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Cited by 87Circadian rhythm and melatoninLight effects on plantsCircular RNAs in diseases

Rhythmic transcription of Bmal1 stabilizes the circadian timekeeping system in mammals

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Abe, Yasuko O., Yoshitane, Hikari, Kim, Dae Wook, Kawakami, Satoshi, Koebis, Michinori, Nakao, Kazuki, Aiba, Atsu, Kim, Jae Kyoung +1 more·2022·Nature Communications
DOI 10.1038/s41467-022-32326-9PMC PMC9399252
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Abstract

In mammals, the circadian clock consists of transcriptional and translational feedback loops through DNA cis -elements such as E-box and RRE. The E-box-mediated core feedback loop is interlocked with the RRE-mediated feedback loop, but biological significance of the RRE-mediated loop has been elusive. In this study, we established mutant cells and mice deficient for rhythmic transcription of Bmal1 gene by deleting its upstream RRE elements and hence disrupted the RRE-mediated feedback loop. We observed apparently normal circadian rhythms in the mutant cells and mice, but a combination of mathematical modeling and experiments revealed that the circadian period and amplitude of the mutants were more susceptible to disturbance of CRY1 protein rhythm. Our findings demonstrate that the RRE-mediated feedback regulation of Bmal1 underpins the E-box-mediated rhythm in cooperation with CRY1-dependent posttranslational regulation of BMAL1 protein, thereby conferring the perturbation-resistant oscillation and chronologically-organized output of the circadian clock.

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  • Disruption of the circadian system is a common comorbidity in ASD and is implicated in exacerbating sleep disturbances, behavioral rhythm abnormalities, and emotional dysregulation, potentially by dysregulating the temporal coordination of neuronal and synaptic processes.

    “Disruption of this system is a common comorbidity in ASD and is implicated in exacerbating sleep disturbances, behavioral rhythm abnormalities, and emotional dysregulation, potentially by dysregulating the temporal coordination of neuronal and synaptic processes”

    From Biological hierarchy from genotype to phenotype in syndromic and non-syndromic autism spectrum disorder (2026) · cites this paper as Abe et al., 2022

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  1. [1]Dunlap JC Molecular bases for circadian clocks Cell 1999 96 271 90 10.1016/S0092-8674(00)80566-8 9988221 · DOI · Paper page
  2. [2]Wilsbacher LD Takahashi JS Circadian rhythms: molecular basis of the clock Curr. Opin. Genet. Dev. 1998 8 595 602 10.1016/S0959-437X(98)80017-8 9794822 · DOI
  3. [3]Ueda HR System-level identification of transcriptional circuits underlying mammalian circadian clocks Nat. Genet. 2005 37 187 92 10.1038/ng1504 15665827 · DOI
  4. [4]Preitner N The orphan nuclear receptor REV-ERBα controls circadian transcription within the positive limb of the mammalian circadian oscillator Cell 2002 110 251 260 10.1016/S0092-8674(02)00825-5 12150932 · DOI · Paper page
  5. [5]Sato TK A functional genomics strategy reveals rora as a component of the mammalian circadian clock Neuron 2004 43 527 537 10.1016/j.neuron.2004.07.018 15312651 · DOI
  6. [6]Ukai-Tadenuma M Delay in feedback repression by cryptochrome 1 is required for circadian clock function Cell 2011 144 268 81 10.1016/j.cell.2010.12.019 21236481 · DOI
  7. [7]Yoshitane, H. et al. Functional D-box sequences reset the circadian clock and drive mRNA rhythms. Commun. Biol. 2, 300 (2019). PMC6687812 31428688
  8. [8]Bunger MK Mop3 is an essential component of the master circadian pacemaker in mammals Cell 2000 103 1009 17 10.1016/S0092-8674(00)00205-1 11163178 PMC3779439 · DOI · Paper page
  9. [9]DeBruyne JP Weaver DR Reppert SM CLOCK and NPAS2 have overlapping roles in the suprachiasmatic circadian clock Nat. Neurosci. 2007 10 543 5 10.1038/nn1884 17417633 PMC2782643 · DOI
  10. [10]van der Horst GT Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms Nature 1999 398 627 30 10.1038/19323 10217146 · DOI · Paper page
  11. [11]Bae K Differential functions of mPer1, mPer2, and mPer3 in the SCN circadian clock Neuron 2001 30 525 36 10.1016/S0896-6273(01)00302-6 11395012 · DOI
  12. [13]Cho H Regulation of circadian behaviour and metabolism by REV-ERB-α and REV-ERB-β Nature 2012 485 123 7 10.1038/nature11048 22460952 PMC3367514 · DOI · Paper page
  13. [14]Kim JK Forger DB A mechanism for robust circadian timekeeping via stoichiometric balance Mol. Syst. Biol. 2012 8 630 10.1038/msb.2012.62 23212247 PMC3542529 · DOI
  14. [15]Pett JP Korenčič A Wesener F Kramer A Herzel H Feedback loops of the Mammalian circadian clock constitute repressilator PLoS Comput. Biol. 2016 12 e1005266 10.1371/journal.pcbi.1005266 27942033 PMC5189953 · DOI
  15. [17]Chen Y Kim JK Hirning AJ Josić K Bennett MR SYNTHETIC BIOLOGY. Emergent genetic oscillations in a synthetic microbial consortium Science 2015 349 986 9 10.1126/science.aaa3794 26315440 PMC4597888 · DOI
  16. [18]Kim JK Long-range temporal coordination of gene expression in synthetic microbial consortia Nat. Chem. Biol. 2019 15 1102 1109 10.1038/s41589-019-0372-9 31611703 PMC6858561 · DOI
  17. [19]Tsai TY-C Robust, tunable biological oscillations from interlinked positive and negative feedback loops Science 2008 321 126 9 10.1126/science.1156951 18599789 PMC2728800 · DOI
  18. [20]Ueda HR A transcription factor response element for gene expression during circadian night Nature 2002 418 534 9 10.1038/nature00906 12152080 · DOI
  19. [21]Kondratov RV Post-translational regulation of circadian transcriptional CLOCK(NPAS2)/BMAL1 complex by CRYPTOCHROMES Cell Cycle 2006 5 890 5 10.4161/cc.5.8.2684 16628007 · DOI
  20. [22]Kwon I BMAL1 shuttling controls transactivation and degradation of the CLOCK/BMAL1 heterodimer Mol. Cell. Biol. 2006 26 7318 30 10.1128/MCB.00337-06 16980631 PMC1592876 · DOI
  21. [23]Yoshitane H Roles of CLOCK phosphorylation in suppression of E-box-dependent transcription Mol. Cell. Biol. 2009 29 3675 86 10.1128/MCB.01864-08 19414601 PMC2698759 · DOI
  22. [24]Akashi M Takumi T The orphan nuclear receptor RORalpha regulates circadian transcription of the mammalian core-clock Bmal1 Nat. Struct. Mol. Biol. 2005 12 441 8 10.1038/nsmb925 15821743 · DOI
  23. [25]Zhang R Lahens NF Ballance HI Hughes ME Hogenesch JB A circadian gene expression atlas in mammals: implications for biology and medicine Proc. Natl Acad. Sci. USA 2014 111 16219 24 10.1073/pnas.1408886111 25349387 PMC4234565 · DOI · Paper page
  24. [26]Terajima H ADARB1 catalyzes circadian A-to-I editing and regulates RNA rhythm Nat. Genet. 2017 49 146 151 10.1038/ng.3731 27893733 · DOI
  25. [27]Liu AC Redundant function of REV-ERBalpha and beta and non-essential role for Bmal1 cycling in transcriptional regulation of intracellular circadian rhythms PLoS Genet. 2008 4 e1000023 10.1371/journal.pgen.1000023 18454201 PMC2265523 · DOI
  26. [28]Hirota T Transcriptional repressor TIEG1 regulates Bmal1 gene through GC box and controls circadian clockwork Genes Cells 2010 15 111 21 10.1111/j.1365-2443.2009.01371.x 20070857 · DOI
  27. [29]Kim JK Modeling and validating chronic pharmacological manipulation of circadian rhythms CPT Pharmacomet. Syst. Pharmacol. 2013 2 57 10.1038/psp.2013.34 PMC3734602 23863866 · DOI
  28. [30]Kim DW Systems approach reveals photosensitivity and PER2 level as determinants of clock-modulator efficacy Mol. Syst. Biol. 2019 15 e8838 10.15252/msb.20198838 31353796 PMC6613017 · DOI
  29. [31]D’Alessandro M A tunable artificial circadian clock in clock-defective mice Nat. Commun. 2015 6 8587 10.1038/ncomms9587 26617050 PMC4674671 · DOI
  30. [32]Dardente H Fortier EE Martineau V Cermakian N Cryptochromes impair phosphorylation of transcriptional activators in the clock: a general mechanism for circadian repression Biochem. J. 2007 402 525 36 10.1042/BJ20060827 17115977 PMC1863574 · DOI
  31. [33]Kondratov RV BMAL1-dependent circadian oscillation of nuclear CLOCK: posttranslational events induced by dimerization of transcriptional activators of the mammalian clock system Genes Dev. 2003 17 1921 32 10.1101/gad.1099503 12897057 PMC196247 · DOI
  32. [34]Hirota T Identification of small molecule activators of cryptochrome Science 2012 337 1094 7 10.1126/science.1223710 22798407 PMC3589997 · DOI
  33. [35]Solt LA Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists Nature 2012 485 62 68 10.1038/nature11030 22460951 PMC3343186 · DOI
  34. [36]Yoshitane, H. et al. CLOCK-controlled polyphonic regulation of circadian rhythms through canonical and noncanonical E-boxes. Mol. Cell. Biol. 34, 1776–87 (2014). PMC4019033 24591654
  35. [37]Doi M Non-coding cis-element of Period2 is essential for maintaining organismal circadian behaviour and body temperature rhythmicity Nat. Commun. 2019 10 2563 10.1038/s41467-019-10532-2 31189882 PMC6561950 · DOI
  36. [38]Adlanmerini, M. et al. REV-ERB nuclear receptors in the suprachiasmatic nucleus control circadian period and restrict diet-induced obesity. Sci. Adv. 7, eabh2007 (2021). PMC8550249 34705514
  37. [39]McDearmon EL Dissecting the functions of the mammalian clock protein BMAL1 by tissue-specific rescue in mice Science 2006 314 1304 8 10.1126/science.1132430 17124323 PMC3756687 · DOI
  38. [40]Pittendrigh CS Minis DH Circadian systems: longevity as a function of circadian resonance in Drosophila melanogaster Proc. Natl Acad. Sci. USA 1972 69 1537 9 10.1073/pnas.69.6.1537 4624759 PMC426743 · DOI
  39. [41]Dodd AN Plant circadian clocks increase photosynthesis, growth, survival, and competitive advantage Science 2005 309 630 3 10.1126/science.1115581 16040710 · DOI
  40. [42]Hirano A A Cryptochrome 2 mutation yields advanced sleep phase in humans Elife 2016 5 e16695 10.7554/eLife.16695 27529127 PMC5398888 · DOI
  41. [43]Patke A Mutation of the Human Circadian Clock Gene CRY1 in Familial Delayed Sleep Phase Disorder Cell 2017 169 203 215.e13 10.1016/j.cell.2017.03.027 28388406 PMC5479574 · DOI · Paper page
  42. [44]Casado P Kinase-substrate enrichment analysis provides insights into the heterogeneity of signaling pathway activation in leukemia cells Sci. Signal. 2013 6 rs6 10.1126/scisignal.2003573 23532336 · DOI
  43. [45]Ran FA Genome engineering using the CRISPR-Cas9 system Nat. Protoc. 2013 8 2281 2308 10.1038/nprot.2013.143 24157548 PMC3969860 · DOI · Paper page
  44. [46]Cong L Multiplex genome engineering using CRISPR/Cas systems Science 2013 339 819 23 10.1126/science.1231143 23287718 PMC3795411 · DOI · Paper page
  45. [47]Naito Y Hino K Bono H Ui-Tei K CRISPRdirect: software for designing CRISPR/Cas guide RNA with reduced off-target sites Bioinformatics 2015 31 1120 3 10.1093/bioinformatics/btu743 25414360 PMC4382898 · DOI
  46. [48]Yoshitane H JNK regulates the photic response of the mammalian circadian clock EMBO Rep. 2012 13 455 61 10.1038/embor.2012.37 22441692 PMC3343351 · DOI
  47. [49]Hashimoto M Takemoto T Electroporation enables the efficient mRNA delivery into the mouse zygotes and facilitates CRISPR/Cas9-based genome editing Sci. Rep. 2015 5 11315 10.1038/srep11315 26066060 PMC4463957 · DOI
  48. [50]Terajima H Yoshitane H Yoshikawa T Shigeyoshi Y Fukada Y A-to-I RNA editing enzyme ADAR2 regulates light-induced circadian phase-shift Sci. Rep. 2018 8 14848 10.1038/s41598-018-33114-6 30287844 PMC6172258 · DOI
  49. [51]Yoo S-H PERIOD2::LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues Proc. Natl Acad. Sci. USA 2004 101 5339 46 10.1073/pnas.0308709101 14963227 PMC397382 · DOI · Paper page
  50. [52]Imamura K ASK family kinases mediate cellular stress and redox signaling to circadian clock Proc. Natl Acad. Sci. USA 2018 115 3646 3651 10.1073/pnas.1719298115 29555767 PMC5889649 · DOI
  51. [53]Brüning F Sleep-wake cycles drive daily dynamics of synaptic phosphorylation Science 2019 366 eaav3617 10.1126/science.aav3617 31601740 · DOI
  52. [54]Ge SX Jung D Yao R ShinyGO: a graphical gene-set enrichment tool for animals and plants Bioinformatics 2020 36 2628 2629 10.1093/bioinformatics/btz931 31882993 PMC7178415 · DOI · Paper page
  53. [55]Wirbel J Cutillas P Saez-Rodriguez J Phosphoproteomics-based profiling of kinase activities in cancer cells Methods Mol. Biol. 2018 1711 103 132 10.1007/978-1-4939-7493-1_6 29344887 PMC6126574 · DOI
  54. [56]Agostinelli F Ceglia N Shahbaba B Sassone-Corsi P Baldi P What time is it? Deep learning approaches for circadian rhythms Bioinformatics 2016 32 i8 i17 10.1093/bioinformatics/btw243 27307647 PMC4908327 · DOI

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Authors
Abe, Y. O., Yoshitane, H., Kim, D. W., Kawakami, S., Koebis, M., Nakao, K., Aiba, A., Kim, J. K., & Fukada, Y.
Affiliations
  • Tokyo Metropolitan Institute of Medical Science (JP)
  • Korea Advanced Institute of Science and Technology (KR)
  • Center for Disease Biology and Integrative Medicine, The University of Tokyo (JP)
Corresponding author
  • Yoshitane, Hikari
  • Kim, Jae Kyoung
  • Fukada, Yoshitaka
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-08-23
Volume
13
Issue
1
Pages
4652-4652
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-022-32326-9
PMC
PMC9399252
OpenAlex
W4292696100
Cited by
87
References
2
Citations by year
2026: 21 · 2025: 30 · 2024: 19 · 2023: 16 · 2022: 1
FWCI
8.71
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • MEXT | Japan Society for the Promotion of Science (JP19J22296)
  • Ministry of Education, Culture, Sports, Science and Technology (JP19H03175, JP21H05130, P21K18231, JP17H06096)
  • Japan Agency for Medical Research and Development (17937210)
  • Korea Basic Science Institute (IBS-R029-C3)
  • National Research Foundation of Korea (NRF-2016 RICIB 3008468)
  • Human Frontier Science Program (RGY0063/2017)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Light effects on plants
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Circular RNAs in diseases
Keywords
Bmal1, circadian clock, E-box, CRY1, post-translational regulation, circadian period, circadian amplitude, transcriptional feedback loop
MeSH terms
Animals, Circadian Rhythm, Mammals, Transcription, Genetic, Mice, CLOCK Proteins, ARNTL Transcription Factors, Cryptochromes, Circadian Clocks

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