Critical role of deadenylation in regulating poly(A) rhythms and circadian gene expression

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. A recent study discovered rhythmicity in poly(A) tail length in mouse liver and its strong correlation with 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 group the rhythmic mRNAs by their peak phases in poly(A) tail length and in abundance of the subpopulation with long poly(A) tails. 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. Author Summary: The biological circadian clock regulates various bodily functions such that they anticipate and respond to the day-and-night cycle. To achieve this, the circadian clock controls rhythmic gene expression, and these genes ultimately drive the rhythmicity of downstream biological processes. As a mechanism of driving circadian gene expression, rhythmic transcriptional control has attracted the central focus. However, mounting evidence has also demonstrated the importance of rhythmic post-transcriptional controls. Here we use mathematical modeling to investigate how transcriptional and post-transcriptional rhythms coordinately control rhythmic gene expression. We have particularly focused on rhythmic regulation of the length of poly(A) tail, a nearly universal feature of mRNAs that controls mRNA stability and translation. Our model reveals that the rhythmicity of deadenylation, the process that shortens the poly(A) tail, is the dominant contributor to the rhythmicity in poly(A) tail length and mRNA translatability. Particularly, the phase of deadenylation nearly overrides the other rhythmic processes in controlling the phases of poly(A) tail length and mRNA translatability. Our finding highlights the critical role of rhythmic deadenylation in circadian gene expression control.