**1. Introduction**

The word epigenetics comes from the Greek word 'epi' that means above; that is, hereditary variations in phenotype that do exclude alterations in the nucleotide sequence in DNA [1]. Epigenetic mechanisms involve DNA methylation, post-translational histone modifications, and noncoding RNAs (ncRNAs) [1]. Many studies focus on the epigenetic mechanisms of various diseases. Epigenetic processes are essential for the healthy growth and development of an organism [1]. Epigenetic mechanisms are implicated in the expression of circadian genes in the suprachiasmatic nucleus (SCN) neurons and peripheral tissues [2]. The accumulation of lifestyle and age-related epigenetic changes could result in the development of metabolic disorders and atherosclerosis [2].

The influence of epigenetic changes on the cardiovascular system is an essential link between genotype to phenotype diversity [3]. Epigenetic changes are potentially reversible and may be affected by environmental factors, nutrition, as well as geneenvironment interactions. Identifying and understanding epigenetic factors represent a new insight into our knowledge of the risks of cardiovascular disease (CVD) [1].

#### **1.1 Circadian rhythm**

The circadian clock is a preserved system that allows organisms to adapt to frequent daily variations, such as the day and night and food availability [4]. This center clock receives signals from the environment and coordinates the daily activity of peripheral clocks found in almost all tissues [4]. The molecular clock is vital in maintaining metabolic and physiological homeostasis [5]. The circadian clock is linked to cellular metabolism so that dysregulation of the circadian rhythm can contribute to various pathological conditions such as diabetes, obesity, metabolic syndrome, inflammation, sleep disorders, and CVDs [5–8].

Genome-wide studies show that 10–15% of all transcripts have a circadian pattern in different tissues involved in the control of metabolism, such as the cardiovascular function [4, 6, 8, 9]. The onset of ischemic cardiopathy is irregularly distributed during the day [1, 10, 11]. A chronobiological strategy to heart disease may present new possibilities to enhance drug development to improve therapeutic outcomes [1]. Genetic evidence supports the function of circadian rhythm in the adjustment of metabolism.

#### **1.2 Cardiovascular diseases**

Cardiovascular diseases are complex and diverse. They include hypertension, coronary artery disease, heart failure, and stroke and are a main worldwide reason for morbidity and death in advanced economies and carry a substantial economic burden [1, 3, 12–15]. CVDs are associated with a variety of hereditary and variable risk factors, but environmental and genetic impacts may explain a smaller fraction of CVD risk variability [1, 12]. Studies showed that there is a wide range between 40 and 80% of the genetic contribution to the onset of cardiovascular disease [16].

The complex pathogenesis of CVD is due to the abundance of genetic and environmental factors, of which epigenetic changes are a significant factor [3]. Several risk factors of CVD, like diet, smoking, stress, circadian rhythm, and pollution, are related to epigenetic modifications [1]. Disorders such as hypertension, diabetes, and obesity are often utilized to recognize and cure people at increased CVDs risk [1]. Epigenetic modifications are associated with the processes involved in the CVD in humans or directly affect the gene expression involved in a major cardiac complication, myocardial infarction (MI). Hypertension is one of the leading causes of CVDs [3], while insulin resistance is one of the most significant precursors of type 2 diabetes and associated cardiometabolic conditions [17].

Changes in the style of living and diet could decrease the risk of CVDs [14]. Epigenetic factors indicate there is interindividual variability from birth. It can be stable over the life span and is considered to be an initiator of early programming for adult-onset diseases [12, 18]. The understanding of epigenetics in the onset of CVDs may provide a new perspective on diseases [14].

#### **1.3 Epigenetics**

Epigenetics studies heritable variations in gene expression that exclude any change in the DNA sequence [16, 19]. Epigenetic changes include modifications of the DNA base, post-translational histone modifications, and ncRNA mechanisms that run in the nucleus [16, 20]. The epigenome moves the genome from a transcriptionally active to a transcriptionally inactive state [4, 21]. Epimutation transmissions occur throughout the life of the individual [2]. The rate of epigenetic variation is higher than that of genetic mutations because the formation of new inherited changes allows adjustment to a new environment [14, 16].

**37**

50% of cellular genes [13, 14, 27].

**2. Molecular background of circadian rhythm**

*Epigenetics of Circadian Rhythm Disruption in Cardiovascular Diseases*

The most studied epigenetic change is cytosine methylation. It is also a method for suppressing gene expression [22]. DNA methyltransferase (DNMT) enzymes perform DNA methylation. DNMTs bind the methyl group to the 5-site cytosine [16]. The methyl group most commonly binds to the cytosine at a CpG site. It is the fundamental and ubiquitous epigenetic mechanism [14]. The DNMT enzyme family, consisting of DNMT1, DNMT3a, and DNMT3b, methylates cytosine into 5-methylcytosine [14]. Promoter methylation is usually connected with inhibition of transcription [14]. DNMT1 controls the mitotic inheritance of methylated DNA, while DNMT3a and DNMT3b are mainly in charge of *de novo* methylation [14]. The different epigenetic modification is DNA hydroxymethylation, including 5-hydroxymethylated cytosines [14]. Different nutritional and lifestyle factors can affect the methylation of particular CpG sites in gene promoters and into adulthood [22]. Nucleosomes are composed of histone proteins around which DNA is wound into chromatin [16]. Nucleosomes consist of eight histone proteins: two dimers of H2A/H2B and two dimers of H3/H4. Each histone has an adjustable aminoacid tail [16]. Histones can change at more than 30 amino acid residues within amino-terminal tails [4]. Histone modifications include various processes such as acetylation, methylation, phosphorylation, sumoylation, and ubiquitination. It has a function in the organization of chromatin composition and gene expression by altering the intensity of chromatin condensation [1, 14, 23]. Histones are mostly acetylated on lysine (K) residues. Histone acetyltransferase (HAT) and histone deacetylase (HDAC) regulate histone acetylation [14]. Histone methyltransferase regulates histone methylation, while histone demethylase catalyzes demethylation. Transcription activation is usually associated with acetylation of lysine residues at histones 3 (H3) and 4 (H4). Depending on the location of the target lysines in the histone tail and the number of methyl groups added, methylation can either activate or inhibit gene expression [14, 24]. Histone phosphorylation is a marker of cell division and has a function in DNA repair, chromatin condensation during division, and regulation of gene expression [14, 25]. The addition of ubiquitin to lysine residues in histones is called ubiquitination and is implicated in DNA repair and control of transcription [14]. Sumoylation is a changeable post-translational adjustment using small ubiquitin-like proteins (SUMO) and has a crucial function in various mechanisms, such as transcription, and cell cycle progression [14, 26]. RNA-based epigenetic mechanisms include long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) [14]. NcRNAs are functional RNAs that do not translate into proteins and play an essential part in epigenetic regulation [14, 16]. The lncRNAs are extremely tissue-specific relative to protein-coding genes [16]. The miRNAs are short (20–22 nucleotides), single-stranded, evolutionarily-conserved ncRNAs that modulate the expression at the post-transcriptional level of more than

Changes in the environment, including temperature, light, and nutritional habits, trigger reversible epigenomic modification that can influence numerous physiological processes [28]. Epigenome-wide association studies (EWAS) provide information about associations between epigenomic perturbations and traits associated with human diseases [29]. EWAS try to evaluate the environmental impact on genetic regulation. The epigenetic variations could explain missing parts of heritability of chronic diseases that have not yet been determined by genome-wide association studies [29].

The primary clock genes show circadian expression in the SCN, and light is one of the key drivers that can reset the rhythm phases. There are several crucial proteins

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

#### *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 circadian clock is a preserved system that allows organisms to adapt to frequent daily variations, such as the day and night and food availability [4]. This center clock receives signals from the environment and coordinates the daily activity of peripheral clocks found in almost all tissues [4]. The molecular clock is vital in maintaining metabolic and physiological homeostasis [5]. The circadian clock is linked to cellular metabolism so that dysregulation of the circadian rhythm can contribute to various pathological conditions such as diabetes, obesity, metabolic

Genome-wide studies show that 10–15% of all transcripts have a circadian pattern in different tissues involved in the control of metabolism, such as the cardiovascular function [4, 6, 8, 9]. The onset of ischemic cardiopathy is irregularly distributed during the day [1, 10, 11]. A chronobiological strategy to heart disease may present new possibilities to enhance drug development to improve therapeutic outcomes [1]. Genetic evidence supports the function of circadian rhythm in the

Cardiovascular diseases are complex and diverse. They include hypertension, coronary artery disease, heart failure, and stroke and are a main worldwide reason for morbidity and death in advanced economies and carry a substantial economic burden [1, 3, 12–15]. CVDs are associated with a variety of hereditary and variable risk factors, but environmental and genetic impacts may explain a smaller fraction of CVD risk variability [1, 12]. Studies showed that there is a wide range between 40 and 80% of the genetic contribution to the onset of cardiovascular disease [16]. The complex pathogenesis of CVD is due to the abundance of genetic and environmental factors, of which epigenetic changes are a significant factor [3]. Several risk factors of CVD, like diet, smoking, stress, circadian rhythm, and pollution, are related to epigenetic modifications [1]. Disorders such as hypertension, diabetes, and obesity are often utilized to recognize and cure people at increased CVDs risk [1]. Epigenetic modifications are associated with the processes involved in the CVD in humans or directly affect the gene expression involved in a major cardiac complication, myocardial infarction (MI). Hypertension is one of the leading causes of CVDs [3], while insulin resistance is one of the most significant precursors of type 2

Changes in the style of living and diet could decrease the risk of CVDs [14]. Epigenetic factors indicate there is interindividual variability from birth. It can be stable over the life span and is considered to be an initiator of early programming for adult-onset diseases [12, 18]. The understanding of epigenetics in the onset of

Epigenetics studies heritable variations in gene expression that exclude any change in the DNA sequence [16, 19]. Epigenetic changes include modifications of the DNA base, post-translational histone modifications, and ncRNA mechanisms that run in the nucleus [16, 20]. The epigenome moves the genome from a transcriptionally active to a transcriptionally inactive state [4, 21]. Epimutation transmissions occur throughout the life of the individual [2]. The rate of epigenetic variation is higher than that of genetic mutations because the formation of new inherited

syndrome, inflammation, sleep disorders, and CVDs [5–8].

diabetes and associated cardiometabolic conditions [17].

CVDs may provide a new perspective on diseases [14].

changes allows adjustment to a new environment [14, 16].

**1.1 Circadian rhythm**

adjustment of metabolism.

**1.2 Cardiovascular diseases**

**36**

**1.3 Epigenetics**

The most studied epigenetic change is cytosine methylation. It is also a method for suppressing gene expression [22]. DNA methyltransferase (DNMT) enzymes perform DNA methylation. DNMTs bind the methyl group to the 5-site cytosine [16]. The methyl group most commonly binds to the cytosine at a CpG site. It is the fundamental and ubiquitous epigenetic mechanism [14]. The DNMT enzyme family, consisting of DNMT1, DNMT3a, and DNMT3b, methylates cytosine into 5-methylcytosine [14]. Promoter methylation is usually connected with inhibition of transcription [14]. DNMT1 controls the mitotic inheritance of methylated DNA, while DNMT3a and DNMT3b are mainly in charge of *de novo* methylation [14]. The different epigenetic modification is DNA hydroxymethylation, including 5-hydroxymethylated cytosines [14]. Different nutritional and lifestyle factors can affect the methylation of particular CpG sites in gene promoters and into adulthood [22].

Nucleosomes are composed of histone proteins around which DNA is wound into chromatin [16]. Nucleosomes consist of eight histone proteins: two dimers of H2A/H2B and two dimers of H3/H4. Each histone has an adjustable aminoacid tail [16]. Histones can change at more than 30 amino acid residues within amino-terminal tails [4]. Histone modifications include various processes such as acetylation, methylation, phosphorylation, sumoylation, and ubiquitination. It has a function in the organization of chromatin composition and gene expression by altering the intensity of chromatin condensation [1, 14, 23]. Histones are mostly acetylated on lysine (K) residues. Histone acetyltransferase (HAT) and histone deacetylase (HDAC) regulate histone acetylation [14]. Histone methyltransferase regulates histone methylation, while histone demethylase catalyzes demethylation. Transcription activation is usually associated with acetylation of lysine residues at histones 3 (H3) and 4 (H4). Depending on the location of the target lysines in the histone tail and the number of methyl groups added, methylation can either activate or inhibit gene expression [14, 24]. Histone phosphorylation is a marker of cell division and has a function in DNA repair, chromatin condensation during division, and regulation of gene expression [14, 25]. The addition of ubiquitin to lysine residues in histones is called ubiquitination and is implicated in DNA repair and control of transcription [14]. Sumoylation is a changeable post-translational adjustment using small ubiquitin-like proteins (SUMO) and has a crucial function in various mechanisms, such as transcription, and cell cycle progression [14, 26].

RNA-based epigenetic mechanisms include long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) [14]. NcRNAs are functional RNAs that do not translate into proteins and play an essential part in epigenetic regulation [14, 16]. The lncRNAs are extremely tissue-specific relative to protein-coding genes [16]. The miRNAs are short (20–22 nucleotides), single-stranded, evolutionarily-conserved ncRNAs that modulate the expression at the post-transcriptional level of more than 50% of cellular genes [13, 14, 27].

Changes in the environment, including temperature, light, and nutritional habits, trigger reversible epigenomic modification that can influence numerous physiological processes [28]. Epigenome-wide association studies (EWAS) provide information about associations between epigenomic perturbations and traits associated with human diseases [29]. EWAS try to evaluate the environmental impact on genetic regulation. The epigenetic variations could explain missing parts of heritability of chronic diseases that have not yet been determined by genome-wide association studies [29].
