Abstract
The mammalian circadian clock is deeply rooted in rhythmic regulation of gene expression. Rhythmic transcriptional control mediated by the circadian transcription factors is thought to be the main driver of mammalian circadian gene expression. However, mounting evidence has demonstrated the importance of rhythmic post-transcriptional controls, and it remains unclear how the transcriptional and post-transcriptional mechanisms collectively control rhythmic gene expression. In mouse liver, hundreds of genes were found to exhibit rhythmicity in poly(A) tail length, and the poly(A) rhythms are strongly correlated with the protein expression rhythms. To understand the role of rhythmic poly(A) regulation in circadian gene expression, we constructed a parsimonious model that depicts rhythmic control imposed upon basic mRNA expression and poly(A) regulation processes, including transcription, deadenylation, polyadenylation, and degradation. The model results reveal the rhythmicity in deadenylation as the strongest contributor to the rhythmicity in poly(A) tail length and the rhythmicity in the abundance of the mRNA subpopulation with long poly(A) tails (a rough proxy for mRNA translatability). In line with this finding, the model further shows that the experimentally observed distinct peak phases in the expression of deadenylases, regardless of other rhythmic controls, can robustly cluster the rhythmic mRNAs by their peak phases in poly(A) tail length and abundance of the long-tailed subpopulation. This provides a potential mechanism to synchronize the phases of target gene expression regulated by the same deadenylases. Our findings highlight the critical role of rhythmic deadenylation in regulating poly(A) rhythms and circadian gene expression.
Highlights
Rhythmic control of gene expression is a hallmark of the circadian system
Our model reveals that the rhythmicities in poly(A) tail length and mRNA translatability are most strongly affected by the rhythmicity in deadenylation, the process that shortens the poly(A) tail
Instead of explicitly tracking the exact length of poly(A) tails, the model divides the mRNA population into a long-tailed fraction and a short-tailed fraction (Fig 1A), which mimics the fractionation conducted in the circadian transcriptome experiment
Summary
Rhythmic control of gene expression is a hallmark of the circadian system. The daily rhythms in biochemistry, physiology and behavior stem from rhythmic gene expression in each cell [1, 2]. Many core clock genes encode transcription factors and interact with their respective target enhancers to exert rhythmic transcriptional control over mRNA expression [6, 9]. Rhythmic transcription and post-transcriptional processes couple with each other and jointly determine the gene expression rhythm. Rhythmic RNA transcription and degradation jointly determine the rhythmicity in the mRNA level [16]. As yet, it remains unclear how the rhythmicities in other post-transcriptional processes affect the gene expression rhythm
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