Ptitsyna Natalia, Boughorbel Sabri, El Anbari Mohammed, Ptitsyn Andrey
Embry-Riddle Aeronautical University, Daytona Beach, FL, 32114, USA.
Sidra Medical and Research Center, P.O. box 26999, Doha, Qatar.
BMC Genomics. 2017 Aug 4;18(1):576. doi: 10.1186/s12864-017-3958-1.
Alternative transcription is common in eukaryotic cells and plays important role in regulation of cellular processes. Alternative polyadenylation results from ambiguous PolyA signals in 3' untranslated region (UTR) of a gene. Such alternative transcripts share the same coding part, but differ by a stretch of UTR that may contain important functional sites.
The methodoogy of this study is based on mathematical modeling, analytical solution, and subsequent validation by datamining in multiple independent experimental data from previously published studies.
In this study we propose a mathematical model that describes the population dynamics of alternatively polyadenylated transcripts in conjunction with rhythmic expression such as transcription oscillation driven by circadian or metabolic oscillators. Analysis of the model shows that alternative transcripts with different turnover rates acquire a phase shift if the transcript decay rate is different. Difference in decay rate is one of the consequences of alternative polyadenylation. Phase shift can reach values equal to half the period of oscillation, which makes alternative transcripts oscillate in abundance in counter-phase to each other. Since counter-phased transcripts share the coding part, the rate of translation becomes constant. We have analyzed a few data sets collected in circadian timeline for the occurrence of transcript behavior that fits the mathematical model.
Alternative transcripts with different turnover rate create the effect of rectifier. This "molecular diode" moderates or completely eliminates oscillation of individual transcripts and stabilizes overall protein production rate. In our observation this phenomenon is very common in different tissues in plants, mice, and humans. The occurrence of counter-phased alternative transcripts is also tissue-specific and affects functions of multiple biological pathways. Accounting for this mechanism is important for understanding the natural and engineering the synthetic cellular circuits.
可变转录在真核细胞中很常见，在细胞过程的调控中发挥重要作用。可变聚腺苷酸化源于基因3'非翻译区（UTR）中模糊的聚腺苷酸化信号。这些可变转录本共享相同的编码部分，但因一段可能包含重要功能位点的UTR而有所不同。
本研究的方法基于数学建模、解析解，随后通过对先前发表研究的多个独立实验数据进行数据挖掘来验证。
在本研究中，我们提出了一个数学模型，该模型结合节律性表达（如由昼夜节律或代谢振荡器驱动的转录振荡）来描述可变聚腺苷酸化转录本的群体动态。对该模型的分析表明，如果转录本衰减率不同，具有不同周转率的可变转录本会获得相位偏移。衰减率的差异是可变聚腺苷酸化的结果之一。相位偏移可以达到等于振荡周期一半的值，这使得可变转录本的丰度相互呈反相振荡。由于反相转录本共享编码部分，翻译速率变得恒定。我们分析了在昼夜时间轴上收集的一些数据集，以寻找符合该数学模型的转录本行为。
具有不同周转率的可变转录本产生整流器的效果。这种“分子二极管”缓和或完全消除了单个转录本的振荡，并稳定了整体蛋白质产生速率。在我们的观察中，这种现象在植物、小鼠和人类的不同组织中非常普遍。反相可变转录本的出现也是组织特异性的，并影响多个生物途径的功能。考虑到这一机制对于理解自然和设计合成细胞回路很重要。
