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      Harmonics of Circadian Gene Transcription in Mammals

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          Abstract

          The circadian clock is a molecular and cellular oscillator found in most mammalian tissues that regulates rhythmic physiology and behavior. Numerous investigations have addressed the contribution of circadian rhythmicity to cellular, organ, and organismal physiology. We recently developed a method to look at transcriptional oscillations with unprecedented precision and accuracy using high-density time sampling. Here, we report a comparison of oscillating transcription from mouse liver, NIH3T3, and U2OS cells. Several surprising observations resulted from this study, including a 100-fold difference in the number of cycling transcripts in autonomous cellular models of the oscillator versus tissues harvested from intact mice. Strikingly, we found two clusters of genes that cycle at the second and third harmonic of circadian rhythmicity in liver, but not cultured cells. Validation experiments show that 12-hour oscillatory transcripts occur in several other peripheral tissues as well including heart, kidney, and lungs. These harmonics are lost ex vivo, as well as under restricted feeding conditions. Taken in sum, these studies illustrate the importance of time sampling with respect to multiple testing, suggest caution in use of autonomous cellular models to study clock output, and demonstrate the existence of harmonics of circadian gene expression in the mouse.

          Author Summary

          Circadian rhythms confer adaptive advantages by allowing organisms to anticipate daily changes in their environment. Over the last few years, many groups have used microarray technology to systematically identify genes under circadian regulation. We have extended on these studies by profiling the circadian transcriptome from the mouse liver and two immortalized cell lines at an unprecedentedly high temporal resolution. We identified over 3,000 different transcripts in the mouse liver that cycle with a period length of approximately 24 hours. To our surprise, we also identified two classes of genes which cycle with period lengths of 12 and 8 hours; i.e., harmonics of the circadian clock. Importantly, we were able to identify harmonics in five other tissue types; however, these rhythms were undetectable in disassociated cells. Moreover, harmonics were lost in the liver when mice are subjected to restricted feeding, suggesting that at least one component of circadian harmonics is driven by feeding.

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          Most cited references 37

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          Statistical significance for genomewide studies.

          With the increase in genomewide experiments and the sequencing of multiple genomes, the analysis of large data sets has become commonplace in biology. It is often the case that thousands of features in a genomewide data set are tested against some null hypothesis, where a number of features are expected to be significant. Here we propose an approach to measuring statistical significance in these genomewide studies based on the concept of the false discovery rate. This approach offers a sensible balance between the number of true and false positives that is automatically calibrated and easily interpreted. In doing so, a measure of statistical significance called the q value is associated with each tested feature. The q value is similar to the well known p value, except it is a measure of significance in terms of the false discovery rate rather than the false positive rate. Our approach avoids a flood of false positive results, while offering a more liberal criterion than what has been used in genome scans for linkage.
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            PERIOD2::LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues.

            Mammalian circadian rhythms are regulated by the suprachiasmatic nucleus (SCN), and current dogma holds that the SCN is required for the expression of circadian rhythms in peripheral tissues. Using a PERIOD2::LUCIFERASE fusion protein as a real-time reporter of circadian dynamics in mice, we report that, contrary to previous work, peripheral tissues are capable of self-sustained circadian oscillations for >20 cycles in isolation. In addition, peripheral organs expressed tissue-specific differences in circadian period and phase. Surprisingly, lesions of the SCN in mPer2(Luciferase) knockin mice did not abolish circadian rhythms in peripheral tissues, but instead caused phase desynchrony among the tissues of individual animals and from animal to animal. These results demonstrate that peripheral tissues express self-sustained, rather than damped, circadian oscillations and suggest the existence of organ-specific synchronizers of circadian rhythms at the cell and tissue level.
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              Coordinated transcription of key pathways in the mouse by the circadian clock.

              In mammals, circadian control of physiology and behavior is driven by a master pacemaker located in the suprachiasmatic nuclei (SCN) of the hypothalamus. We have used gene expression profiling to identify cycling transcripts in the SCN and in the liver. Our analysis revealed approximately 650 cycling transcripts and showed that the majority of these were specific to either the SCN or the liver. Genetic and genomic analysis suggests that a relatively small number of output genes are directly regulated by core oscillator components. Major processes regulated by the SCN and liver were found to be under circadian regulation. Importantly, rate-limiting steps in these various pathways were key sites of circadian control, highlighting the fundamental role that circadian clocks play in cellular and organismal physiology.
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                Author and article information

                Affiliations
                [1 ]Department of Pharmacology, Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America
                [2 ]Regulatory Biology, Salk Institute for Biological Studies, La Jolla, California, United States of America
                Stanford University School of Medicine, United States of America
                Author notes

                Conceived and designed the experiments: ME Hughes, L DiTacchio, S Panda, JB Hogenesch. Performed the experiments: ME Hughes, L DiTacchio, KR Hayes, C Vollmers, S Pulivarthy, JE Baggs. Analyzed the data: ME Hughes, KR Hayes, JE Baggs, S Panda, JB Hogenesch. Contributed reagents/materials/analysis tools: ME Hughes, KR Hayes, S Panda, JB Hogenesch. Wrote the paper: ME Hughes, L DiTacchio, S Panda, JB Hogenesch.

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                April 2009
                April 2009
                3 April 2009
                : 5
                : 4
                2654964
                19343201
                08-PLGE-RA-1766R2
                10.1371/journal.pgen.1000442
                (Editor)
                Hughes et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Counts
                Pages: 12
                Categories
                Research Article
                Cell Biology/Gene Expression
                Computational Biology/Genomics
                Genetics and Genomics
                Genetics and Genomics/Gene Expression

                Genetics

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