythmic, circadian clock driven genes, such as those in the liver, do not involve de novo transcription. This group investigated the contribution of RNA methylation in circadian clock function by exploiting the cellular “methylation potential” or the SAM/SAH ratio using 3-deazaadenosine (DAA), an inhibitor of methylation. The SAM/SAH ratio is the amount of S-adenosylmethionine (SAM, Adomet), the universal methyl donor cosubstrate, to the relative amount of its by-product, S-adenosylhomocysteine (SAH), which acts as a competitive inhibitor. The authors show that m⁶A RNA methylation modulates RNA processing thereby regulating biological circadian clock speed and stability (2).
Their findings are summarized below:

• The circadian clock is sensitive to global methylation inhibition, with the period length being inversely proportional to the methylation potential.  Inhibition of methylation lengthens the circadian period (based on in vitro and in vivo studies) by retaining circadian RNAs in the nucleus.
• High-throughput sequencing revealed that circadian genes, as well as RNA-processing genes, are dysregulated when methylation potential is disrupted.
• m⁶A methylation regulates the nuclear processing of mRNA.
• Circadian clock genes have multiple m⁶A methylation sites. Therefore, lack of m⁶A-RNA methylation causes a delay in RNA processing, affecting clock gene expression dynamics.
• Overall, their findings demonstrate that RNA-methylation-dependent RNA processing is critical for circadian clock function.

Source: Read more about their findings and get all of the details here: Fustin, J, et al., RNA-Methylation-Dependent RNA Processing Controls the Speed of the Circadian Clock. Cell (2013) 155,793-806.

References:

1. Niu Y., Zhao X., Wu Y., Li M., Wang X., Yang Y. N⁶-methyl-adenosine (m⁶A) in RNA: An Old Modification with a Novel Epigenetic Function. Genomics Proteomics Bioinformatics (2013)11, 8-17.
2. Hastings M.H. m⁶A mRNA Methylation: A New Circadian Pacesetter. Cell (2013) 155, 740-741.