Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America.
Genetics, Bioinformatics, and Computational Biology program, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America.
PLoS Comput Biol. 2020 Apr 27;16(4):e1007842. doi: 10.1371/journal.pcbi.1007842. eCollection 2020 Apr.
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.
哺乳动物的生物钟深深植根于基因表达的节律调节中。昼夜节律转录因子介导的节律转录控制被认为是哺乳动物昼夜节律基因表达的主要驱动因素。然而，越来越多的证据表明，转录后调控的重要性，目前尚不清楚转录和转录后机制如何共同控制节律基因表达。在小鼠肝脏中，数百个基因被发现在多聚（A）尾长上表现出节律性，并且多聚（A）节律与蛋白质表达节律强烈相关。为了了解节律性多聚（A）调节在昼夜节律基因表达中的作用，我们构建了一个简约的模型，该模型描述了基本 mRNA 表达和多聚（A）调节过程（包括转录、脱腺苷酸化、多聚腺苷酸化和降解）所施加的节律控制。模型结果揭示了脱腺苷酸化的节律性是多聚（A）尾长和具有长多聚（A）尾的 mRNA 亚群丰度的节律性的最强贡献者（mRNA 翻译能力的大致代表）。与这一发现一致，该模型进一步表明，尽管存在其他节律控制，但实验观察到的脱腺苷酸酶表达中的明显峰相可以通过多聚（A）尾长和长尾亚群的丰度来稳健地对节律性 mRNA 进行聚类。这为通过相同的脱腺苷酸酶同步靶基因表达的相位提供了一种潜在的机制。我们的研究结果强调了节律性脱腺苷酸化在调节多聚（A）节律和昼夜节律基因表达中的关键作用。
