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Dec1 and Dec2 are regulators of the mammalian molecular clock

Abstract

The circadian rhythms in mammals are regulated by a pacemaker located in the suprachiasmatic nucleus of the hypothalamus1,2. Four clock-gene families have been found to be involved in a transcription–translation feedback loop that generates the circadian rhythm at the intracellular level3. The proteins Clock and Bmal1 form a heterodimer which activates the transcription of the Per gene from the E-box elements in its promoter region4,5. Protein products of Per act together with Cry proteins to inhibit Per transcription6,7, thus closing the autoregulatory feedback loop. We found that Dec1 and Dec2, basic helix–loop–helix transcription factors, repressed Clock/Bmal1-induced transactivation of the mouse Per1 promoter through direct protein–protein interactions with Bmal1 and/or competition for E-box elements. Dec1 and Dec2 are expressed in the suprachiasmic nucleus in a circadian fashion, with a peak in the subjective day. A brief light pulse induced Dec1 but not Dec2 expression in the suprachiasmic nucleus in a phase-dependent manner. Dec1 and Dec2 are regulators of the mammalian molecular clock, and form a fifth clock-gene family.

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Figure 1: Repression of the Clock/Bmal1-induced E54-TK reporter activity by Dec1 and Dec2, and mechanisms of the repression.
Figure 2: Circadian profiles of Dec1 and Dec2 expression in the SCN.
Figure 3: Response of Dec1 and Dec2 expression to 30 min light.
Figure 4: Circadian variation of Dec1 and Dec2 expression in the brain structures outside the SCN.

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Acknowledgements

This work was supported in part by Grants-in-Aid for Scientific Research and Special Coordination Funds for Promoting Science and Technology from the Ministry of Education, Culture, Sports, Science and Technology, the Japanese Government.

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Correspondence to Sato Honma.

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Honma, S., Kawamoto, T., Takagi, Y. et al. Dec1 and Dec2 are regulators of the mammalian molecular clock. Nature 419, 841–844 (2002). https://doi.org/10.1038/nature01123

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