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

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dc.contributor.authorYao, Xiangyuen
dc.contributor.authorKojima, Shihokoen
dc.contributor.authorChen, Jingen
dc.contributor.departmentBiological Sciencesen
dc.contributor.departmentFralin Life Sciences Instituteen
dc.date.accessioned2020-09-02T12:44:31Zen
dc.date.available2020-09-02T12:44:31Zen
dc.date.issued2020-04en
dc.description.abstractThe 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. Author summary The biological circadian clock aligns bodily functions to the day-and-night cycle and is important for maintaining health. The rhythms in various biological processes ultimately stem from rhythmic gene expression in each single cell. Because several proteins in the mammalian core clock machinery are transcription factors, studies of mammalian circadian gene expression have focused on rhythmic transcriptional control. However, many recent studies have suggested the importance of rhythmic post-transcriptional controls. Here we use mathematical modeling to investigate how transcriptional and post-transcriptional rhythms jointly control rhythmic gene expression. We particularly focus on rhythmic post-transcriptional regulation of the mRNA poly(A) tail, a nearly universal feature of mRNAs which controls mRNA stability and translation. 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. Particularly, the phases of poly(A) tail length and mRNA translatability are dominated by the phase of deadenylation. In light of our findings, rhythmic control of deadenylation deserves greater future attention in the field of circadian gene expression.en
dc.description.notesThis project was supported by the startup fund (to J.C.) from the Department of Biological Sciences, Virginia Tech. X.Y. was partially supported by a fellowship from the GBCB graduate program at Virginia Tech. Virginia Tech Open Access Subvention Fund (OASF) provided financial support for the publication fee. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.en
dc.description.sponsorshipDepartment of Biological Sciences, Virginia Tech; GBCB graduate program at Virginia Tech; Virginia Tech Open Access Subvention Fund (OASF)en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1371/journal.pcbi.1007842en
dc.identifier.eissn1553-7358en
dc.identifier.issn1553-734Xen
dc.identifier.issue4en
dc.identifier.othere1007842en
dc.identifier.pmid32339166en
dc.identifier.urihttp://hdl.handle.net/10919/99894en
dc.identifier.volume16en
dc.language.isoenen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titleCritical role of deadenylation in regulating poly(A) rhythms and circadian gene expressionen
dc.title.serialPLoS Computational Biologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.dcmitypeStillImageen

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