Circadian rhythms in the absence of the clock gene Bmal1
Redundancy in circadian clocks?
The transcription factor BMAL1 is a core component of the mammalian circadian clock; without it, circadian behaviors are abolished. However, Ray et al. found that in animals lacking BMAL1, peripheral tissues synchronized with a brief pulse of the glucocorticoid hormone dexamethasone appear to retain a 24-hour pacemaker that sustains rhythmic gene expression, protein abundance, and protein phosphorylation in excised liver cells and fibroblasts (see the Perspective by Brown and Sato). These oscillations persisted in the absence of cues from changes in light or temperature. The results raise intriguing questions about the possible nature of the oscillator that maintains the observed rhythms.
Abstract
Circadian (~24 hour) clocks have a fundamental role in regulating daily physiology. The transcription factor BMAL1 is a principal driver of a molecular clock in mammals. Bmal1 deletion abolishes 24-hour activity patterning, one measure of clock output. We determined whether Bmal1 function is necessary for daily molecular oscillations in skin fibroblasts and liver slices. Unexpectedly, in Bmal1 knockout mice, both tissues exhibited 24-hour oscillations of the transcriptome, proteome, and phosphoproteome over 2 to 3 days in the absence of any exogenous drivers such as daily light or temperature cycles. This demonstrates a competent 24-hour molecular pacemaker in Bmal1 knockouts. We suggest that such oscillations might be underpinned by transcriptional regulation by the recruitment of ETS family transcription factors, and nontranscriptionally by co-opting redox oscillations.
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Supplementary Material
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References and Notes
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Volume 367 | Issue 6479
14 February 2020
14 February 2020
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Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Received: 20 January 2019
Accepted: 14 January 2020
Published in print: 14 February 2020
Acknowledgments
We thank the Advanced Sequencing and Bioinformatics scientific technology platforms at the Francis Crick Institute for their support with next-generation sequencing. Funding: A.B.R. acknowledges funding from the Perelman School of Medicine, University of Pennsylvania, and the Institute for Translational Medicine and Therapeutics (ITMAT), Perelman School of Medicine, University of Pennsylvania. A.B.R. also acknowledges funding from the European Research Council (ERC Starting Grant no. 281348, MetaCLOCK), the EMBO Young Investigators Programme, and the Lister Institute of Preventive Medicine. A.B.R. was supported in part by a Wellcome Trust Senior Fellowship in Clinical Science (100333/Z/12/Z) at the University of Cambridge, and also in part by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001534), the UK Medical Research Council (FC001534), and the Wellcome Trust (FC001534). Author contributions: S.R., U.K.V., and A.B.R. conceived and designed the experiments. S.R., U.K.V., A.S., and G.D. performed the MSFs and liver tissue time-course experiments. U.K.V. performed the RNA-Seq and quantitative real-time reverse-transcriptase polymerase chain reaction experiments and analyzed the data. S.R. performed the quantitative proteomics and phosphoproteomics and analyzed the data with support from A.P.S. and S.A.H. A.B.R. supervised the whole study. The manuscript was written by S.R., U.K.V., and A.B.R. All authors agreed on the interpretation of data and approved the final version of the manuscript. Competing interests: The authors declare no competing interests. Data and materials availability: The RNA-seq data have been deposited in the Gene Expression Omnibus (accession nos. GSE111696 and GSE134333). The mass spectrometry proteomics and phosphoproteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE (35) partner repository with the dataset identifier PXD009243.
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Funding Information
Wellcome Trust: 100333/Z/12/Z
Wellcome Trust: FC001534
Francis Crick Institute: FC001534
Medical Research Council: FC001534
Cancer Research UK: FC001534
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