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Circadian processes in the RNA life cycle

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The circadian clock drives daily rhythms of multiple physiological processes, allowing organisms to anticipate and adjust to periodic changes in environmental conditions. These physiological rhythms are associated with robust oscillations in the expression of at least 30% of expressed genes. While the ability for the endogenous timekeeping system to generate a 24‐hr cycle is a cell‐autonomous mechanism based on negative autoregulatory feedback loops of transcription and translation involving core‐clock genes and their protein products, it is now increasingly evident that additional mechanisms also govern the circadian oscillations of clock‐controlled genes. Such mechanisms can take place post‐transcriptionally during the course of the RNA life cycle. It has been shown that many steps during RNA processing are regulated in a circadian manner, thus contributing to circadian gene expression. These steps include mRNA capping, alternative splicing, changes in splicing efficiency, and changes in RNA stability controlled by the tail length of polyadenylation or the use of alternative polyadenylation sites. RNA transport can also follow a circadian pattern, with a circadian nuclear retention driven by rhythmic expression within the nucleus of particular bodies (the paraspeckles) and circadian export to the cytoplasm driven by rhythmic proteins acting like cargo. Finally, RNA degradation may also follow a circadian pattern through the rhythmic involvement of miRNAs. In this review, we summarize the current knowledge of the post‐transcriptional circadian mechanisms known to play a prominent role in shaping circadian gene expression in mammals. This article is categorized under: RNA Processing > Splicing Regulation/Alternative Splicing RNA Processing > RNA Editing and Modification RNA Export and Localization > Nuclear Export/Import
Transcriptional and post‐transcriptional mechanisms in the circadian timekeeping system of mammals. (a) Transcriptional Mechanisms: Circadian oscillations are generated by two interlocking transcription/translation feedback loops (TTFLs) that function together to produce cycles with a period close to 24 hr. The core TTFL is driven by two activators, BMAL1 and CLOCK, that after dimerization form the positive arm of the loop and activate the transcription of Per, Cry, Rev‐erb and Ror genes by binding to a specific E‐box. PER and CRY proteins may be phosphorylated by CK1 kinases in the cytoplasm. PER/CRY heterodimers translocate to the nucleus where they repress their own transcription. A second TTFL represses or activates the transcription of Bmal1 through the actions on RORE elements of REV‐ERB or ROR, respectively. The circadian oscillator drives the circadian pattern of downstream target genes known as clock‐controlled genes (CCG) that may be direct targets when containing E‐box or ROREs in their promoter. CCG(s) can also be indirect targets of the circadian oscillator by means of circadian transcription factors (TFs) acting through CRE elements or D‐Box or others, or by means of circadian co‐transcriptional factors (co‐TFs). (b) Post‐Transcriptional Mechanisms: In addition to the transcription that may follow a circadian pattern, every step in the life cycle of a (pre‐) mRNA including processing, transport and degradation could be regulated in a circadian manner
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miRNA targeting the circadian system in mouse and human. Some microRNAs regulate core‐clock genes or clock‐controlled genes. Among them, some follow a circadian expression pattern
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Circadian RNA transport and editing. In the nucleus mRNA may be rhythmically retained by paraspeckles. These nuclear bodies that are formed around a long non‐coding RNA, Nuclear Enriched Abundant Transcript 1 (Neat1, purple lines), and several RNA‐binding proteins (colored circles), vary in number within the nucleus during a circadian period. Editing of mRNA can also follow a circadian pattern driven by the circadian expression of ADAR, an A‐to‐I RNA editing enzyme. mRNA containing double strand RNA (dsRNA) in their 3’ UTR can be A‐to‐I edited and edited RNAs are preferentially retained in the nucleus by paraspeckles. The circadian timekeeping system can also control mRNA nuclear export by means of some RNA‐binding proteins including Cold Inducible RNA Binding Protein (CIRBP), Fragile X mental retardation 1 (FMR1), Fragile X related gene 1 and 2 (FXR1 and FXR2) and probably other proteins that act like a cargo by forming complexes with mRNA
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RNA Export and Localization > Nuclear Export/Import
RNA Processing > RNA Editing and Modification
RNA Processing > Splicing Regulation/Alternative Splicing

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