The rich mammalian cellular circadian output affects thousands of genes in many cell types and has been the subject of genome-wide transcriptome and proteome studies. The results have been enigmatic because transcript peak abundances do not always follow the peaks of gene-expression activity in time. We posited that circadian degradation of mRNAs and proteins plays a pivotal role in setting their peak times. To establish guiding principles, we derived a theoretical framework that fully describes the amplitudes and phases of biomolecules with circadian half-lives. We were able to explain the circadian transcriptome and proteome studies with the same unifying theory, including cases in which transcripts or proteins appeared before the onset of increased production rates. Furthermore, we estimate that 30% of the circadian transcripts in mouse liver and Drosophila heads are affected by rhythmic posttranscriptional regulation.

SignificanceRhythms in gene expression propelled by the circadian clock and environmental signals are ubiquitous across cells and tissues. In particular, in mouse tissues, thousands of transcripts show oscillations with a period of 24 hours. Keys question are how such rhythms propagate and eventually exert functions, but also how these are generated. Here, we developed a mathematical model based on total RNA-seq to classify genes according to the respective contributions of transcriptional and posttranscriptional regulation toward mRNA expression profiles. We found that about one-third of rhythmically accumulating mRNA are under posttranscriptional regulation. Such regulation is only partially dependent on the circadian clock, showing that systemic pathways and feeding patterns contribute important posttranscriptional control of gene expression in liver.

Circadian clocks synchronize organisms to the 24 h rhythms of the environment. These clocks persist under constant conditions, have their origin at the cellular level, and produce an output of rhythmic mRNA expression affecting thousands of transcripts in many mammalian cell types. Here, we review the charting of circadian output rhythms in mRNA expression, focusing on mammals. We emphasize the challenges in statistics, interpretation, and quantitative descriptions that such investigations have faced and continue to face, and outline remaining outstanding questions.

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Adipose tissue (AT) is a key metabolic organ which functions are rhythmically regulated by an endogenous circadian clock. Feeding is a "zeitgeber" aligning the clock in AT with the external time, but mechanisms of this regulation remain largely unclear. We tested the hypothesis that postprandial changes of the hormone insulin directly entrain circadian clocks in AT and investigated a transcriptional-dependent mechanism of this regulation. We analyzed gene expression in subcutaneous AT (SAT) of obese subjects collected before and after the hyperinsulinemic-euglycemic clamp or control saline infusion (SC). The expressions of core clock genes PER2, PER3, and NR1D1 in SAT were differentially changed upon insulin and saline infusion, suggesting insulin-dependent clock regulation. In human stem cell-derived adipocytes, mouse 3T3-L1 cells, and AT explants from mPer2 Luc knockin mice, insulin induced a transient increase of the Per2 mRNA and protein expression, leading to the phase shift of circadian oscillations, with similar effects for Per1. Insulin effects were dependent on the region between 264 and 243 in the Per2 promoter but not on CRE and E-box elements. Our results demonstrate that insulin directly regulates circadian clocks in AT and isolated adipocytes, thus representing a primary mechanism of feeding-induced AT clock entrainment.Adipose tissue (AT) is a key energy storage strongly contributing to the regulation of carbohydrate and lipid metabolism. AT also acts as an endocrine organ, secreting adipokines and cytokines that are able to modulate systemic insulin sensitivity, systemic inflammation, and appetite regulation and therefore plays an essential role in the pathogenesis of metabolic diseases (1). Many metabolic and secretory AT functions are time of day