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Rhythmic CLOCK-BMAL1 binding to multiple E-box motifs drives circadian Dbp transcription and chromatin transitions

Nature Genetics volume 38, pages 369–374 (2006)Cite this article

Abstract

Mammalian circadian rhythms are based on transcriptional and post-translational feedback loops. Essentially, the activity of the transcription factors BMAL1 (also known as MOP3) and CLOCK is rhythmically counterbalanced by Period (PER) and Cryptochrome (CRY) proteins to govern time of day–dependent gene expression1. Here we show that circadian regulation of the mouse albumin D element–binding protein (Dbp) gene involves rhythmic binding of BMAL1 and CLOCK and marked daily chromatin transitions. Thus, the Dbp transcription cycle is paralleled by binding of BMAL1 and CLOCK to multiple extra- and intragenic E boxes, acetylation of Lys9 of histone H3, trimethylation of Lys4 of histone H3 and a reduction of histone density. In contrast, the antiphasic daily repression cycle is accompanied by dimethylation of Lys9 of histone H3, the binding of heterochromatin protein 1α and an increase in histone density. The rhythmic conversion of transcriptionally permissive chromatin to facultative heterochromatin relies on the presence of functional BMAL1-CLOCK binding sites.

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Figure 1: Mapping of binding regions for BMAL1 and CLOCK.
Figure 2: Circadian in vitro binding of BMAL1 and CLOCK to the promoter E-box motif.
Figure 3: Mapping of circadian histone H3 modifications and determination of histone H3 abundance.
Figure 4: E-box motifs are required for circadian Dbp transcription and histone H3 modifications.
Figure 5: Schematic illustrating the dynamic chromatin changes accompanying circadian Dbp transcription.

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Acknowledgements

We are grateful to U. Albrecht for supplying us with Per1−/−/Per2Brdm/Brdm mice; D. Shore and R. Sternglanz for discussions, S. Brown, H. Reinke, D. Gatfield and the other members of our lab for discussions and N. Roggli for preparation of the figures. This work was supported by the Canton of Geneva, the Swiss National Science Foundation (through an individual grant to U.S. and the Swiss National Center for Competence in Research program grant 'Frontiers in Genetics'), the Louis Jeantet Foundation of Medicine and the Bonizzi-Theler Stiftung.

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  1. Jürgen A Ripperger

    Present address: Section of Biochemistry, Department of Medicine, University of Fribourg, Switzerland

Authors and Affiliations

  1. Department of Molecular Biology and National Center of Competence in Research 'Frontiers in Genetics', Sciences III, University of Geneva, 30, Quai Ernest-Ansermet, Geneva, 4, CH-1211, Switzerland

    Jürgen A Ripperger & Ueli Schibler

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  1. Jürgen A Ripperger
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Correspondence to Ueli Schibler.

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Supplementary information

Supplementary Fig. 1

Dynamic histone modifications depend on functional circadian oscillators. (PDF 13 kb)

Supplementary Fig. 2

Mapping of CpG methylation within the Dbp gene. (PDF 45 kb)

Supplementary Fig. 3

The promoter-proximal E-box motif is not required for circadian Dbp transcription. (PDF 23 kb)

Supplementary Table 1

Primer sequences. (PDF 12 kb)

Supplementary Methods (PDF 11 kb)

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Ripperger, J., Schibler, U. Rhythmic CLOCK-BMAL1 binding to multiple E-box motifs drives circadian Dbp transcription and chromatin transitions. Nat Genet 38, 369–374 (2006). https://doi.org/10.1038/ng1738

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