|Year : 2021 | Volume
| Issue : 4 | Page : 147-153
Risk factors which influence DNA methylation in childhood obesity
Suneesh Kaimala1, Suraiya Anjum Ansari2, Bright Starling Emerald3
1 Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, UAE
2 Department of Biochemistry, College of Medicine and Health Sciences, United Arab Emirates University; Zayed Center for Health Sciences, United Arab Emirates University, Al Ain, UAE
3 Department of Biochemistry, College of Medicine and Health Sciences, United Arab Emirates University; Zayed Center for Health Sciences, United Arab Emirates University; Zayed Center for Health Sciences, United Arab Emirates University, Al Ain, UAE
|Date of Submission||01-Apr-2021|
|Date of Decision||27-Jun-2021|
|Date of Acceptance||20-Sep-2021|
|Date of Web Publication||11-Jan-2022|
Bright Starling Emerald
College of Medicine and Health Sciences, United Arab Emirates University, P O Box 17666, Al Ain, Abu Dhabi
Source of Support: None, Conflict of Interest: None
Introduction: Obesity is a metabolic disease that accumulates an excessive level of fat. It also leads to comorbidities such as cardiovascular diseases, type 2 diabetes, high blood pressure, osteoarthritis and hormonal imbalances. Obesity has also been associated with an increased risk of developing cancers and may also enhance cancer-related mortality. The global prevalence rate of obesity and overweight, especially among children, is on the rise, and the United Arab Emirates (UAE) is no exception. Methods: A recent report suggests that the prevalence of overweight and obesity is 17% and 16%, respectively, in the UAE among children between 6 and 18 years of age. Thus, this is a serious health problem that needs urgent attention. Hence in this review we have analysed the risk factors which influence DNA Methylation in Childhood Obesity by using published literature. Results: Although genetic factors contribute to childhood obesity, epigenetic factors also play a significant role in its development. Discussion: This review article discusses the different risk factors and their contribution/s through epigenetic modification, DNA methylation and the associated changes in gene expression that eventually lead to childhood obesity. Understanding how these risk factors modulate gene expression could help to avoid or reduce the impact of exposures to such factors and thus may help to evolve a healthy future generation.
Keywords: Childhood obesity, DNA methylation, epigenetics, gene expression, risk factors
|How to cite this article:|
Kaimala S, Ansari SA, Emerald BS. Risk factors which influence DNA methylation in childhood obesity. Hamdan Med J 2021;14:147-53
| Introduction|| |
Obesity is a metabolic disorder with profusive accumulation of fat in the body that leads to comorbidities that adversely affect the physical well-being of a person. Overweight and obesity are determined using the body mass index (BMI) scale. According to the norms of the Centre for Disease Control and Prevention, BMI at or above the 85th percentile and below the 95th percentile for children and teens of the same age and sex are categorised as overweight whereas, BMI at or above the 95th percentile for children and teens of the same age and sex are classified as obese. Investigations among the children in United Arab Emirates (UAE) using the World Health Organization's (WHO) standards for obesity measurements shows that in children between 6 and 18 y of age, the prevalence of overweight and obesity are 17% and 16%, respectively. A recent study reported that about 28.2% of children in UAE are overweight or obese, which is nearly four times higher than the global prevalence. The major causes of childhood obesity among children in the UAE have been delineated as sedentary lifestyle, consumption of unhealthy food and family history. In this review article, we discuss the risk factors that mediate epigenetic change through DNA methylation and the associated methylation changes in genes that contribute to the development of obesity among children.
| Risk Factors in Childhood Obesity|| |
Both genetic and epigenetic factors contribute to the development of childhood obesity. Some of those risk factors which had been shown to contribute are the length of breastfeeding, maternal exposure to toxic chemicals during pregnancy, maternal hyperglycaemia during pregnancy, periconceptional maternal and paternal BMI, maternal smoking, socioeconomic status of the children and parents and lack of exercise in both parents and children.,,,,, In addition, changes in gene expressions caused by the epigenetic changes induced by these factors affect several pathways, including immune function, development, metabolism and circadian rhythm.,,
| DNA Methylation|| |
Maintenance of proper epigenetic marks is essential for the preservation of the cell's genetic information, and the inability to do so may lead to inappropriate gene expression that results in different diseases. More than 80% of mammalian DNA is methylated. They play critical roles in maintaining the integrity of the chromatin structure and the regulation of transcription in normal mammalian cells. During the synthesis (S) phase of the cell cycle, the newly synthesised DNA strand does not carry the cytosine methylation marks found in parental cells. However, mammalian cells maintain the parental methylation marks faithfully between successive cell divisions with the help of proteins known as DNA (cytosine-5) methyltransferases (DNMTs). In eukaryotic cells, three DNMTs, namely, DNA methyltransferase 1 (DNMT1), DNA methyltransferase 3a (DNMT3a) and DNA methyltransferase 3b (DNMT3b), are predominantly engaged in methylation. Among these, DNMT1 shows a strong preference for hemimethylated DNA in vitro. DNMT3a and DNMT3b function during early embryonic development to establish novel genome methylation patterns. During DNA methylation, S-adenosyl methionine donates a methyl group to cytosine nucleotide bonded to a guanine nucleotide (CpG dinucleotide). In the mammalian genome, promoter and enhancer regions of many genes are enriched for the CpG nucleotides, and such regions are called CpG islands. Methylation at CpG islands is highly dynamic in nature. Based on the nature of the dynamics, methylation can be hypermethylation or hypomethylation. An increase in methylation is referred to as hypermethylation, and it leads to the downregulation of gene expression. A decrease in methylation is referred to as hypomethylation, which leads to the upregulation of gene expression.,
Hypomethylation of genomic regions is mediated by an enzymatic pathway catalysed by the members of the ten-eleven translocation (Tet family) enzymes. They catalyse the conversion of methyl cytosines to hydroxymethyl cytosine intermediaries. Eventually, these intermediate products are replaced by unmodified cytosine residues during DNA repair by a base excision repair mechanism. The transcriptional gene silencing effect of DNA methylation is partly mediated through HDAC inhibitors' recruitment.
| Methylation Changes in Childhood Obesity|| |
A key epigenetic feature associated with metabolic pathologies is DNA methylation changes at the gene coding or regulatory regions of the genome. Differential DNA methylations could lead to gene expression changes in genes involved in major metabolic pathways or immune function, leading to pathological development over time.
Several loci have been identified as differentially methylated regions (DMRs) that contribute to the development of childhood obesity. The analysis of obesity-associated DNA methylation patterns revealed 277 differentially-methylated CpGs, including 143 genes which contribute to 51 canonical pathways with enrichment for pathways involved in immune function. Another study using genome-wide DNA methylation analysis discovered 734 CpG sites with differential methylations between obese and lean children, with more hypermethylated CpGs in the gene coding region and an increased hypomethylation at the promoter regions. One gene with the strongest correlation with BMI was PTPRS, in which, out of 13 CpG sites studied, the CpG sites between CpG_6 and CpG_3 correlated significantly with BMI z-score. Furthermore, circadian rhythm signalling and the related habitual energy and carbohydrate intake were highly correlated with differentially methylated CpG sites in genes Vasoactive Intestinal Peptide Receptor 2 (VIPR2), (Glutamate Ionotropic Receptor NMDA Type Subunit 2D) (GRIN2D), ADCYAP Receptor Type I (ADCYAP1R1) and Period Circadian Regulator 3 (PER3). Childhood obesity is also associated with hypomethylations at cg22593959 (located in an intergenic region [chr7q31.3]) and cg22436429 in the gene, Transcription Factor AP-2 Epsilon (TFAP2E). In addition, methylations at four genomic regions namely Formin 1 (FMN1), Membrane Associated Guanylate Kinase (MAGI2), Src Kinase Associated Phosphoprotein 2 (SKAP2) and Bone Morphogenetic Protein Receptor Type 1B (BMPR1B) are shown to be associated with skinfold thickness.
Cord blood serves as an excellent tissue to verify the methylation patterns that affect the child's growth patterns and metabolism. Cord blood leptin levels have been found to be associated with methylations at 247 CpG sites as well as 18 differentially methylated gene regions, including DnaJ Heat Shock Protein Family (Hsp40) Member A4 (DNAJA4), Transferrin Receptor 2 (TFR2), SMAD3, SMAD Family Member 3 (PLAG1), Fibroblast Growth Factor 1 and Hepatocyte Nuclear Factor 4 Alpha (HNF4A). The methylation status of Melanocortin 4 Receptor (MC4R) and HNF4α in cord blood showed significant association with childhood BMI and triglyceride (TG) levels. Hypomethylation of MC4R at birth was significantly correlated with elevated TG levels at age 7–8 years. Similarly, hypomethylation at the promoter region of HNF4α at birth was negatively associated with the TG level in childhood.
Protein tyrosine phosphatase, receptor type N2 (PTPRN2), an islet autoantigen involved in type-1 diabetes, has been associated with childhood obesity. CpG methylations at cg17429772 and cg158269415 in PTPRN2 in blood samples have been found to be positively correlated with BMI and waist-hip ratio (WHR) in children. BMI and WHR in children are also associated with methylations at CpG sites (cg141441481, cg01852095 and cg141441470) of Lipoprotein receptor protein 1B (LRP1B). Single nucleotide polymorphism (rs431809) in intron 4 of LRP1B has been shown to genetically influence the CpG methylation patterns at these CpG sites and the expression of the LRP1B gene. Similarly, hypermethylation at CpG sites in paternally expressed gene 10 (PEG10) associates with anthropometric measurements in male children where hypermethylation of the DMR regulating mesoderm-specific transcript (MEST) negatively correlates anthropometric measurements in female children at 1 year. CpG methylations at the transcription factor (TF) binding sites could affect the binding of critical TF binding at the promoter region and gene expression. Methylation at the GATA1 binding site (CpG 13424229) at the promoter of CPA3 has been found to induce childhood obesity by altering CPA3 expression. Another genome-scale analysis of DNA methylation has identified a correlation between the CpG methylation levels at birth in the promoter of a 3.8 kb non-coding RNA transcribed from the CDKN2A gene locus, antisense non-coding RNA in the INK4 locus (ANRIL), and per cent of fat mass at 6 years of age. This CpG methylation regulated the expression of ANRIL in vivo by altering the binding of oestrogen receptor-α containing protein complex at the promoter region of ANRIL and thereby its transcription. Hypoxia Inducible Factor 3 Alpha Subunit (HIF3A), a gene that associates with BMI or BMI change. When assessed for the correlation between its methylation status and obesity and other obesity-related phenotypes in Chinese children, it showed significantly higher methylation levels in obese children than in controls at positions 46801642 and 46801699 within the gene. BMI has also been found associated with cg07814318 hypermethylation of Kruppel-like factor 13 (KLF13) gene among Europeans. When methylation at cg07814318 and its cis-meQTL (cis-methylation quantitative loci) of KLF13 was analysed among a childhood obesity cohort, significant associations were found with obesity and several obesity-related physical and biochemical traits. Furthermore, subjects with high BMI showed hypermethylation at cg07814318 site in pre-adipocytes and islets. CpG methylations at repetitive DNA and long non-coding DNA regions have also been shown to be associated with childhood obesity.,,, Hypermethylation at CpG sites within LINE sequences has positively correlated with Skinfold thickness and waist circumference in boys, whereas it negatively correlated with birth weight of children. Differential methylation within or near the coding regions of the microRNAs, miR-1203, miR-412 and miR-216A, also affect BMI in children.
| Parental Body Mass Index|| |
One of the major factors contributing to the development of childhood obesity is the BMI of parents.,, It has been shown that children of obese parents carry 10–12 times higher risk of developing obesity than children of normal parents. One of the reasons for this could be the obesity-induced alterations in the imprinting genes in sperms and the resultant epigenetic alterations in the offspring. Paternal BMI has been found to associate with the DNA methylation at ADP Ribosylation Factor GTPase Activating Protein 3 (ARFGAP3) in cord blood nucleated cells. Its expression is important for the function of the Golgi apparatus and vesicular transport. Higher parental BMI also induces hypomethylation at the locus cg04763273, a region between Transcription Factor AP-2 Gamma (TFAP2C) and Bone morphogenic protein 7 (BMP7) genes associated with development and metabolism, respectively. Maternal pre-pregnancy obesity has been shown associations with CpGs in or in the vicinities of TAP Binding Protein (TAPBP). A total of 74 CpG sites related to maternal obesity (57 CpGs in females and 17 CpGs in male offspring) corresponding to the TAPBP gene were identified. Having located among the class 1 major histocompatibility complex group of genes, the regulation of its expression by CpG methylation could be critical for the regulation of adipokines and obesity.
Metastable epialleles are genomic loci in which epigenetic patterning is variable between isogenic organisms and are conserved across time and tissues. These are useful as molecular biomarkers to understand the influence of the maternal environment on the development and are also predictive markers of postnatal growth. In placental tissue, they are also susceptible to parental BMI and lead to postnatal metabolic alterations and obesity in children. Hypermethylation at Mesoderm-specific transcript homolog protein (MEST) and Histone deacetylase 4 (HDAC4) have been observed in placental tissues of children of high BMI parents. In the female placenta specifically, BMI is also associated with methylations in PLAG1 like zinc finger 1 (PLAGL1). HDAC4 plays crucial roles in adipocyte expansion, regulation of energy expenditure and protection from obesity, and hence, the dysregulation of its expression in placental tissue could trigger metabolic compromises in the offspring. PLAGL1 has shown positive correlations with anthropometric measures at 32 weeks of gestation and is an essential component of metabolic pathways. Parental obesity not only affects the birth weight of children but also the weight gain during childhood as well. Children of obese parents have shown an increased tendency for weight gain during their childhood. Furthermore, parental BMI epigenetically regulates Neuronal Growth Regulator 1 (NEGR1), a gene involved in both energy balance and behaviour regulation. Methylation at cg23166710, a CpG site located in the first intron of NEGR1 was found to correlate with its low expression in the placenta and increased BMI in children at 3 years of age, suggesting that the epigenetic alterations at this site play a role in growth and metabolism. In adolescents, 5669 intragenic CpG sites and 103,466 intergenic sites have been identified, associating to BMI percentile, out of which 28 were identified within obesity-related genes. SIM BHLH TF 1 (SIM1) was an outstanding candidate gene identified with significantly altered CpG methylations relating to higher BMI. However, most of these studies rely on the extraembryonic tissues or blood, and the effect of these modifications in tissues of metabolic relevance such as adipose tissue is limited.
In mice, offspring of mothers fed with a high-fat diet (HFD) showed differential methylation at 36%–46% of genes in the liver, and these changes affected the body weights, organ weights and serum biomarkers in the female pups. Young ones of the HFD mothers showed increased weight gain and adiposity compared to the young ones of normal mothers when fed with HFD. In a similar study in mice, young ones of obese mothers fed with HFD gained more weight, presented higher blood cholesterol levels and abdominal adipose tissue than mice born to mothers fed with a control diet. Together these studies suggest that the diet and BMI of mothers influence the epigenome of the young ones and their metabolic outcome in future.
| Parental Hyperglycaemia|| |
Periconception maternal hyperglycaemia causes short-term and long-term outcomes in offspring. This includes increased adiposity in childhood and increased risk of obesity and type 2 diabetes later in life, and epigenetic factors contribute significantly to these effects. One of the critical links between maternal hyperglycaemia and childhood obesity is leptin. Hyperglycaemia-induced epigenetic dysregulation of the leptin pathway could lead to increased adiposity and obesity in the offspring. Methylation at cg15758240, a CpG located at 4501 bp upstream of the leptin gene, was highly correlated with maternal glucose levels during the second trimester of pregnancy and cord blood leptin levels. Children of mothers with gestational diabetes show a tendency for altered lipid metabolism due to alterations in DNA methylation in genes, Peptidoglycan Recognition Protein 1 (PGLYRP1), Scratch Family Transcriptional Repressor 1 (SCRT1), Xylosetransferase 2 (XYLT2), ALK Receptor Tyrosine Kinase (ALK) and Transmembrane Protein 263 (TMEM263) that can eventually lead to childhood obesity. A DMR of the long non-coding RNA, Maternally Expressed 3 (MEG3), is another target for epigenetic modifications mediated by gestational diabetes. Five MEG3 CpG islands (CpG9 (chr14:101,292,225), CpG11 (chr14:101,292,392), CpG12 (chr14:101,292,398), CpG15 (chr14:101,292,460) and CpG16 (chr14:101,292,463) in the placental tissue at mother's side have been shown to correlate with gestational diabetes and birth weight of the offspring.
| Exposure to Toxic Chemicals During Pregnancy|| |
Changes in lifestyle and urbanisation have introduced several potentially harmful toxic chemicals into the environment. Some of these chemicals have been classified as “obesogens” based on their ability to induce obesity upon exposure. Evidence suggests that exposure to some of these obesogens can reprogram the epigenome of the foetus and induce childhood obesity. Compelling evidence suggests obesity is programmed early in life in the intrauterine period itself.,,, Bisphenol A (BPA) has been classified as an obesogen and was found to have a positive association with the BMI of boys and waist circumference of girls. In humans, prenatal BPA exposure leads to hypermethylation at cg19196862, located in the 16th exon of Insulin-like growth factor 2 receptor (IGF2R), and cause an increase in BMI in children. Hypermethylation of cg19196862 (IGF2R) at age 2 years showed persistent association with BMI in girls during 2–8 years of age.
Polycyclic aromatic hydrocarbons (PAH) are products of incomplete combustion that can cause cancer and disrupt the endocrine system. PAH exposure during pregnancy increases child BMI and causes childhood obesity. When mice were exposed to polycyclic aromatic hydrocarbon during pregnancy, the offspring were overweight and had increased white adipose tissue composition. The white adipose tissue in the exposed group of mice showed an increased expression of Peroxisome proliferator-activated receptor gamma (Pparg), CCAAT/enhancer-binding protein alpha (C/ebpa), Adiponectin, Fas Cell Surface Death Receptor (Fas) and Cyclooxygenase2 (Cox 2). Corresponding to the overexpression of Pparg, there was hypomethylation in the CpG islands at its promoter region. These evidence suggests that prenatal exposure to toxic chemicals alter the postnatal growth and development of offspring by altering the composition of their epigenome.
| Breastfeeding|| |
According to the WHO recommendation, exclusive breastfeeding for 6 months and complementary breastfeeding for up to 2 years are required for proper infant nourishment and associated healthy development. Adequate breastfeeding has been shown to provide protection from respiratory diseases, help in neuronal development, reduce the risk of diabetes and reduce chances of childhood leukaemia. In addition, breastfeeding reduces the chances of developing childhood obesity. Human breast milk components such as long-chain polyunsaturated fatty acids and lactoferrin are capable of inducing epigenetic changes in the offspring. Breastfeeding duration has been found to be negatively correlated with methylation at cg23381058 in Leptin (LEP) gene, and with more duration, a gain of weight in offspring for a transient period was observed. This CpG site is located within an intron of the LEP gene, in a TF-binding site. The duration of breastfeeding has shown an association with the DNA methylation in buccal epithelial cells also, where breastfeeding duration negatively correlates with methylations in the LEP gene and positively correlates with the regulator of human subcutaneous adiposity, Retinoid X Receptor Alpha (RXRA) gene. Significantly lower methylation of RXRA was observed in children who were breastfed for 4–6 months when compared to children who were not breastfed and children who were breastfed for 1–3 months 7–9 months, or 10–12 months. Similarly, children who were breastfed for 10–12 months showed the lowest LEP methylation levels when compared to those breastfed for 1–3 months or 7–9 months.
| Parental Lifestyle Factors|| |
The lifestyle of mothers during pregnancy affects the maternal metabolic homeostasis, glucose metabolism, and eventually increases the risk of developing metabolic syndrome and also influences the epigenome of the unborn child. Studies in mice and humans have shown that maternal exercise during the pregnancy period significantly reduces fat mass in the offspring with a significant reduction in leptin levels and increase in brain-derived neurotrophic factor levels. Similarly, pregnant women obtaining 11000 steps per day showed reduced levels of high sensitivity C-reactive protein (CRP) compared to non-compliant women. High carbohydrate intake also enhances high sensitivity CRP, significantly pointing to the importance of physical activity during pregnancy for better outcome of child health parameters.
People with lower socioeconomic backgrounds have a higher tendency for developing obesity in adulthood, especially among women. Recent evidence suggests that socioeconomic status in childhood can affect the epigenome and induce obesity. Methylation of specific CpG sites in adipose tissue, particularly in Fatty acid synthase (FASN), Signal transducer and activator of transcription 3 (STAT3) and Transmembrane protein 88 (TMEM88) in females, and Neuritin 1 (NRN1) in males mediate the association between childhood SES and adulthood BMI. Adverse childhood experiences (such as abuse or neglect) have been shown to interact with 10 CpG sites with eight of the methylation sites located in genes known to associate with obesity risk, such as Phosphoenolpyruvate Carboxykinase 2 (PCK2), C-X-C Motif Chemokine Ligand 10 (CxCl10), Branched Chain Amino Acid Transaminase 1 (BCAT1), HID1 Domain Containing (HID1), PR domain containing 16 (PRDM16), MAP Kinase Activating Death Domain (MADD), Peroxidasin (PXDN), UDP-Galactose-4-Epimerase (GALE).
Maternal smoking during pregnancy is considered a major risk factor for low birth weight and related health problems in children. Smoking-induced CpG methylations on DMRs have been attributed to causing these effects. A study using meta-analysis of pregnant women with smoking habits has identified about 6000 differentially methylated CpG sites with significant alterations in methylation by smoking, several of which are mapped to the promoters and coding regions of genes involved in different metabolic pathways. Tobacco smoke exposure in utero beyond the 12th week of gestation has been shown to affect methylation at five CpG sites in gene regions of Myosin IG (MYO1G) (cg12803068, cg22132788, cg19089201), Contactin Associated Protein 2 (CNTNAP2) (cg25949550) and FERM Domain Containing 4A (FRMD4A) (cg11813497) that are critical in regulating inflammation and cell proliferation.
The summary of the risk factors and the genes they epigenetically modify through DNA methylation are shown in [Figure 1] and [Table 1].
|Figure 1: The risk factors and the genes they epigenetically modify through DNA methylation in childhood obesity|
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|Table 1: The list of the risk factors and the genes modified through DNA methylation with a link to childhood obesity|
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| Conclusions|| |
Epigenetic regulation plays a major role in mediating the effects of developmental, genetic and environmental factors such as parental lifestyle, breastfeeding, parental hyperglycaemia and exposure to toxic chemicals on the development of childhood obesity. The strong association of epigenetic factors with the development of overweight and obesity among children points to the importance of following a healthy lifestyle along with the consideration of developmental and genetic backgrounds. Understanding how these factors regulate CpG methylations and the target genomic regions where they alter the methylations help to control the adverse effects of exposure to such factors and control the development of childhood obesity. The emergence of epigenetic therapies using chemicals that can reverse the epigenetic modifications could be useful in avoiding childhood obesity in future.
Acknowledgements: Financial support
The work in the laboratory was supported by the Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences MRG16/2013–2014. United Arab Emirates University, UPAR grant # 3IM307, Zayed Center for Health Sciences grants #31R089 #3IM336 and #31R228.
Conflicts of interest
There are no conflicts of interest.
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