Epigenetic regulation of the circadian clock: role of 5-aza-2′-deoxycytidine

Tomita, Tatsunosuke; Kurita, Ryoji; Onishi, Yoshiaki

doi:10.1042/bsr20170053

Cited by 16 publications

(11 citation statements)

References 48 publications

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“…Taniguchi et al reported that CpG islands of the Bmal1 promoter are hypermethylated in diffuse large B-cell lymphoma and in acute lymphocytic and myeloid leukaemia [42]. We also reported this phenomenon and that the methylation pattern of the Per2 promoter region does not change in RPMI8402 cells [46]. The aberrant methylation pattern of the Bmal1 promoter was restored, and the intrinsic rhythm was revived after 1 day of aza-dC treatment.…”

Section: Cancersupporting

confidence: 71%

“…We recently found that recovery from DNA methylation by 5-aza-2 0 -deoxycytidine (aza-dC) differs between the Bmal1 and Rpib9 genes, suggesting that the release of methylation depends on the locus/gene or sequence and that methylation status is specific to the DNA site [46]. Taken together, these findings imply that methylation is specific to gene function and that an early response to the aza-dC demethylation of sites in Bmal1 might be functionally important for adaptation to environmental change.…”

Section: Transcriptional Regulation Of the Bmal1 Genementioning

confidence: 99%

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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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Section: Cancersupporting

confidence: 71%

Section: Transcriptional Regulation Of the Bmal1 Genementioning

confidence: 99%

Epigenetic Modulation of Circadian Rhythms: Bmal1 Gene Regulation

Tomita¹,

Onishi²

2020

Chromatin and Epigenetics

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“…In specific cases, this remains, of course, a possibility for downregulation. However, in some detailed investigations, the Per2 promoter was instead found to be hypomethylated, despite the observed suppression of the gene [46,47]. This is, however, also explainable under conditions of silenced Bmal1, because the BMAL1 protein is required for Per2 expression.…”

Section: Circadian Oscillators and Melatonin In The Context Of Dna Momentioning

confidence: 98%

“…In several ovarian cancer cell lines, methylation at Bmal1 was associated with silencing of this gene, although this was accompanied by enhanced histone methylation (H3K27me3) [44]. In various other tumor cell lines, hypermethylation of the Bmal1 promoter was shown to silence this gene and to suppress circadian rhythmicity [11,25,[45][46][47]. Hypermethylation of a CpG island in the 5' region and hypomethylation in the first exon of Bmal1 were reported for cases of bipolar disorder [48].…”

Section: Circadian Oscillators and Melatonin In The Context Of Dna Momentioning

confidence: 99%

Untitled

2017

J Geriatr Med Gerontol

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Melatonin is a highly pleiotropic regulator molecule that influences numerous functions in many cell types. Its actions comprise direct and circadian oscillator-mediated effects. The levels of circulating melatonin typically decline in the course of aging. Additionally,various aging-associated diseases further decrease melatonin concentrations. With regard to its remarkably broad spectrum of actions, control mechanisms upstream and downstream of melatonin should be investigated much more in detail with regard to the contribution of epigenetic modulation. The importance of epigenetic alterations has already become evident in the fields of both gerontology and chronobiology. Therefore, it seems necessary to fill the gaps concerning corresponding processes related to melatonin, especially under the aspects of physiologic malfunctions because of aging-associated decreases of melatonin. This review outlines the findings on melatonin's epigenetic actions, as obtained to date, and sets these results in correspondence to general knowledge and many specific findings concerning circadian rhythms. These considerations focus on DNA methylation and erasure of 5-methylcytosine, on histone modification, in particular, acetylation/deacetylation and methylation/demethylation, and on the manifold roles of noncoding RNAs, especially microRNAs. With regard to melatonin's spectrum of actions in the gerontological context, emphasis is given to its contribution to circadian oscillation amplitudes, to anti-inflammatory actions and to antioxidative protection.

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“…Joska et al argue that because perturbation of the circadian clock will alter the methylation status, hypermethylation of clock genes in cancer cells may simply be a result of defective clock gene expression and its impact on DNA methylation patterns . Interestingly, however, reversing DNA methylation, via treatment with a methylation inhibitor, such as 5‐aza‐2′‐deoxycytidine, regenerates endogenous circadian rhythms in RPMI8402 lymphoblastic leukaemia cells, via restoration of BMAL1 expression , suggesting that hypermethylation of circadian clock genes might be a mechanism by which circadian rhythms are suppressed within tumour cells.…”

Section: Core Circadian Clock Genes Are Dysregulated In Cancer Cellsmentioning

confidence: 99%

The tumour suppressing role of the circadian clock

et al. 2019

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The circadian clock and the ~24 h rhythms it generates are essential in maintaining regular tissue functioning. At the molecular level, the circadian clock comprises a core set of rhythmically expressed genes and gene products that are able to drive rhythmic expression of other genes to generate overt circadian rhythms. It has recently come to light that perturbations of circadian rhythms contribute to the development of pathological states such as cancer, and altered expression and/or regulation of circadian clock genes has been identified in multiple tumour types. This review summarises the important role the circadian system plays in regulating cellular processes, including the cell cycle, apoptosis, DNA repair, the epithelial‐to‐mesenchymal transition, metabolism and immunity and how its dysregulation has widespread implications and could be a critical player in the development of cancer. Understanding its role in cancer development is important for the field chronotherapy, where the timing of chemotherapy administration is optimised based on differences in circadian clock functioning in normal and cancer cells. This has been found to influence the patient response, minimising the side effects commonly associated with chemotherapy. © 2019 IUBMB Life, 2019

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Epigenetic regulation of the circadian clock: role of 5-aza-2′-deoxycytidine

Cited by 16 publications

References 48 publications

Epigenetic Modulation of Circadian Rhythms: Bmal1 Gene Regulation

Epigenetic Modulation of Circadian Rhythms: Bmal1 Gene Regulation

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The tumour suppressing role of the circadian clock

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