Level of constitutively expressed BMAL1 affects the robustness of circadian oscillations

The circadian rhythm is a biological oscillation of physiological activities with a period of approximately 24 h, that is driven by a cell-autonomous oscillator called the circadian clock. The current model of the mammalian circadian clock is based on a transcriptional-translational negative feedbac...

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Bibliographic Details
Published in:	Scientific reports Vol. 12; no. 1; p. 19519
Main Authors:	Padlom, Apirada, Ono, Daisuke, Hamashima, Rio, Furukawa, Yuko, Yoshimura, Takashi, Nishiwaki-Ohkawa, Taeko
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 14-11-2022 Nature Publishing Group Nature Portfolio
Subjects:	631/45 631/57 631/80/105 Animals ARNTL Transcription Factors - genetics ARNTL Transcription Factors - metabolism BMAL1 protein Circadian Clocks - genetics Circadian rhythm Circadian Rhythm - genetics Circadian rhythms Clock gene CLOCK Proteins - genetics CLOCK Proteins - metabolism Doxycycline Doxycycline - pharmacology Gene Expression Regulation Humanities and Social Sciences Mammals - metabolism multidisciplinary Oscillations Period 2 protein Science Science (multidisciplinary)
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Summary:	The circadian rhythm is a biological oscillation of physiological activities with a period of approximately 24 h, that is driven by a cell-autonomous oscillator called the circadian clock. The current model of the mammalian circadian clock is based on a transcriptional-translational negative feedback loop in which the protein products of clock genes accumulate in a circadian manner and repress their own transcription. However, several studies have revealed that constitutively expressed clock genes can maintain circadian oscillations. To understand the underlying mechanism, we expressed Bmal1 in Bmal1 -disrupted cells using a doxycycline-inducible promoter and monitored Bmal1 and Per2 promoter activity using luciferase reporters. Although the levels of BMAL1 and other clock proteins, REV-ERBα and CLOCK, showed no obvious rhythmicity, robust circadian oscillation in Bmal1 and Per2 promoter activities with the correct phase relationship was observed, which proceeded in a doxycycline-concentration-dependent manner. We applied transient response analysis to the Bmal1 promoter activity in the presence of various doxycycline concentrations. Based on the obtained transfer functions, we suggest that, at least in our experimental system, BMAL1 is not directly involved in the oscillatory process, but modulates the oscillation robustness by regulating basal clock gene promoter activity.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2045-2322 2045-2322
DOI:	10.1038/s41598-022-24188-4