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

Onishi, Yoshiaki; Kawano, Yasuhiro

doi:10.1093/nar/gks779

Cited by 19 publications

(15 citation statements)

References 49 publications

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“…This TOP1 association was less pronounced in the presence of CPT (Figure 6B). TOP1 participates in re-shaping the chromatin structure of its target genes and shows enrichment at chromatin marks such as H3K4me3 [42,43]. As inflammatory cytokines subsequently also lead to changes in histone modifications at inflammatory genes including IL8 [39], it was interesting to test whether CPT might also affect these events.…”

Section: Resultsmentioning

confidence: 99%

Chemotherapeutic Drugs Inhibiting Topoisomerase 1 Activity Impede Cytokine-Induced and NF-κB p65-Regulated Gene Expression

Riedlinger

Bartkuhn

Zimmermann

et al. 2019

Cancers

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Inhibitors of DNA topoisomerase I (TOP1), an enzyme relieving torsional stress of DNA by generating transient single-strand breaks, are clinically used to treat ovarian, small cell lung and cervical cancer. As torsional stress is generated during transcription by progression of RNA polymerase II through the transcribed gene, we tested the effects of camptothecin and of the approved TOP1 inhibitors Topotecan and SN-38 on TNFα-induced gene expression. RNA-seq experiments showed that inhibition of TOP1 but not of TOP2 activity suppressed the vast majority of TNFα-triggered genes. The TOP1 effects were fully reversible and preferentially affected long genes. TNFα stimulation led to inducible recruitment of TOP1 to the gene body of IL8, where its inhibition by camptothecin reduced transcription elongation and also led to altered histone H3 acetylation. Together, these data show that TOP1 inhibitors potently suppress expression of proinflammatory cytokines, a feature that may contribute to the increased infection risk occurring in tumor patients treated with these agents. On the other hand, TOP1 inhibitors could also be considered as a therapeutic option in order to interfere with exaggerated cytokine expression seen in several inflammatory diseases.

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Section: Resultsmentioning

confidence: 99%

Chemotherapeutic Drugs Inhibiting Topoisomerase 1 Activity Impede Cytokine-Induced and NF-κB p65-Regulated Gene Expression

Riedlinger

Bartkuhn

Zimmermann

et al. 2019

Cancers

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“…One of the most important findings was that altering the DNA configuration of the Bmal1 promoter causes the epigenetic regulation of Bmal1 circadian transcription [86]. Topoisomerase I (TOP1) is located at an intermediate region between two ROREs that are critical cis-elements of circadian transcription, which is required for transcriptional suppression in cooperation with the distal RORE.…”

Section: Assays Of Bmal1 Transcription Modulatorsmentioning

confidence: 99%

Epigenetic Modulation of Circadian Rhythms: Bmal1 Gene Regulation

Tomita¹,

Onishi²

2020

Chromatin and Epigenetics

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Circadian rhythms that function in behaviour and physiology have adaptive significance for living organisms from bacteria to humans and reflect the presence of a biological clock. The engine of circadian rhythms is a transcription-translation feedback loop that is finetuned by epigenetic regulation in higher eukaryotes. We elucidated the chromatin structure of the Bmal1 gene, a critical component of the mammalian clock system, and have continued to investigate transcriptional regulation including DNA methylation. Various ailments including metabolic diseases can disrupt circadian rhythms, and many human diseases are associated with altered DNA methylation. Therefore, regulated circadian rhythms are important for human health. Here, we summarise the importance of epigenetic clock gene regulation, including DNA methylation of the Bmal1 gene, from the viewpoint of relationships to diseases.

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“…Topoisomerases, including type I (TOPI) and type II (TOPII), are key enzymes for DNA replication, transcription, recombination and chromatin remodeling [65]. In a recent study, it was shown that TOPI suppressed Bmal1 transcription via binding to an intermediate region between the two RORE elements in the promoter.…”

Section: Targets Of Small-molecule Clock Modulatorsmentioning

confidence: 99%

“…In a recent study, it was shown that TOPI suppressed Bmal1 transcription via binding to an intermediate region between the two RORE elements in the promoter. Camptothecin, a TOPI inhibitor, enhanced Bmal1 transcription and lengthened the circadian period [65]. In addition, the TOPI inhibitor harmine also lengthened the circadian period by enhancing the trans-activating function of RORα in vitro and in vivo [66, 67].…”

Section: Targets Of Small-molecule Clock Modulatorsmentioning

confidence: 99%

Molecular Targets for Small-Molecule Modulators of Circadian Clocks

He¹,

Chen

2016

CDM

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Background Circadian clocks are endogenous timing systems that regulate various aspects of mammalian metabolism, physiology and behavior. Traditional chronotherapy refers to the administration of drugs in a defined circadian time window to achieve optimal pharmacokinetic and therapeutic efficacies. In recent years, substantial efforts have been dedicated to developing novel small-molecule modulators of circadian clocks. Methods Here, we review the recent progress in the identification of molecular targets of small-molecule clock modulators and their efficacies in clock-related disorders. Specifically, we examine the clock components and regulatory factors as possible molecular targets of small molecules, and we review several key clock-related disorders as promising venues for testing the preventive/therapeutic efficacies of these small molecules. Finally, we also discuss circadian regulation of drug metabolism. Results Small molecules can modulate the period, phase and/or amplitude of the circadian cycle. Core clock proteins, nuclear hormone receptors, and clock-related kinases and other epigenetic regulators are promising molecular targets for small molecules. Through these targets small molecules exert protective effects against clock-related disorders including the metabolic syndrome, immune disorders, sleep disorders and cancer. Small molecules can also modulate circadian drug metabolism and response to existing therapeutics. Conclusion Small-molecule clock modulators target clock components or diverse cellular pathways that functionally impinge upon the clock. Target identification of new small-molecule modulators will deepen our understanding of key regulatory nodes in the circadian network. Studies of clock modulators will facilitate their therapeutic applications, alone or in combination, for clock-related diseases.

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

Cited by 19 publications

References 49 publications

Chemotherapeutic Drugs Inhibiting Topoisomerase 1 Activity Impede Cytokine-Induced and NF-κB p65-Regulated Gene Expression

Chemotherapeutic Drugs Inhibiting Topoisomerase 1 Activity Impede Cytokine-Induced and NF-κB p65-Regulated Gene Expression

Epigenetic Modulation of Circadian Rhythms: Bmal1 Gene Regulation

Molecular Targets for Small-Molecule Modulators of Circadian Clocks

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