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Edited by Joseph S. Takahashi, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, and approved September 19, 2014 (received for review May 13, 2014)
Significance
We generated high-resolution multiorgan expression data showing that nearly half of all genes in the mouse genome oscillate with circadian rhythm somewhere in the body. Such widespread transcriptional oscillations have not been previously reported in mammals. Applying pathway analysis, we observed new clock-mediated spatiotemporal relationships. Moreover, we found a majority of best-selling drugs in the United States target circadian gene products. Many of these drugs have relatively short half-lives, and our data predict which may benefit from timed dosing.
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.
Footnotes
↵1R.Z. and N.F.L. contributed equally to this work.
- ↵2To whom correspondence may be addressed. Email: hogenesc{at}mail.med.upenn.edu or hughesmi{at}umsl.edu.
Author contributions: M.E.H. and J.B.H. designed research; R.Z., N.F.L., H.I.B., and M.E.H. performed research; R.Z. and N.F.L. analyzed data; and R.Z., N.F.L., M.E.H., and J.B.H. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE54652).
See Commentary on page 15869.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1408886111/-/DCSupplemental.
Freely available online through the PNAS open access option.
- Ray Zhanga,1,
- Nicholas F. Lahensa,1,
- Heather I. Ballancea,
- Michael E. Hughesb,2, and
- John B. Hogenescha,2
- aDepartment of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; and
- bDepartment of Biology, University of Missouri, St. Louis, MO 63121
Edited by Joseph S. Takahashi, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, and approved September 19, 2014 (received for review May 13, 2014)
Significance
We generated high-resolution multiorgan expression data showing that nearly half of all genes in the mouse genome oscillate with circadian rhythm somewhere in the body. Such widespread transcriptional oscillations have not been previously reported in mammals. Applying pathway analysis, we observed new clock-mediated spatiotemporal relationships. Moreover, we found a majority of best-selling drugs in the United States target circadian gene products. Many of these drugs have relatively short half-lives, and our data predict which may benefit from timed dosing.
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.
- circadian
- genomics
- gene networks
- noncoding RNA
- chronotherapy
Footnotes
↵1R.Z. and N.F.L. contributed equally to this work.
- ↵2To whom correspondence may be addressed. Email: hogenesc{at}mail.med.upenn.edu or hughesmi{at}umsl.edu.
Author contributions: M.E.H. and J.B.H. designed research; R.Z., N.F.L., H.I.B., and M.E.H. performed research; R.Z. and N.F.L. analyzed data; and R.Z., N.F.L., M.E.H., and J.B.H. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE54652).
See Commentary on page 15869.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1408886111/-/DCSupplemental.
Freely available online through the PNAS open access option.
A circadian gene expression atlas in mammals
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