title: A circadian gene expression atlas in mammals: implications for biology and medicine.
abstract: To characterize the role of the circadian clock in mouse physiology and behavior, we used RNA-seq and DNA arrays to quantify the transcriptomes of 12 mouse organs over time. We found 43% of all protein coding genes showed circadian rhythms in transcription somewhere in the body, largely in an organ-specific manner. In most organs, we noticed the expression of many oscillating genes peaked during transcriptional "rush hours" preceding dawn and dusk. Looking at the genomic landscape of rhythmic genes, we saw that they clustered together, were longer, and had more spliceforms than nonoscillating genes. Systems-level analysis revealed intricate rhythmic orchestration of gene pathways throughout the body. We also found oscillations in the expression of more than 1,000 known and novel noncoding RNAs (ncRNAs). Supporting their potential role in mediating clock function, ncRNAs conserved between mouse and human showed rhythmic expression in similar proportions as protein coding genes. Importantly, we also found that the majority of best-selling drugs and World Health Organization essential medicines directly target the products of rhythmic genes. Many of these drugs have short half-lives and may benefit from timed dosage. In sum, this study highlights critical, systemic, and surprising roles of the mammalian circadian clock and provides a blueprint for advancement in chronotherapy.
authors.affiliation: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; and.
authors.forename: Ray
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; and.
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Lahens
authors.affiliation: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; and.
authors.forename: Heather I
authors.initials: HI
authors.lastname: Ballance
authors.affiliation: Department of Biology, University of Missouri, St. Louis, MO 63121 hogenesc@mail.med.upenn.edu hughesmi@umsl.edu.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Hughes
authors.affiliation: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; and hogenesc@mail.med.upenn.edu hughesmi@umsl.edu.
authors.forename: John B
authors.initials: JB
authors.lastname: Hogenesch
mesh_terms: D000818:Animals; D019454:Chronotherapy / Q000379:methods; D002940:Circadian Rhythm / Q000502:physiology*; D030561:Databases, Nucleic Acid; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D051379:Mice; D059467:Transcriptome / Q000502:physiology*
keywords: chronotherapy; circadian; gene networks; genomics; noncoding RNA