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      The Circadian Clock and Viral Infections

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          Abstract

          The circadian clock controls several aspects of mammalian physiology and orchestrates the daily oscillations of biological processes and behavior. Our circadian rhythms are driven by an endogenous central clock in the brain that synchronizes with clocks in peripheral tissues, thereby regulating our immune system and the severity of infections. These rhythms affect the pharmacokinetics and efficacy of therapeutic agents and vaccines. The core circadian regulatory circuits and clock-regulated host pathways provide fertile ground to identify novel antiviral therapies. An increased understanding of the role circadian systems play in regulating virus infection and the host response to the virus will inform our clinical management of these diseases. This review provides an overview of the experimental and clinical evidence reporting on the interplay between the circadian clock and viral infections, highlighting the importance of virus-clock research.

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          Most cited references133

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          A SARS-CoV-2 Protein Interaction Map Reveals Targets for Drug-Repurposing

          SUMMARY The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 2.3 million people, killed over 160,000, and caused worldwide social and economic disruption 1,2 . There are currently no antiviral drugs with proven clinical efficacy, nor are there vaccines for its prevention, and these efforts are hampered by limited knowledge of the molecular details of SARS-CoV-2 infection. To address this, we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), identifying 332 high-confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (29 FDA-approved drugs, 12 drugs in clinical trials, and 28 preclinical compounds). Screening a subset of these in multiple viral assays identified two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the Sigma1 and Sigma2 receptors. Further studies of these host factor targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.
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            Transcriptional architecture of the mammalian circadian clock

            Next-generation sequencing approaches have yielded new insights into circadian function. Here, Takahashi reviews genome-wide analyses of the clock transcriptional feedback loop in mammals, which reveal a global circadian regulation of transcription factor occupancy, RNA polymerase II recruitment and initiation, nascent transcription and chromatin remodelling.
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              Transcriptional architecture and chromatin landscape of the core circadian clock in mammals.

              The mammalian circadian clock involves a transcriptional feed back loop in which CLOCK and BMAL1 activate the Period and Cryptochrome genes, which then feedback and repress their own transcription. We have interrogated the transcriptional architecture of the circadian transcriptional regulatory loop on a genome scale in mouse liver and find a stereotyped, time-dependent pattern of transcription factor binding, RNA polymerase II (RNAPII) recruitment, RNA expression, and chromatin states. We find that the circadian transcriptional cycle of the clock consists of three distinct phases: a poised state, a coordinated de novo transcriptional activation state, and a repressed state. Only 22% of messenger RNA (mRNA) cycling genes are driven by de novo transcription, suggesting that both transcriptional and posttranscriptional mechanisms underlie the mammalian circadian clock. We also find that circadian modulation of RNAPII recruitment and chromatin remodeling occurs on a genome-wide scale far greater than that seen previously by gene expression profiling.
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                Author and article information

                Journal
                J Biol Rhythms
                J Biol Rhythms
                JBR
                spjbr
                Journal of Biological Rhythms
                SAGE Publications (Sage CA: Los Angeles, CA )
                0748-7304
                1552-4531
                9 November 2020
                February 2021
                : 36
                : 1
                : 9-22
                Affiliations
                [1-0748730420967768]Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
                Author notes
                [*] [2 ]Xiaodong Zhuang, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7FZ, UK; e-mail: xiaodong.zhuang@ 123456ndm.ox.ac.uk
                [1]

                Shared senior authorship.

                Author information
                https://orcid.org/0000-0001-7269-7925
                https://orcid.org/0000-0002-6870-9003
                Article
                10.1177_0748730420967768
                10.1177/0748730420967768
                7924106
                33161818
                ba46799b-555a-4cc3-8d52-a1a35a02ca8c
                © 2020 The Author(s)

                This article is distributed under the terms of the Creative Commons Attribution 4.0 License ( https://creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                Funding
                Funded by: Wellcome Trust, FundRef https://doi.org/10.13039/100004440;
                Award ID: IA 200838/Z/16/Z
                Funded by: Medical Research Council, FundRef https://doi.org/10.13039/501100000265;
                Award ID: MR/R022011/1
                Categories
                New Investigator
                Custom metadata
                ts1

                Cell biology
                circadian rhythm,viruses,covid-19,virus-clock,virology
                Cell biology
                circadian rhythm, viruses, covid-19, virus-clock, virology

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