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      Circadian Clock Control of Translation Initiation Factor eIF2α Activity Requires eIF2γ-Dependent Recruitment of Rhythmic PPP-1 Phosphatase in Neurospora crassa

      research-article
      a , a , a , a , a ,
      mBio
      American Society for Microbiology
      eIF2α, PPP-1, phosphatase, translation initiation, circadian clock, eIF2γ, Neurospora crassa

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          ABSTRACT

          The circadian clock controls the phosphorylation and activity of eukaryotic translation initiation factor 2α (eIF2α). In Neurospora crassa, the clock drives a daytime peak in the activity of the eIF2α kinase CPC-3, the homolog of yeast and mammalian GCN2 kinase. This leads to increased levels of phosphorylated eIF2α (P-eIF2α) and reduced mRNA translation initiation during the day. We hypothesized that rhythmic eIF2α activity also requires dephosphorylation of P-eIF2α at night by phosphatases. In support of this hypothesis, we show that mutation of N. crassa PPP-1, a homolog of the yeast eIF2α phosphatase GLC7, leads to high and arrhythmic P-eIF2α levels, while maintaining core circadian oscillator function. PPP-1 levels are clock-controlled, peaking in the early evening, and rhythmic PPP-1 levels are necessary for rhythmic P-eIF2α accumulation. Deletion of the N terminus of N. crassa eIF2γ, the region necessary for eIF2γ interaction with GLC7 in yeast, led to high and arrhythmic P-eIF2α levels. These data supported that N. crassa eIF2γ functions to recruit PPP-1 to dephosphorylate eIF2α at night. Thus, in addition to the activity of CPC-3 kinase, circadian clock regulation of eIF2α activity requires dephosphorylation by PPP-1 phosphatase at night. These data show how the circadian clock controls the activity a central regulator of translation, critical for cellular metabolism and growth control, through the temporal coordination of phosphorylation and dephosphorylation events.

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          NIH Image to ImageJ: 25 years of image analysis

          For the past twenty five years the NIH family of imaging software, NIH Image and ImageJ have been pioneers as open tools for scientific image analysis. We discuss the origins, challenges and solutions of these two programs, and how their history can serve to advise and inform other software projects.
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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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              Molecular architecture of the mammalian circadian clock.

              Circadian clocks coordinate physiology and behavior with the 24h solar day to provide temporal homeostasis with the external environment. The molecular clocks that drive these intrinsic rhythmic changes are based on interlocked transcription/translation feedback loops that integrate with diverse environmental and metabolic stimuli to generate internal 24h timing. In this review we highlight recent advances in our understanding of the core molecular clock and how it utilizes diverse transcriptional and post-transcriptional mechanisms to impart temporal control onto mammalian physiology. Understanding the way in which biological rhythms are generated throughout the body may provide avenues for temporally directed therapeutics to improve health and prevent disease. Copyright © 2013 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                mBio
                mBio
                mbio
                mbio
                mBio
                American Society for Microbiology (1752 N St., N.W., Washington, DC )
                2150-7511
                18 May 2021
                May-Jun 2021
                : 12
                : 3
                : e00871-21
                Affiliations
                [a ]Department of Biology and Center for Biological Clocks Research, Texas A&M University, College Station, Texas, USA
                Karlsruhe Institute of Technology
                Article
                mBio00871-21
                10.1128/mBio.00871-21
                8262944
                34006661
                30387916-17ed-4262-bf9a-7cc5ec5beceb
                Copyright © 2021 Ding et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

                History
                : 26 March 2021
                : 31 March 2021
                Page count
                supplementary-material: 10, Figures: 5, Tables: 0, Equations: 0, References: 69, Pages: 13, Words: 9617
                Funding
                Funded by: HHS | NIH | National Institute of General Medical Sciences (NIGMS), FundRef https://doi.org/10.13039/100000057;
                Award ID: GM126966
                Award Recipient :
                Funded by: HHS | NIH | National Institute of General Medical Sciences (NIGMS), FundRef https://doi.org/10.13039/100000057;
                Award ID: GM058529
                Award Recipient :
                Categories
                Research Article
                Custom metadata
                May/June 2021

                Life sciences
                eif2α,ppp-1,phosphatase,translation initiation,circadian clock,eif2γ,neurospora crassa
                Life sciences
                eif2α, ppp-1, phosphatase, translation initiation, circadian clock, eif2γ, neurospora crassa

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