Epigenetic Modulation of Circadian Rhythms: Bmal1 Gene Regulation

Abstract

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.

Withanolide Derivative 2,3-Dihydro-3β-methoxy Withaferin-A Modulates the Circadian Clock via Interaction with RAR-Related Orphan Receptor α (RORa)

“…Our results (Figure 2C and Figure 3A) showed that PER2 and Bmal1 did not show opposite oscillation patterns to each other, which is consistent with the previous report that peak times of the mRNA and protein expressions of the Per2 gene are different for 6−7 h. 28 The potential to modify circadian rhythms of 3βmWi-A is attractive in an era where commonplace 24 h lifestyles have led to an increased prevalence of circadian rhythm disorders. 29 Nontoxic technologies/ reagents with potential to manipulate the circadian period are desirable to avoid such disorders. However, the circadian clock is a robust system against stimuli other than light, and it cannot be easily modified by external factors.…”

“…Many chronic disorders including cancers and mood disorders are reported to link with circadian rhythm. 29 We can expect that some of these disorders are treated or prevented by this compound by manipulating RORa function.…”

“…These compounds are not yet reported as rhythm modulators via RORa, and further investigation should be conducted. Many chronic disorders including cancers and mood disorders are reported to link with circadian rhythm . We can expect that some of these disorders are treated or prevented by this compound by manipulating RORa function.…”