Circadian clocks throughout the body drive rhythmic expression of thousands of genes, resulting in rhythms in biochemistry, physiology and behavior. Disruption of these rhythms in mammals has been shown to result in significant health problems. In addition to causing major deleterious effects on metabolism (including obesity and diabetes), increased risk of some types of cancer and cardiovascular problems, recent evidence has also shown a close tie between circadian clocks and affective disorders, sleep abnormalities and major depression. Although circadian control of transcription has been widely studied, recent data have demonstrated that post- transcriptional control, although much less well understood, is also critical for normal rhythmic protein expression profiles. One type of post transcriptional control is regulation of mRNA poly (A) tail length, which impacts the stability and translational regulation of mRNA. We have identified hundreds of mouse liver mRNAs that exhibit robust circadian rhythms in the length of their poly (A) tails. In many of these cases, the rhythmic tail lengths are the result of rhythmic cytoplasmic polyadenylation and deadenylation rhythms and many components of the cytoplasmic polyadenylation and deadenylation machinery are themselves under circadian control. Furthermore, the rhythmic poly (A) tails is closely correlated with the rhythmic protein expression. Therefore, the circadian clock regulates dynamic polyadenylation status of many mRNAs that can drive rhythmic protein expression independent of the steady-state levels of the message. In this proposal, we will explore the mechanisms that cause poly (A) tail rhythms and how these regulate the resulting protein production. In the first specific aim, we will test the hypothesis that the RNA-binding protein CPEB2 binds to specific mRNA targets and controls their polyadenylation state by coordinating the relative activities of deadenylases and poly (A) polymerases in a time of day-dependent manner. In the second specific aim, will test the hypothesis that the deadenylase Nocturnin is responsible for deadenylation and will determine whether deadenylation by Nocturnin leads to decay of those mRNAs that have tails that are modulated during the night phase. And in the third aim we will determine whether the poly (A) tail lengths are themselves the determining factor in regulating the translation of these mRNAs and will examine how the circadian clock controls rhythmic translation. These are important studies because the post-transcriptional mechanisms that regulate poly (A) tail lengths are critical for the generation of the appropriate rhythmic protein profiles and thus the appropriate rhythmic function of the liver.
The circadian clock controls many aspects of behavior and physiology and disruption of the clock results in significant health problems. In this proposal we present data that the clock makes significant use of regulation of mRNA poly (A) tail length to control rhythmic protein expression and normal physiology. This proposal will determine the molecular mechanisms by which the clock controls this fundamental, but still mysterious, cellular process.
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