**4. DNA methylation and CVDs**

DNA methylation is a durable, relatively constant epigenetic change. It involves the covalent attachment of a methyl group to the cytosine [3, 55]. The primary role of DNA methylation is to regulate gene expression by altering the availability of DNA to the transcription factors [3, 13].

DNA methylation links the steady genome and the changing environment. It is an instrument through which environmental changes influence metabolism [7]. Disruption of DNA methylation has been associated with different metabolic diseases such as diabetes [56], obesity, and insulin resistance [57]. Furthermore, the epigenetic mechanisms control circadian rhythm, and circadian disturbance leads to DNA methylation changes of the clock genes [7, 51, 58]. Adiposity, metabolic syndrome, and weight loss are linked to DNA methylation changes of the *ARNTL*, *CLOCK*, and *PER2* gene promoters [7]. It indicates the significance of determining the impact of DNA methylation in epigenetic studies in complex human disorders [7].

DNA methylation is cell- or tissue-specific, but epimutations are not restricted to the affected tissue and may also be observed in peripheral blood [7]. Compared to other genes, the regulatory regions of circadian rhythm genes are plentiful in CpG sites [59, 60]. Patients with coronary artery disease have altered methylation patterns relative to controls [1, 61, 62]. All mentioned supports the assumption that epigenetic variations are associated with an increased CVD risk [1].

Epigenetic alterations of circadian genes are related to obesity and metabolic disorders [17, 63]. A positive association was found between the alteration of the *ARNTL* gene methylation and weight loss, and its activity is included in the control of adipogenesis and lipid metabolism [63]. The long-term shiftwork, associated with obesity and metabolic syndrome risk, induces hypomethylation of the *CLOCK* gene promoter [22]. *CLOCK* gene SNPs are associated with a

**41**

*Epigenetics of Circadian Rhythm Disruption in Cardiovascular Diseases*

predisposition to metabolic syndrome [22, 64]. Long-term shift work, obesity, and metabolic syndrome are associated with *CRY2* hypermethylation in peripheral blood [22]. Genetic variants of the human *PER2* gene are related to abdominal obesity and CVDs [22, 65]. The methylation status of CpG sites in the *PER2* gene is

Global hypomethylation of DNA is present in atherosclerotic lesions [3, 66]. The severity of atherosclerotic lesions correlates with DNA methylation [3, 14, 67, 68]. There are notable variations in DNA methylation after an MI event [69, 70]. DNA

Environmental and behavioral factors, such as inflammation, smoking, physical activity, or stress, can alter the epigenome [63, 73]. Elevated gene expression in the inflammatory pathway is associated with decreased gene methylation [46]. DNA methylation relies on the accessibility of methyl groups obtained from methionine, and the existence of certain nutrients in the food influences epigenetic changes with possible cardiovascular outcomes [46]. Although methylation changes are related to healthy aging, they could be in the background of the development of some diseases, such as CVD [46, 74]. Reduction in global DNA methylation occurs

Post-translational modifications occur at amino acid residues in the amino-terminal regions of histone and cover histone acetylation, methylation, phosphorylation, sumoylation, and ubiquitination. It controls chromatin remodeling and gene expression [3, 23]. Histone acetylation is a sign of transcription activation [75], while histone methylation can both stimulate and inhibit transcription [28, 75]. Post-translational histone modifications control genes coding clock proteins [46, 75]. Epigenetic irregularities are related to different disorders, including atherosclerosis [4, 76]. Histone modifications occur at the CCG promoters in a circadian fashion [4, 44, 77, 78]. The core clock protein, CLOCK, has HAT activity. It revealed the molecular association among epigenetic mechanisms and circadian rhythm [4, 19, 59, 79]. CLOCK acetylates ARNTL, which facilitates CRY-dependent repression [19, 28], and interaction of CRY1 with the ARNTL-CLOCK heterodimer [9]. CLOCK and NPAS2 attract different HATs to the promoter of the *PER1* in vascular tissues [59, 78]. The rhythmic binding of ARNTL and CLOCK transcriptional activators directly influences the acetylation of specific histone lysine residues near the DNA-binding site without the involvement of additional HAT enzymes [59]. CLOCK acetylates additional nonhistone proteins that have crucial roles in the regulation of different cellular events [4]. SIRT1 is an NAD + -dependent histone deacetylase [4, 59, 80]. It is needed for rhythmic transcription of some clock genes, such as *ARNTL*, *CRY1*, and *PER2* [80, 81]. STIR1 represents the molecular connection between metabolic processes, chromatin remodeling, and circadian physiology [4]. SIRT1 plays a crucial role in metabolism. It deacetylates some proteins of the metabolic pathways and regulates gene expression by histone deacetylation [75]. *SIRT1* expression levels are nearly constant over 24 h, just like relatively constant *CLOCK* gene expression levels\*\*\* [4, 82–85]. The HAT function of CLOCK is balanced by SIRT1, which deacetylates H3 and ARNTL, and PER2 [79, 83, 86]. SIRT1 binds to ARNTL-CLOCK within a chromatin complex that, in a circadian fashion, binds to CCG promoters [4, 87]. ARNTL and PER2 are SIRT1 targets [4]. SIRT1 associates with ARNTL-CLOCK heterodimers and improves the deacetylation and degradation of PER2 [86]. SIRT1 deacetylates clock proteins in a circadian fashion [4]. HDAC3 is a deacetylase that modulates histone acetylation of circadian genes, especially those included in lipid

associated with obesity, metabolic syndrome, and weight loss [7, 22].

methylation status in blood samples is related to CVD [71, 72].

*DOI: http://dx.doi.org/10.5772/intechopen.92057*

throughout the human lifespan [46].

**5. Histone modification and CVDs**

#### *Epigenetics of Circadian Rhythm Disruption in Cardiovascular Diseases DOI: http://dx.doi.org/10.5772/intechopen.92057*

*Cardiac Diseases - Novel Aspects of Cardiac Risk, Cardiorenal Pathology and Cardiac Interventions*

the intensity of myocardial ischemia, especially after MI [16]. Inhibition of HDAC can promote angiogenesis and reduce myocardial damage after MI [16], such as valproic acid (VPA), which is an HDAC inhibitor [2]. Histone deacetylases, SIRT1 (sirtuin 1), and SIRT6 participate in the histone modification, thus controlling gene expression [35] and providing a molecular connection among metabolism and circadian rhythm [6]. SIRT1 deacetylates regulatory proteins and acts as a rhythm-promoting agent in circadian oscillators [35]. SIRT1 has a unique role in central and peripheral circadian rhythms [35]. The purpose of histone phosphorylation in CVDs is minimal [14], while SUMO proteins influence the activity of several essential factors that are important for cardiac development [14]. There are connections between circadian rhythm

Numerous lncRNAs have essential regulatory functions in various CVDs [14]. The miRNAs regulate cholesterol metabolism, oxidative stress, and endothelial dysfunction, diverse cellular processes involved in atherosclerosis [14]. MiRNAs may be relevant regulators of circadian rhythm [1]. Circulating miRNA-145 and miRNA-126 are decreased in patients with coronary artery disease, while miRNA-1, miRNA-499, and miRNA-133b are increased during acute myocardial infarction

Circadian rhythms combine metabolic and environmental signals and alter gene expression when adapting the organism to particular circumstances [6]. Many epigenetic regulators in some tissues are controlled in a circadian fashion [19, 53]. The challenge is to determine whether epigenetic variations happen in a rhythmic pattern in tissues included in the CVD development [12, 19]. Epigenetics can contribute to enhancing CVD therapies and finding new markers for CVD screening [16, 54].

DNA methylation is a durable, relatively constant epigenetic change. It involves the covalent attachment of a methyl group to the cytosine [3, 55]. The primary role of DNA methylation is to regulate gene expression by altering the availability of

DNA methylation links the steady genome and the changing environment. It is an instrument through which environmental changes influence metabolism [7]. Disruption of DNA methylation has been associated with different metabolic diseases such as diabetes [56], obesity, and insulin resistance [57]. Furthermore, the epigenetic mechanisms control circadian rhythm, and circadian disturbance leads to DNA methylation changes of the clock genes [7, 51, 58]. Adiposity, metabolic syndrome, and weight loss are linked to DNA methylation changes of the *ARNTL*, *CLOCK*, and *PER2* gene promoters [7]. It indicates the significance of determining the impact of

DNA methylation is cell- or tissue-specific, but epimutations are not restricted to the affected tissue and may also be observed in peripheral blood [7]. Compared to other genes, the regulatory regions of circadian rhythm genes are plentiful in CpG sites [59, 60]. Patients with coronary artery disease have altered methylation patterns relative to controls [1, 61, 62]. All mentioned supports the assumption that

Epigenetic alterations of circadian genes are related to obesity and metabolic disorders [17, 63]. A positive association was found between the alteration of the *ARNTL* gene methylation and weight loss, and its activity is included in the control of adipogenesis and lipid metabolism [63]. The long-term shiftwork, associated with obesity and metabolic syndrome risk, induces hypomethylation of the *CLOCK* gene promoter [22]. *CLOCK* gene SNPs are associated with a

DNA methylation in epigenetic studies in complex human disorders [7].

epigenetic variations are associated with an increased CVD risk [1].

regulators, chromatin modifications, and cellular metabolism [1, 52].

[13]. All those miRNAs can be biomarkers of CVD.

**4. DNA methylation and CVDs**

DNA to the transcription factors [3, 13].

**40**

predisposition to metabolic syndrome [22, 64]. Long-term shift work, obesity, and metabolic syndrome are associated with *CRY2* hypermethylation in peripheral blood [22]. Genetic variants of the human *PER2* gene are related to abdominal obesity and CVDs [22, 65]. The methylation status of CpG sites in the *PER2* gene is associated with obesity, metabolic syndrome, and weight loss [7, 22].

Global hypomethylation of DNA is present in atherosclerotic lesions [3, 66]. The severity of atherosclerotic lesions correlates with DNA methylation [3, 14, 67, 68]. There are notable variations in DNA methylation after an MI event [69, 70]. DNA methylation status in blood samples is related to CVD [71, 72].

Environmental and behavioral factors, such as inflammation, smoking, physical activity, or stress, can alter the epigenome [63, 73]. Elevated gene expression in the inflammatory pathway is associated with decreased gene methylation [46]. DNA methylation relies on the accessibility of methyl groups obtained from methionine, and the existence of certain nutrients in the food influences epigenetic changes with possible cardiovascular outcomes [46]. Although methylation changes are related to healthy aging, they could be in the background of the development of some diseases, such as CVD [46, 74]. Reduction in global DNA methylation occurs throughout the human lifespan [46].
