Biology and Medicine

DNA Hypomethylation in Chronic Non-Communicable Diseases

Claudia Rebolledo Quezada, Liliam Sanhueza Carrasco, Marcela Hinojosa-Moreno and Paulina Fernandez-Garces^* Department of Medicine, Medical Technologist, University of Concepción, Concepción, Chile
^*Correspondence: Paulina Fernandez-Garces, Department of Medicine, Medical Technologist, University of Concepción, Concepción, Chile, Email:

Received: 08-Oct-2022, Manuscript No. BLM-22-18246; Editor assigned: 11-Oct-2022, Pre QC No. BLM-22-18246(PQ); Reviewed: 25-Oct-2022, QC No. BLM-22-18246; Revised: 01-Nov-2022, Manuscript No. BLM-22-18246(R); Published: 08-Nov-2022, DOI: 10.35248/0974-8369.22.14.511

Abbreviations

DNMTs: DNA Methyltransferase Enzymes; CNCD: Chronic Non-Communicable Diseases; TET: Ten- Eleven Translocation Enzymes; CVD: Cardiovascular Diseases; SAM: S-adenosyl-L-Methionine; CpG: Cytosine phosphate- Guanosine Dinucleotides; 5mC: 5-methylCytosine; mESC: Mouse Embryonic Stem Cells; ESC: Embryonic Stem Cells; PCNA: Proliferating Cell Nuclear Antigen; TopIIα: Topoisomerase II α; miRNAs: microRNAs; 5hmC: 5-hydroxymethylCytosine; MMLV: Murine Leukemia Virus; PAHO: Pan American Health Organization; WHO: World Health Organization; PRMT6: Protein Arginine Methyltransferase 6; H3R2me2a: H3R2 Dimethylation; GWAS: Genome-Wide Association Studies; IR: Insulin Resistance; T2DM: Type 2 Diabetes Mellitus; IS: Ischemic Stroke; LAA: Large Arteries from Atherosclerotic Stroke; COPD: Chronic Obstructive Pulmonary Disease; AHRR: Aryl hydrocarbon Receptor Repressor Gene; DOHaD: Origins of Health and Disease Development; VEGFβ: Vascular Endothelial Growth Factor Receptor 2β; TNFα: Tumor Necrosis Factor α.

INTRODUCTION

Epigenetics is defined as the control of gene expression through mechanisms that do not modify the DNA sequence [1]. One of the main epigenetic modifications is methylation, which consists of the addition of a methyl group to the carbon five of a cytosine, a process that affects the regulation of gene expression [2,3]. For this process to take place, DNA MethylTransferase (DNMT) enzymes are required, which establish the genome methylation pattern in de novo methylation and are also in charge of maintaining this pattern during semiconservative DNA replication [4,5]. The reverse process, demethylation, is carried out by ten-eleven Translocation Enzymes (TET) [6]. Therefore, even though DNA methylation is considered a relatively stable modification, can be reversed by being influenced by environmental factors such as nutrition and chemical and industrial pollutants in addition to aging, being able to lead to the development of diseases such as cancer, obesity, diabetes, Cardiovascular Diseases (CVD), and respiratory diseases, among others [1,7,8].

Among the remodeling that the DNA methylation pattern undergoes in these situations, a loss of the methylated sites is included, causing hypomethylation of DNA, affecting numerous genomic regions, and representing a common feature of many tumors [8-10]. In the same context, since DNA methylation is susceptible to external stimuli, long-term changes in gene expression can be generated, which could lead to the development of pathologies contributing to the onset of Chronic Non-Communicable Diseases (CNCD) [11]. Approximately 22% of the world’s population (from subjects under 20 years of age to those aged 70 years or older) suffer from at least one chronic disease [12]. CNCDs caused approximately 35 million deaths, representing 60% of all deaths, and NCDs constituted 80% of the global disease by 2020 [13]. The incidence of CNCDs has been increasing due to modifiable factors such as exercise, diet, and smoking (factors that in turn impact genomic methylation patterns) [14,15]. However, only 1% of the world’s resources are destined to prevent the CNCDs. Because of the great impact that triggers of these diseases have on genome methylation levels it is relevant to review CNCDs from the perspective of DNA hypomethylation, as this epigenetic phenomenon could be used as a biomarker to prevent, diagnose, or evaluate the prognosis of these pathologies [11,16]. This review details the processes of DNA methylation and demethylation as well as the hypomethylation present in the most prevalent chronic non-communicable diseases.

Genome Methylation

In 1975, it was proposed that DNA methylation play a fundamental role in gene transcription, indicating that it constitutes the event responsible for the maintenance of a particular gene expression pattern through cell division [17,18]. Currently, DNA methylation is known as an important biological process characterized by being inheritable, stable, and reversibly essential for embryonic development and other phenomena, such as regulation of transcription, genomic imprinting, genome stability, X chromosome inactivation, and transcriptional repression [19-21] among other events.

In this process, a methyl group derived from S-Adenosyl-L-Methionine (SAM) covalently adheres to carbon 5 of a DNA base, specifically to the cytosine of Cytosine phosphate-Guanosine dinucleotides (CpG), thus transforming cytosine into 5-methylcytosine (5mC) [22]. Studies in mouse Embryonic Stem Cells (mESC) have shown that DNMTs are responsible for this process, and enzymes have been identified as DNMT3a and DNMT3b. Towards the end of the 90s, these enzymes were genetically inactivated in murine models, resulting in non-methylated DNA, causing lethality and multiple defects in the development of early embryos, indicating the role of these enzymes in de novo methylation of the genome during early embryogenesis. Later, in methylated genomic sequences from germ cells of murine and human models, it was observed that DNMT3a and DNMT3b interact directly with another DNMT, DNMT3L, which stimulates the activity of these enzymes and, therefore, DNA methylation [23,24].

On the other hand, Baubec et al. determined the genomic binding of DNMT3a and DNMT3b in mESC, showing that de novo DNMTs preferentially bind to regions of DNA rich in CpG sequences thus, approximately 80% of these dinucleotides are methylated in the genome, while the rest of the unmethylated CpG dinucleotides are mainly near promoter regions in dense clusters known as CpG islands, where the methylation percentage is less than 10% [25,26].

In mammals, three active DNMTs can be found in charge of regulating the methylation pattern: DNMT3a and DNMT3b, and the maintenance methyltransferase DNMT1, whose function is to maintain DNA methylation, copying the pattern in the strand of DNA synthesized during semi-conservative replication to maintain the cellular phenotype [27,28]. In Embryonic Stem Cells (ESC) as been shown, DNMT1 enzyme forms complexes with the UHRF1 protein and Proliferating Cell Nuclear Antigen (PCNA) in hemimethylated regions of DNA during replication [29]. However, in similar studies with ESC cell knock-out for the UHRF1 gene, the location of hemimethylated sites by DNMT1 has not been established, which shows the importance of UHRF1 in maintaining DNA methylation owing to its ability to bind to methylated CpGs [29,30].

Additionally, mass spectrometry revealed that UHRF1 and topoisomerase IIα (TopIIα) are co-expressed in hemimethylated zones [30]. Since the function of TopIIα in DNA copying is to decrease the tension on the replication fork, it was verified in mice with and without mutations in UHRF1 that the interaction between these proteins is important in the recognition of the methylated DNA chain, giving DNMT1 access to the complementary strand unmethylated cytosines [30,31].

Since DNA methylation is essential for the activation or repression of certain pathways and, therefore, for transcriptional regulation, this mark constitutes one of the main epigenetic modifications, together with the modification of histones and microRNAs (miRNAs) [32]. Pioneering studies on DNA methylation have considered this process irreversible; however, it is known that DNA demethylation is associated with the transcriptional repression of promoter regions and is a crucial step in determining cell fate in embryos and cell reprogramming. While DNA methylation is related to the suppression of gene expression, demethylation induces the reactivation and expression of genes [33,34].

Different studies postulate that enzymes of the TET family, TET- 1 and TET-2, produce demethylation of the genome because its expression is correlated with a decrease in 5mC levels and an increase in its oxidized form, 5-hydroxymethylcytosine (5 hmC) [35-38]. This has been confirmed in HEK293 cells, which present an increase in 5hmC, 5-formylcytosine and 5-caboxylcytosine when overexpress TET-2 was overexpressed [39]. Furthermore, using murine transgenic lines, we studied the changes in level RNA messenger expression levels of TET and DNMT during global DNA demethylation and observed a gradual increase in the expression of TET1 and TET2 RNA messengers as DNA demethylates, while the genes encoding DNMT1 and the associated protein UHRF1 are constitutively expressed [40].

Genome Hypomethylation

As mentioned above, because methylation is a reversible process, changes in the expression levels or mutations of the enzymatic machinery involved in genome methylation can lead to genomic hypomethylation, a phenomenon that can be reflected in the alteration of physiological processes, and therefore, in the development of diseases [41, 42].

Jia et al. described that the UHRF2 protein causes DNA hypomethylation by suppressing DNMT3a because an increase in methylation is observed in different knockdown cell lines for UHRF2. In general, the investigators observed that in mESC knockout for DNMT3a/b or DNMT1, the reduced expression of UHRF2 significantly increased methylation (p<0.05), demonstrating that knockdown of UHRF2 or UHRF1 resulted in an increase in the protein of DNMT3a and not in DNMT3b, both without variation at the mRNA level, concluding that UHRF1/2 inhibits the methylation of de novo downregulating DNMT3a protein [43].

DNA hypomethylation involves the loss of the methyl group in genomic regions where it is normally present and is associated with aging, the development of non-communicable diseases, and tumor progression. It is frequently detected in human cancers due the loss of methylation would have a direct impact on the integrity of the chromatin, thus increasing genomic instability [44-47]. To investigate this phenomenon, Gaudet et al. (2003) generated mice carrying a hypomorphic allele of DNMT1, which reduced the expression of this enzyme by 10%, causing hypomethylation in all tissues [48]. When comparing hypomethylated tumors and thymic murine leukemia virus (MMLV) tumors induced in transgenic mice, it was observed that 10 of the 12 hypomethylated tumors exhibited a gain in chromosome 15, while only two of the 12 induced MMLV tumors presented this trisomy, suggesting that hypomethylation plays a role in genomic instability during tumorigenesis. On the other hand, a case-control study carried out in 2017 by Shen et al. with 390 patients with glioma and 390 healthy patients evaluated the levels of methylation in leukocyte DNA using 5mC levels as a marker, showing that their levels were significantly lower in glioma cases than in healthy controls (3.45 vs. 3.82, p=0.001) [48,49]. In summary, it is possible to point out that the dysregulation of this epigenetic mark can initiate the development of various pathologies. Similarly, it has been observed that improvements in the quality of life have a positive impact on infectious diseases because their incidence decreases; however, CNCDs have had a contrary behaviour, shedding light on a permanent change in the expression of certain genes [50]. Today, CNCDs present a high prevalence worldwide, being responsible for around 80% of the deaths in America according to the Pan American Health Organization (PAHO), where the highest mortality rates are associated with cardiovascular diseases (150.7/100,000) and cancer (105.7/100,000), followed by other CNCDs such as diabetes and chronic respiratory diseases with an index higher than 30/100,000 [51].

Genome Hypomethylation and Cancer

Cancer is one of the main causes of morbidity and mortality from non-communicable diseases in the 21st century. In 2018, 9.6 million people worldwide perished from this pathology [52]. According to the World Health Organization (WHO), the three most common types of cancer are lung, breast and colorectal [53]. The disease is initiated by genetic and epigenetic alterations that lead to uncontrolled cell division, invasion, and metastasis [54]. Genomic hypomethylation was first described in 1983 when a decrease in 5mC was observed in human tumor tissues compared to normal tissues [55]. Subsequent studies have shown that hypomethylation is common in cancer and influences tumorigenesis in different types of cancer [56,57]. The tumorigenic capacity of the cells was evidenced by a plasmid pUP with regions of DNMT1 capable of binding to PCNA and UHRF1, which prevented the formation of the DNMT1/UHRF1 complex, which is necessary for the maintenance of methylation, and a decrease in 5mC levels was observed in the treated cells (p<0.05). Furthermore, the cells showed a decrease in their doubling times, and the apoptosis induced by irradiation and tumor formation was evidenced; therefore, the interruption of this complex and the consequent global hypomethylation is one of the main routes that contribute to the oncogenic phenotype favoring genomic instability and increased aneuploidy, classic hallmarks of cancer [57,58].

Furthermore, the large epigenetic changes observed in cancer may be the result of mutations in chromatin remodeling complexes that affect the homeostasis of DNA methylation, thus promoting the active or passive elimination of the methyl groups of cytosines, which could be a consequence of the dysregulated activation of members of the TET family or partial loss of function of DNMT proteins [59]. Thus, in cancer cell lines, an increase in UHRF1/2 expression was observed, leading to global hypomethylation as a result of passive demethylation [43].

Similarly, overexpression of protein arginine methyltransferase 6 (PRMT6) was observed in bladder cancer samples compared to normal samples (p<0.0001). Veland et al. verified this increased expression in different human cancer cell lines and demonstrated in mESC clones with an overexpression of human PRMT6 that PRMT6 and its methyltransferase activity negatively regulate global DNA methylation, due PRMT6 is the enzyme responsible for asymmetric H3R2 dimethylation (H3R2me2a) and when evaluating the mESC, an increase in H3R2me2a is observed together with lower 5mC levels in relation to the control (p<0.01) [60,61]. Furthermore, ChIP experiments confirmed that the increase in H3R2me2a induced by the overexpression of PRMT6 deteriorates the association of UHRF1 with chromatin, resulting in failure to maintain DNA methylation [61].

Genome Hypomethylation in Obesity and Diabetes

Obesity is currently considered a pandemic, the WHO notes that more than 1.9 billion adults are overweight and more than 650 million are obese, constituting a great burden on the global health system [62,63]. This disease is characterized by being highly heritable; however, through Genome-Wide Association Studies (GWAS), it has been shown that the genetic variants related to obesity have limited predictive power, in addition to the genetic component, it is influenced by epigenetic changes conditioned mainly by diet, particularly during pregnancy and childhood [64,65]. These trigger reprogramming of the germline epigenome, which increases the transmission of disease susceptibility to future generations through transgenerational epigenetic inheritance [63,64]. Using microarrays, Rhee et al. examined the levels of DNA methylation in peripheral leukocytes of 12 young, six obese, and six normal weight children, identifying 95.7% of differentially methylated CpG sites in transcriptional regions, highlighting low levels of DNA methylation in obese children compared to the control group [66].

Obesity can lead to serious conditions such as cardiovascular disease, osteoarthritis, non-alcoholic fatty liver disease, kidney disease, musculoskeletal disorders, some cancers, and Type 2 Diabetes Mellitus (T2DM) [64,67-69]. This last pathology is a disease of multifactorial origin, influenced by genetic predisposition and environmental factors such as diet and exercise [70-72]. In 2017, Thongsroy et al., using samples of patients classified as healthy patients, patients with T2DM, and patients with pre-DM, showed a decrease in methylation in Alu sites in samples from patients with DM compared to normal samples (p<0.001) [73].

In contrast, hepatic Insulin Resistance (IR) is a hallmark of T2DM. Nilsson et al. studied IR through the DNA methylation pattern of all liver genomes in people with T2DM and identified 251 CpG sites with differential DNA methylation in the liver of patients with T2DM, compared to non-diabetic subjects (p<0.5). These included CpG sites recorded in genes that are biologically relevant to the development of T2DM, such as GRB10, ABCC3, MOGAT1, and PRDM16 [74].

Additionally, Kirchner et al. carried out an analysis of the methyloma and transcriptome of the whole genome of the liver of people of the same age, classifying them as metabolically healthy non-obese, nondiabetic obese, and obese with T2DM, and discovered that the key genes involved in hepatic glycolysis and de novo lipogenesis were hypomethylated and activated in obese nondiabetic and obese patients with T2DM, compared to non-obese control subjects [71].

VanderJagt et al. conducted a longitudinal evaluation of the transition to 11 patients diagnosed with pre-DM to T2DM and observed a decrease in DNA methylated sites during progression to T2DM. They identified six genes (SLC22A12, TRPM6, AQP9, HP, AGXT, and HYAL2) hypomethylated in all patients, which are related to the development of diabetic nephropathy [75].

Genome Hypomethylation and Cardiovascular Diseases

DNA methylation is involved in the processes underlying CVD, including atherosclerosis, inflammation, high blood pressure, and coronary heart disease [76-78]. Various studies have investigated the role of hypomethylation in CVD, and it has been observed that the key genes involved in the development of these pathologies are hypomethylated. Thus, Miao et al. showed that the CXCL12 gene is hypomethylated in samples with coronary heart disease, increasing the expression of the gene, which is elevated in the inflammatory response, promoting the differentiation of endothelial cells to foam cells, causing vascular endothelial damage and, eventually, atherosclerosis, in this same line, Janssens et al., through association analysis of the epigenome of Large Arteries from Atherosclerotic stroke (LAA), identified 12 cases and 12 controls, a total of 1012 methylated CpG loci corresponding to 672 genes that presented a differential methylation pattern between LAA stroke cases and controls (p<0.01); of these, 438 CpG sites showed hypomethylation [79,80].

Hypomethylated genes are involved in both immune and metabolic functions. In parallel, it has been shown that MTRNR2L8 is hypomethylated in Ischemic Stroke (IS), obtaining a predictive value for the prognosis of this pathology [81]. Gallego et al. also studied differential methylation of CpG sites in patients treated with clopidogrel (an antiplatelet agent), 21 patients with recurrent vascular events, and 21 patients without vascular recurrence. During the first year of follow in patients with obtain vascular recurrence during treatment with Clopidogrel, was observed of lower levels in DNA methylation in TRAF3 genes, which could indicate that hypomethylation of TRAF3 gene may be directly related to vascular recurrence, independent of treatment with Clopidogrel [82].

Genome Hypomethylation and Chronic Respiratory Diseases

Chronic Obstructive Pulmonary Disease (COPD), bronchitis, allergic rhinitis, lung cancer. These pathologies have been related to changes in DNA methylation, with hypomethylation observed both in the global genome and in specific genes that give rise to and promote the progression of these pathologies [83- 85]. Hypomethylation at CpG sites corresponding to IL-13 has been shown in patients with allergic rhinitis sensitized to house dust mites, a phenomenon associated with an increased risk of susceptibility to allergic rhinitis (r=1.22; p=0.018). In contrast, hypomethylation of the Aryl Hydrocarbon Receptor Repressor gene (AHRR) has been reported to be associated with respiratory diseases, being hypomethylated in smoking patients and in those with subsequent exacerbation of COPD and lung cancer. In addition, spirometry has studied the forced expiratory volume in 1 s and the forced vital capacity to assess lung function, observing that AHRR gene hypomethylation is associated with a decrease in the AHRR receptor in patients with respiratory symptoms [86,87].

As has been extensively studied, CS exposure to cigarette smoke is associated with respiratory pathologies. A study in A549 human lung adenocarcinoma cells exposed to cigarette smoke extracts and lipopolysaccharide showed significant global hypomethylation of DNA in relation to the control (p 0.0001 ), and blocking of the TET enzyme by antibodies showed that this enzyme is fundamental for the methylation changes that occur when exposed to cigarette smoke [85].

In conclusion, the presence of DNA hypomethylation in NCD (global or specific genes) leads to alterations in gene expression that may be related to the predisposition or development of these diseases.

Discussion

Evidence indicates the presence of hypomethylated genes in different diseases which supports the idea that DNA hypomethylation induces changes in gene expression, representing one of the main components in the initiation and development of CNCD [42,45,70,73,75,88-90]. A crucial factor is nutrition, both in intrauterine life and in the first years of life, which is studied by the area “Origins of Health and Disease Development” (DOHaD) [91]. Various authors support the idea that early nutrition is one of the main causes of increased susceptibility to various pathologies, since it induces expression changes in key genes involved in different metabolic pathways during development [92-98]. Nutrients that affect SAM or SAH, inhibitors of methyltransferases, have the potential to modify methylation and, therefore, gene expression [98]. Among the first studies to initiate this idea is that conducted in 1998 in Dutch men and women born before, during and after the 1944-1945 Nazi famine, where it was shown that adults exposed to famine in half or late gestation had less glucose tolerance compared to those who were never exposed or were exposed in early gestation. Years later, Finer and his group evidenced alterations in the methylation of offspring exposed to gestational diabetes, which has a functional impact on placental endocytic processes and other extra and intracellular signalling pathways involved in growth and metabolism, while Ayonrinde et al., conversely, the duration of breastfeeding and the age of onset of supplemental formula milk consumption with the subsequent diagnosis of non-alcoholic fatty liver in adolescence [92,99,100]. In contrast, a study in murine models observed that a low-protein maternal diet during pregnancy and lactation promoted early onset glucose intolerance in offspring mice [101]. In this way, the environment influences epigenetics from intrauterine life, as the diet, both maternal and individual, is one of the reasons for the increase in the prevalence of these pathologies, for which nutri-epigenomics and nutri-epigenetics play a relevant role in the control of CNCDs [102].

The main objective of these disciplines is the effective design of personalized nutritional strategies that not only result in weight loss, but also contribute to preventing metabolic disorders such as T2DM, hypertension, dyslipidemia, and cardiovascular diseases [93]. Nutri-epigenetics is the study of how nutrition regulates the activation or deactivation of a specific gene, whereas nutriepigenomics analyzes the interaction between various genes and nutrition, establishing those nutritional interventions can modify the epigenome and susceptibility to the development of diseases [103,104]. Considering this, it has been observed that dietary fatty acids can cause changes in methylation levels in gene promoters, such as vascular endothelial growth factor receptor 2β (VEGFβ) and Tumor Necrosis Factor α (TNFα), whose expression varies according to the type of fatty acid present in the diet, and can influence resistance to insulin, inflammatory processes, cardiovascular risk, and DMT2 [104,105]. In addition, nutri-epigenomics is related to cancer, as low-folate diets have been associated with hypomethylation and an increased risk of pancreatic and colorectal cancer [1]. The study of nutri-epigenetics and nutri-epigenomics is fundamental, because personalized nutrition can prevent the development of CNCD.

DNA methylation is also indirectly affected by other environmental factors such as the economy, country of residence and education [91]. Taking relevance in addition to biological factors, socioeconomics, the current lifestyle in most of the world’s population is characterized by a high consumption of fast food and ultra-processed foods, few hours of sleep, high levels of stress, and a sedentary lifestyle, which are responsible for the epidemic that today make up the ECNT.

In summary, global or specific gene hypomethylation constitutes an epigenetic marker highly prevalent in NCD, which is triggered by modifications in the DNA methylation pattern caused by genetic, environmental, and socioeconomic influences. Therefore, to overcome this burden on the health system, it is necessary to conduct multidisciplinary work, which includes political, medical, and scientific measures. The discovery of epigenetic markers allows considerable improvement in the approach to these pathologies, not only allowing a timely diagnosis, but also facilitating monitoring and providing new therapeutic options.

As it has been exposed in this review, DNA hypomethylation is one of the main epigenetic alterations responsible for the development of CNCDs, there being a vast group of hypomethylated genes present in various pathologies, which present functions that are altered and contribute to the onset and development of diseases. The current challenge, as new hypomethylated sites are identified, is to discriminate between hypomethylation marks, which influence pathophysiology and could constitute new epigenetic biomarkers useful for their early appearance in diseases and the association between molecular markers and lifestyle [16,38,90,106,107].

Conclusion

In addition, owing to its stability, frequency, reversibility, and accessibility in body fluids, it has great potential for the development of clinical trials to support the management of patients with CNCD, whether as an epigenetic biomarker for diagnosis, prognosis, resistance to treatment, or even because of its reversibility, can be established as a therapeutic objective. The development and application of epigenetic biomarkers are projected to be a promising line within the health system; however, it should be borne in mind that the priority of health services should focus on preventive measures for CNCDs, mainly through the empowerment of lifestyle changes.

Declarations

Ethical compliance

It is not applicable to this article because has not been worked with animals or people during the current review.

Data Access Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

Funding Statement

This review was carried out under “Research Tutorial Course” in the Medical Technology career, of Faculty of Medicine in University of Concepción.

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