Rhythmic binding of Topoisomerase I impacts on the transcription of Bmal1 and circadian period

The Bmal1 gene is essential for the circadian system, and its promoter has a unique open chromatin structure. We examined the mechanism of topoisomerase I (Top1) to understand the role of the unique chromatin structure in Bmal1 gene regulation. Camptothecin, a Top1 inhibitor, and Top1 small interfer...

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Bibliographic Details
Published in:Nucleic acids research 2012-10, Vol.40 (19), p.9482-9492
Main Authors: Onishi, Yoshiaki, Kawano, Yasuhiro
Format: Article
Language:English
Subjects:
ARNTL Transcription Factors - genetics
Binding Sites
BMAL1 protein
Camptothecin
Camptothecin - pharmacology
Cell Line
Chromatin
Chromatin - chemistry
Chromatin - drug effects
Circadian Rhythm - drug effects
Circadian Rhythm - genetics
Circadian rhythms
Data processing
DNA
DNA topoisomerase
DNA Topoisomerases, Type I - metabolism
Gene Expression Regulation
Gene Regulation, Chromatin and Epigenetics
Handedness
Nuclear Receptor Subfamily 1, Group D, Member 1 - metabolism
Oscillations
Promoter Regions, Genetic
Promoters
siRNA
Superhelical DNA
Topoisomerase I Inhibitors - pharmacology
Transcription
Transcription, Genetic - drug effects
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Summary:The Bmal1 gene is essential for the circadian system, and its promoter has a unique open chromatin structure. We examined the mechanism of topoisomerase I (Top1) to understand the role of the unique chromatin structure in Bmal1 gene regulation. Camptothecin, a Top1 inhibitor, and Top1 small interfering RNA (siRNA) enhanced Baml1 transcription and lengthened its circadian period. Top1 is located at an intermediate region between two ROREs that are critical cis-elements of circadian transcription and the profile of Top1 binding indicated anti-phase circadian oscillation of Bmal1 transcription. Promoter assays showed that the Top1-binding site is required for transcriptional suppression and that it functions cooperatively with the distal RORE, supporting that Bmal1 transcription is upregulated by Top1 inhibition. A DNA fragment between the ROREs, where the Top1-binding site is located, behaved like a right-handed superhelical twist, and modulation of Top1 activity by camptothecin and Top1 siRNA altered the footprint profile, indicating modulation of the chromatin structure. These data indicate that Top1 modulates the chromatin structure of the Bmal1 promoter, regulates Bmal1 transcription and influences the circadian period.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gks779