Clock genes and their possible functions for cancer suppression.
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 fine-tuned 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.
Keywords
- molecular clock
- transcriptional mechanism
- cytosine methylation
- chromatin
- cancer
- metabolic syndrome
1. Introduction
Circadian rhythms function in most living organisms and govern many behavioural and biochemical processes with 24-h periodicity regardless of changes in the cellular environment. This is closely associated with the natural rhythm of the sun, which provides light and heat with 24-h periodicity. The master clock that generates circadian rhythms in mammals is located in the suprachiasmatic nucleus (SCN) of the hypothalamus and is governed by blue-light sensing in eyes. Peripheral organs also contain molecular clocks. These biological clocks control all aspects of physiology such as sleep-wake cycles, body temperature, hormone secretion, blood pressure and metabolism [1]. Biological clocks oscillate via a mechanism based on interlocking transcriptional-translational feedback loops that have both positive and negative elements. The circadian oscillator orchestrates the rhythmic mRNA expression and output of hundreds or thousands of clock-controlled genes (CCG) that temporally coordinate many cellular functions [2]. Circadian transcriptional regulators are apparently involved in the initial stages of RNA polymerase II recruitment and initiation, as well as the histone modifications associated with these events to set the stage for gene expression [3]. The methylation of cytosine on CpG dinucleotides, which is also epigenetic regulation of gene expression, either directly interferes with the binding of transcriptional regulators or indirectly inactivates a gene by modulating chromatin to a repressive structure. About 43% of all protein-encoding genes in mice exhibit circadian rhythms of mRNA abundance somewhere in the body, largely in an organ-specific manner [4]. The temporal coordination of cellular functions is lost when circadian rhythms are disrupted by age, the environment or genetic mutation, with deleterious effects on health. For instance, the adrenal steroid hormone glucocorticoid that controls various physiological processes, such as metabolism, the immune response, cardiovascular activity and brain function, is under the control of the circadian clock [5], implying that several diseases are closely associated with disrupted circadian rhythms.
2. Transcriptional mechanism of the circadian clock
2.1. Basic regulation of circadian transcription
The engine of the mammalian molecular clock consists of a transcription-translation feedback loop initiated by the transcription factor BMAL1-CLOCK heterodimer. BMAL1 and CLOCK have paralogs, known as BMAL2 and NPAS2, respectively. Heterodimers such as BMAL1-CLOCK bind to E-box enhancer sequences and activate the transcription of three
2.2. Epigenetic mechanism: effect of chromatin structure
Transcriptional regulation initially requires the coordinated control of chromatin and the genome structure [3]. In general, genetic information is packed into the chromatin structure, of which the nucleosome is the most basic unit; it determines the large-scale chromatin structure as a building block and influences transcription. Eukaryotic promoter regions are thought to have inactive states, assured by the tendency of nucleosomes to inhibit transcription by protecting protein-DNA interaction. Therefore, chromatin remodelling and loosening of the nucleosomal barrier including histone tail modifications are key steps in circadian modifications followed by sequence-specific, transcription factor binding that regulates gene expressions [14]. Distinct chromatin states are determined by unique histone post-translational modifications. First, histone acetylation levels fluctuate rhythmically at clock gene promoters and enhancers. Specifically, acetylated histone H3 at Lys27 (H3K27ac), a marker of active enhancers, and H3 at Lys9 (H3K9ac) are rhythmic and positively correlate with clock gene expression. For example, rhythmic BMAL1-CLOCK binding and H3K9ac are required as well as rhythmic histone H3 abundance at the start site for
2.3. DNA methylation
The most common epigenetic modification is DNA methylation, which is a covalent chemical alteration that plays a crucial role in numerous biological processes. It occurs in mammals predominantly on cytosine residues in cytosine-guanine (CpG) dinucleotides, and tissue-specific genomic DNA methylation patterns play a fundamental role in establishing cell identity during differentiation. Generally, although about 70% of all CpG sequences in mouse and human genomes are methylated, CpG islands in promoter sequences are methylated at a relatively lower level [33]. Overall, DNA methylation exhibits no major rhythmic changes and the cellular function of DNA methylation depends on which gene is methylated. One of the most important issues regarding DNA methylation is how the machinery is directed towards and maintains specific genomic sequences. One mechanism might be the PML-RAT fusion protein in leukaemia, which induces DNA hypermethylation and gene silencing at specific target promoters [34]. Another is siRNA-mediated, RNA-directed DNA methylation, which is a stepwise process initiated by dsRNA that recruits DNMT to catalyse the
3. Transcriptional regulation of the Bmal1 gene
We recently found that recovery from DNA methylation by 5-aza-2′-deoxycytidine (aza-dC) differs between the
4. Disease
Appropriate circadian gene expression is necessary for the normal cell development. That is, distorted clock gene expression leads to various diseases. This chapter focuses on cancers and some other diseases.
4.1. Cancer
Close relationships between clock gene expression and the initiation and progression of cancer are obvious from the findings of many studies. Clock gene expression is altered in many types of malignancies including breast, lung, haematopoietic, pancreatic and skin cancers. Clock genes are apt to be downregulated in many cancer types, as shown in Table 1. These phenomena imply that clock genes have some anti-tumour effects. The physiological disruption of circadian rhythms and the genetic loss of
Gene | Expression | Mechanism | Cancer type | DNA methylation | References |
---|---|---|---|---|---|
Downregulated | Apoptosis | Colon, lung, breast | — | [38] | |
Downregulated | Apoptosis | Lung, lymphocyte | — | [36, 37] | |
Downregulated | MYC-downregulation | Lung, breast | — | [34, 36, 37] | |
Downregulated | p53-upregulation | Lung, breast | — | [36, 37] | |
Downregulated | Unknown | Breast | Hypermethylation | [39, 40] | |
Downregulated | p53 pathway | Pancreas | — | [35] | |
Downregulated | p300, CAT activation | Leukaemia | Hypermethylation | [29, 33, 34] |
The roles of clock genes seem to differ among stages or tissues in patients with cancer. In addition to classical genetic mutations, the epigenetic landscapes of cancer cells are rather contorted. From an epigenetic perspective, clock genes functionally associate with histone modifying genes that are responsible for cancer progression and maintenance. Mixed lineage leukaemia (MLL) genes were originally discovered through detailed analyses of leukaemogenic rearrangement but they are now thought to be responsible for histone H3K4 methyltransferase activity and promoters of target gene transcription. Mutations of MLL genes literally trigger mixed lineage leukaemia and are necessary to maintain malignancy through aberrant epigenetic gene regulation [56]. The relationship between MLL genes and circadian rhythm maintenance through histone modification has been studied in detail. According to Katada et al., MLL1 has CLOCK-associated histone modifying activity, and it is necessary to generate circadian rhythms in fibroblasts [57]. Kim et al. found that MLL3 and 4 are factors that regulate circadian rhythmic homeostasis in the liver [58]. In addition, MLL3 contributes to circadian rhythm generation in mouse embryonic fibroblasts (MEFs) [59]. The histone modifying enzyme EZH2 is another histone-lysine N methyl transferase that is responsible for histone H3K27 methyl transfer. This modification results in transcription repression.
Considering the altered methylation patterns of the promoter regions of clock genes, the features of epigenetic abnormalities of cancer cells comprise highly methylated CpG islands of specific genes accompanied by low methylation status of other genes [61]. Some studies have indicated that this phenomenon is true for clock genes. The
As noted above, many studies have emphasised close relationships between epigenetic modification and circadian clock genes in cancer proliferation and progression. However, the precise mechanisms seem highly complex and remain obscure. Further investigation is required to elucidate these mechanisms.
4.2. Other diseases
Circadian rhythms are also associated with diseases other than cancer through effects on the cardiovascular, renal, immune, endocrine, neuropsychiatric and metabolic systems [5, 62, 63, 64, 65, 66, 67]. Many physiological processes cannot be harmonised when the intrinsic rhythm is aberrant and such dyssynchrony leads to many diseases.
Here, we consider neuropsychiatric disorders. Disrupted sleep-wake cycles, depression, Alzheimer’s disease and mood disorders among neuropsychiatric disorders are notably linked to altered circadian rhythms. However, circadian epigenomics have received less consideration in studies of neuropsychiatric disorders compared with cancers.
Alzheimer’s disease is an age-dependent neurodegenerative disorder that is associated with severe cognitive impairment, and its incidence is increasing, particularly in developed countries due to extended life spans. The typical clinical symptoms are disordered circadian rhythms and abnormal sleep patterns. Amyloid beta is a key molecule in this neurodegeneration [68], and it reportedly degrades BMAL1 protein [69]. The lack of this powerful rhythm generator disrupts circadian rhythms in many patients. Furthermore, the methylation rhythm of the
According to many studies, contorted clock gene expression patterns and mood disorders are closely associated in experimental animal models. Genetic experiments have found that CLOCK is a key factor in maniac states because
Patients with depression frequently have insomnia and abnormal circadian rhythms that could reasonably relate to altered clock gene expression. Circadian clock gene expression has been compared between post-mortem brain samples from patients with major depressive disorder (MDD) and age-matched controls [76]. The findings showed abnormal clock gene phasing and decreased
5. Assays of Bmal1 transcription modulators
The circadian clock controls the daily oscillations of gene expression and physiological function at the cellular level, indicating that the control of circadian rhythms at the cellular level is important for human health. After we elucidated the transcriptional mechanism of the non-redundant essential unique clock gene,
One of the most important findings was that altering the DNA configuration of the
Another important finding was the epigenetic inactivation or DNA methylation of the
6. Conclusion
Circadian rhythms control all aspects of physiology. When they are disrupted by changes in clock gene expression, various critical intracellular physiological processes become dysregulated, and this can lead to diseases that are induced partly by epigenetic effects including DNA methyation. The pathologies that are closely associated with disrupted circadian rhythms include cancer [88], dementia [89], Parkinson’s disease [90] and obesity [91]. Among the clock genes,
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