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The histone methyltransferase MLL1 permits the oscillation of circadian gene expression

Abstract

The classical view of the molecular clock is based on interlocked transcriptional-translational feedback loops. Because a substantial fraction of the mammalian genome is expressed in a circadian manner, chromatin remodeling has been proposed to be crucial in clock function. Here we show that Lys4 (K4) trimethylation of histone H3 is rhythmic and follows the same profile as previously described H3 acetylation on circadian promoters. MLL1, a mammalian homolog of Drosophila trithorax, is an H3K4-specific methyltransferase implicated in transcriptional control. We demonstrate that MLL1 is essential for circadian transcription and cyclic H3K4 trimethylation. MLL1 is in a complex with CLOCK–BMAL1 and contributes to its rhythmic recruitment to circadian promoters and to H3 acetylation. Yet MLL1 fails to interact with CLOCKΔ19, providing an explanation for this mutation's dominant negative phenotype. Our results favor a scenario in which H3K4 trimethylation by MLL1 is required to establish a permissive chromatin state for circadian transcription.

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Figure 1: Histone H3K4 methyltransferase MLL1 synergistically activate CLOCK–BMAL1-mediated gene transcription.
Figure 2: MLL1 governs circadian oscillation of histone modifications and gene expression.
Figure 3: Global analysis of gene expression profile in WT and MLL1-KO MEFs.
Figure 4: MLL1 interacts with CLOCK and BMAL1 and is recruited in circadian fashion.
Figure 5: Impaired H3K4me3 and less recruitment of BMAL1 and MLL1 proteins in c/c mutant MEFs.
Figure 6: CLOCK and MLL1 physically interact at the level of clock-controlled promoters (with E-boxes).

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Acknowledgements

We thank J. Hsieh (Washington University) for the MEFs derived from the MLL1-null mice and the Flag-MLL1-Myc cDNA, R. Roeder (Rockefeller University) for MLL1 (C-terminal) antibody and MLL1 fragment sequences, K. Yagita (Osaka University) for the mDbp promoter-Luciferase, D.G. Skalnik (Indiana University) for Flag-hSet1A cDNA and J. Hess (University of Pennsylvania) for providing the Flag-MLL1 and Flag-MLL1ΔSET cDNA. We thank all members of the Sassone-Corsi laboratory for help, reagents and discussions. This work was supported in part by grants from the Japan Society for the Promotion of Science (JSPS), Postdoctoral Fellowships for Research Abroad to S.K., and from the National Institute of Health (R01-GM081634 and R21-AG033888), Inserm (France) and Sirtris Pharmaceutical Inc. to P.S.-C.

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S.K. conceived the project, designed and conducted the experiments, and wrote the manuscript. P.S.-C. conceived the project, provided conceptual support and contributed to writing the manuscript.

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Correspondence to Paolo Sassone-Corsi.

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Katada, S., Sassone-Corsi, P. The histone methyltransferase MLL1 permits the oscillation of circadian gene expression. Nat Struct Mol Biol 17, 1414–1421 (2010). https://doi.org/10.1038/nsmb.1961

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