Editing Circadian clock (section)

== Post-transcriptional modification ==
For a long time, it was thought the transcriptional activation/repression cycles driven by the transcriptional regulators constituting the circadian clock was the main driving force for circadian gene expression in mammals. More recently, however, it was reported that only 22% of messenger RNA cycling genes are driven by de novo transcription.<ref name="Koike">{{cite journal | vauthors = Koike N, Yoo SH, Huang HC, Kumar V, Lee C, Kim TK, Takahashi JS | title = Transcriptional architecture and chromatin landscape of the core circadian clock in mammals | journal = Science | volume = 338 | issue = 6105 | pages = 349–354 | date = October 2012 | pmid = 22936566 | pmc = 3694775 | doi = 10.1126/science.1226339 | bibcode = 2012Sci...338..349K }}</ref> RNA-level post-transcriptional mechanisms driving rhythmic protein expression were later reported, such as mRNA polyadenylation dynamics.<ref name="Kojima">{{cite journal | vauthors = Kojima S, Sher-Chen EL, Green CB | title = Circadian control of mRNA polyadenylation dynamics regulates rhythmic protein expression | journal = Genes & Development | volume = 26 | issue = 24 | pages = 2724–2736 | date = December 2012 | pmid = 23249735 | pmc = 3533077 | doi = 10.1101/gad.208306.112 }}</ref>

Fustin{{who?|date=November 2019}} and co-workers identified methylation of internal adenosines (m<sup>6</sup>A) within mRNA (notably of clock transcripts themselves) as a key regulator of the circadian period. Inhibition of m<sup>6</sup>A methylation via pharmacological inhibition of cellular methylations or more specifically by siRNA-mediated silencing of the m<sup>6</sup>A methylase ''Mettl3'' led to the dramatic elongation of the circadian period. In contrast, overexpression of ''Mettl3'' ''in vitro'' led to a shorter period. These observations clearly demonstrated the importance of RNA-level post-transcriptional regulation of the circadian clock, and concurrently established the physiological role of (m<sup>6</sup>A) RNA methylation.<ref name="Fustin">{{cite journal | vauthors = Fustin JM, Doi M, Yamaguchi Y, Hida H, Nishimura S, Yoshida M, Isagawa T, Morioka MS, Kakeya H, Manabe I, Okamura H | display-authors = 6 | title = RNA-methylation-dependent RNA processing controls the speed of the circadian clock | journal = Cell | volume = 155 | issue = 4 | pages = 793–806 | date = November 2013 | pmid = 24209618 | doi = 10.1016/j.cell.2013.10.026 | doi-access = free }}</ref>