Quantification of protein abundance and interaction defines a mechanism for operation of the circadian clock

Alexander Koch, James Bagnall, Nicola J Smyllie, Nicola Begley, Antony Adamson, Jennifer L Fribourgh, David Spiller, Qing-Jun Meng, Carrie L Partch, Korbinian Strimmer, Thomas House, Michael H. Hastings, Andrew Loudon

Research output: Contribution to journalArticlepeer-review


The mammalian circadian clock exerts control of daily gene expression through cycles of DNA binding. Here, we develop a quantitative model of how a finite pool of BMAL1 protein can regulate thousands of target sites over daily time scales. We used quantitative imaging to track dynamic changes in endogenous labelled proteins across peripheral tissues and the SCN. We determine the contribution of multiple rhythmic processes coordinating BMAL1 DNA binding, including cycling molecular abundance, binding affinities, and repression. We find nuclear BMAL1 concentration determines corresponding CLOCK through heterodimerisation and define a DNA residence time of this complex. Repression of CLOCK:BMAL1 is achieved through rhythmic changes to BMAL1:CRY1 association and high-affinity interactions between PER2:CRY1 which mediates CLOCK:BMAL1 displacement from DNA. Finally, stochastic modelling reveals a dual role for PER:CRY complexes in which increasing concentrations of PER2:CRY1 promotes removal of BMAL1:CLOCK from genes consequently enhancing ability to move to new target sites.

Original languageEnglish
Article numbere73976
Publication statusPublished - 14 Mar 2022


  • ARNTL Transcription Factors/genetics
  • Animals
  • CLOCK Proteins/genetics
  • Circadian Clocks/genetics
  • Circadian Rhythm/genetics
  • Mammals/metabolism

Research Beacons, Institutes and Platforms

  • Lydia Becker Institute
  • Thomas Ashton Institute


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