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Nutriepigenomics
Nutriepigenomics also called nutritional genomics, is the study of how food nutrients and bioactive compounds influence human health through epigenetic modifications, such as DNA methylation, histone modifications, and non-coding RNA regulation. While nutrigenomics broadly explores how nutrients and diet impact gene expression, nutriepigenomics specifically examines how these dietary factors induce epigenetic changes without altering the underlying DNA sequence. There is now considerable evidence that nutritional imbalances—especially during gestation, lactation, and early development—can lead to long-term epigenetic alterations, increasing the risk of non-communicable diseases, such as obesity, cardiovascular disease, diabetes, hypertension, and cancer. If metabolic disturbances occur during critical time windows of development, these epigenetic modifications can result in lasting changes to gene expression, tissue function, and disease susceptibility.
Epigenetics relates to heritable changes in gene function that occur independently of alterations in primary DNA sequence. Two major epigenetic mechanisms implicated in nutriepigenomics are DNA methylation and histone modification. DNA methylation in gene promoter regions usually results in gene silencing and influences gene expression. While this form of gene silencing is extremely important in development and cellular differentiation, aberrant DNA methylation can be detrimental and has been linked to various disease processes, such as cancer. The methyl groups used in DNA methylation are often derived from dietary sources, such as folate and choline, and explains why diet can have a significant impact on methylation patterns and gene expression. Gene silencing can also be reinforced through the recruitment of histone deacetylases to decrease transcriptional activation. Conversely, histone acetylation induces transcriptional activation to increase gene expression. Dietary components can influence these epigenetic events, thereby altering gene expression and disturbing functions such as appetite control, metabolic balance and fuel utilization.
Various genetic sequences can be targeted for epigenetic modification. A transcriptome-wide analysis in mice found that a protein-restricted (PR) diet during gestation resulted in differential gene expression in approximately 1% of the fetal genes analyzed (235/22,690). Specifically, increased expression was seen in genes involved in the p53 pathway, apoptosis, negative regulators of cell metabolism, and genes related to epigenetic control. Additional studies have investigated the effect of a PR-diet in rats and found changes in promoter methylation of both the glucocorticoid receptor and peroxisome proliferator-activated receptor (PPAR). Altered expression of these receptors can result in elevated blood glucose levels and affect lipid and carbohydrate metabolism. Feeding a PR-diet to pregnant and/or lactating mice also increased expression of glucokinase, acetyl-CoA carboxylase, PPARα, and acyl-CoA oxidase. Changes in expression were reportedly due to epigenetic regulation of either the gene promoter itself, or promoters of transcription factors that regulate gene expression. Additional genes that have been shown, either by in vitro or in vivo studies, to be regulated by epigenetic mechanisms include leptin, SOCS3, glucose transporter (GLUT)-4, POMC, 11-β-hydroxysteroid dehydrogenase type 2 and corticotrophin releasing hormone. Epigenetic modification of these genes may lead to "metabolic programming" of the fetus and result in long-term changes in metabolism and energy homeostasis.
The period of development in which the nutritional imbalance occurs is very important in determining which disease-related genes will be affected. Different organs have critical developmental stages, and the time point at which they are compromised will predispose individuals to specific diseases. Epigenetic modifications that occur during development may not be expressed until later in life depending on the function of the gene. While the majority of studies implicate prenatal and perinatal periods as critical time windows, some research has shown that nutritional intake during adulthood can also affect the epigenome.
Developmental plasticity is the process in which fetuses adapt to their environment. Environmental cues, including dietary components, present in the in utero environment can induce significant changes in the expression of the genome through epigenetic modifications. Fetal developmental plasticity responses can cause changes in lean body mass, endocrinology, blood flow and vascular loading, and lead to increased risk of various diseases in adulthood. To better understand the long-term consequences of prenatal conditions, the following sections will explore specific outcomes such as low birth weight, obesity, and folate developmental effects. Each of these illustrates how prenatal exposures can shape the long-term health of a person's offspring.
Fetal exposure to calcium, folate, magnesium, high or low protein, and zinc have all been associated with birth weight. Numerous studies have investigated the link between birth weight and risk of disease and have found that low birth weight is significantly associated with coronary heart disease, stroke and type-2 diabetes. Most importantly, these associations occurred after adjusting for lifestyle factors, implying a genetic basis for onset of disease. Impaired insulin secretion is associated with low birth weight and can lead to insulin resistance as babies accumulate body fat. Studies using intrauterine growth retarded (IUGR) rats have found that growth inhibition can lead to decreased expression of PDX1 transcription factor, which is essential for differentiation and function of pancreatic beta cells. Decreased histone acetylation at the proximal promoter of PDX1 is responsible for reduced PDX1 expression and subsequently results in a cascade of histone deacetylation and methylation events that can result in type-2 diabetes.
Obesity during pregnancy and high-fat maternal diets both show strong associations with obesity in offspring. As the number of overweight reproductive-age women increases, the number of overweight children and infants also increases. It has been postulated that maternal obesity causes an accumulation of fat in fetal adipose tissue (adiposity) and predisposes babies for obesity in childhood and adulthood. Animal studies have shown that maternal overnutrition may impact brain development and cause disruptions to programming of the hypothalamus. Offspring that were exposed to a high-fat or high-caloric maternal diet had increased levels of insulin, glucose and leptin. It is hypothesized that these elevations are due to disturbances in the complex neuronal network that includes the neuropeptide Y (NPY) and proopiomelanocortin (POMC) pathways. This altered neuronal signaling can consequently impact food-intake behavior and lead to diet-induced obesity in adulthood. While epigenetic modifications are most likely involved in the development of obesity, the specific target genes have yet to be identified. Genes involved in adipogenesis, such as fibroblast growth-factor-2, phosphatase and tensin homologue, cyclin-dependent kinase inhibitor 1A and oestrogen receptor-alpha, possess multiple CpG islands in their promoter sites and may act as epigenetic targets. Furthermore, it has been shown that prenatal exposure to a hypomethylating agent, such as bisphenol A (BPA), is associated with increased body weight and suggests modified DNA methylation as a mechanism for increasing susceptibility to obesity.
It has long been realized that maternal folate intake during pregnancy is linked to fetal development and growth, and can reduce the risk of serious birth defects. Folate is a source of S-adenosyl methionine (SAM), which is used to supply DNA methyltransferases with methyl groups. Therefore, changes in folate supply have a substantial effect on DNA methylation patterns. Low levels of folate are associated with an increased risk of preterm delivery, poor growth of the placenta and uterus, and intrauterine growth retardation. Several complex diseases, including cancer, cardiovascular diseases and autism have also been linked to maternal folate status. Based on animal studies it has been hypothesized that reduced folate intake could increase the risk of neural tube defects by reducing the amount of methylated DNA during cranial neural tube closure. Recently it was discovered that folate protection from congenital heart defects is linked to epigenetics and Wnt signaling. Multiple environmental factors target the Wnt signaling pathway during embryogenesis and can cause misregulation of the pathway. Folic acid metabolism generates SAM, thereby altering the methylation states of histones H3K9, H3K4, and H3K27 and genetically altering Wnt signaling.
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Nutriepigenomics
Nutriepigenomics also called nutritional genomics, is the study of how food nutrients and bioactive compounds influence human health through epigenetic modifications, such as DNA methylation, histone modifications, and non-coding RNA regulation. While nutrigenomics broadly explores how nutrients and diet impact gene expression, nutriepigenomics specifically examines how these dietary factors induce epigenetic changes without altering the underlying DNA sequence. There is now considerable evidence that nutritional imbalances—especially during gestation, lactation, and early development—can lead to long-term epigenetic alterations, increasing the risk of non-communicable diseases, such as obesity, cardiovascular disease, diabetes, hypertension, and cancer. If metabolic disturbances occur during critical time windows of development, these epigenetic modifications can result in lasting changes to gene expression, tissue function, and disease susceptibility.
Epigenetics relates to heritable changes in gene function that occur independently of alterations in primary DNA sequence. Two major epigenetic mechanisms implicated in nutriepigenomics are DNA methylation and histone modification. DNA methylation in gene promoter regions usually results in gene silencing and influences gene expression. While this form of gene silencing is extremely important in development and cellular differentiation, aberrant DNA methylation can be detrimental and has been linked to various disease processes, such as cancer. The methyl groups used in DNA methylation are often derived from dietary sources, such as folate and choline, and explains why diet can have a significant impact on methylation patterns and gene expression. Gene silencing can also be reinforced through the recruitment of histone deacetylases to decrease transcriptional activation. Conversely, histone acetylation induces transcriptional activation to increase gene expression. Dietary components can influence these epigenetic events, thereby altering gene expression and disturbing functions such as appetite control, metabolic balance and fuel utilization.
Various genetic sequences can be targeted for epigenetic modification. A transcriptome-wide analysis in mice found that a protein-restricted (PR) diet during gestation resulted in differential gene expression in approximately 1% of the fetal genes analyzed (235/22,690). Specifically, increased expression was seen in genes involved in the p53 pathway, apoptosis, negative regulators of cell metabolism, and genes related to epigenetic control. Additional studies have investigated the effect of a PR-diet in rats and found changes in promoter methylation of both the glucocorticoid receptor and peroxisome proliferator-activated receptor (PPAR). Altered expression of these receptors can result in elevated blood glucose levels and affect lipid and carbohydrate metabolism. Feeding a PR-diet to pregnant and/or lactating mice also increased expression of glucokinase, acetyl-CoA carboxylase, PPARα, and acyl-CoA oxidase. Changes in expression were reportedly due to epigenetic regulation of either the gene promoter itself, or promoters of transcription factors that regulate gene expression. Additional genes that have been shown, either by in vitro or in vivo studies, to be regulated by epigenetic mechanisms include leptin, SOCS3, glucose transporter (GLUT)-4, POMC, 11-β-hydroxysteroid dehydrogenase type 2 and corticotrophin releasing hormone. Epigenetic modification of these genes may lead to "metabolic programming" of the fetus and result in long-term changes in metabolism and energy homeostasis.
The period of development in which the nutritional imbalance occurs is very important in determining which disease-related genes will be affected. Different organs have critical developmental stages, and the time point at which they are compromised will predispose individuals to specific diseases. Epigenetic modifications that occur during development may not be expressed until later in life depending on the function of the gene. While the majority of studies implicate prenatal and perinatal periods as critical time windows, some research has shown that nutritional intake during adulthood can also affect the epigenome.
Developmental plasticity is the process in which fetuses adapt to their environment. Environmental cues, including dietary components, present in the in utero environment can induce significant changes in the expression of the genome through epigenetic modifications. Fetal developmental plasticity responses can cause changes in lean body mass, endocrinology, blood flow and vascular loading, and lead to increased risk of various diseases in adulthood. To better understand the long-term consequences of prenatal conditions, the following sections will explore specific outcomes such as low birth weight, obesity, and folate developmental effects. Each of these illustrates how prenatal exposures can shape the long-term health of a person's offspring.
Fetal exposure to calcium, folate, magnesium, high or low protein, and zinc have all been associated with birth weight. Numerous studies have investigated the link between birth weight and risk of disease and have found that low birth weight is significantly associated with coronary heart disease, stroke and type-2 diabetes. Most importantly, these associations occurred after adjusting for lifestyle factors, implying a genetic basis for onset of disease. Impaired insulin secretion is associated with low birth weight and can lead to insulin resistance as babies accumulate body fat. Studies using intrauterine growth retarded (IUGR) rats have found that growth inhibition can lead to decreased expression of PDX1 transcription factor, which is essential for differentiation and function of pancreatic beta cells. Decreased histone acetylation at the proximal promoter of PDX1 is responsible for reduced PDX1 expression and subsequently results in a cascade of histone deacetylation and methylation events that can result in type-2 diabetes.
Obesity during pregnancy and high-fat maternal diets both show strong associations with obesity in offspring. As the number of overweight reproductive-age women increases, the number of overweight children and infants also increases. It has been postulated that maternal obesity causes an accumulation of fat in fetal adipose tissue (adiposity) and predisposes babies for obesity in childhood and adulthood. Animal studies have shown that maternal overnutrition may impact brain development and cause disruptions to programming of the hypothalamus. Offspring that were exposed to a high-fat or high-caloric maternal diet had increased levels of insulin, glucose and leptin. It is hypothesized that these elevations are due to disturbances in the complex neuronal network that includes the neuropeptide Y (NPY) and proopiomelanocortin (POMC) pathways. This altered neuronal signaling can consequently impact food-intake behavior and lead to diet-induced obesity in adulthood. While epigenetic modifications are most likely involved in the development of obesity, the specific target genes have yet to be identified. Genes involved in adipogenesis, such as fibroblast growth-factor-2, phosphatase and tensin homologue, cyclin-dependent kinase inhibitor 1A and oestrogen receptor-alpha, possess multiple CpG islands in their promoter sites and may act as epigenetic targets. Furthermore, it has been shown that prenatal exposure to a hypomethylating agent, such as bisphenol A (BPA), is associated with increased body weight and suggests modified DNA methylation as a mechanism for increasing susceptibility to obesity.
It has long been realized that maternal folate intake during pregnancy is linked to fetal development and growth, and can reduce the risk of serious birth defects. Folate is a source of S-adenosyl methionine (SAM), which is used to supply DNA methyltransferases with methyl groups. Therefore, changes in folate supply have a substantial effect on DNA methylation patterns. Low levels of folate are associated with an increased risk of preterm delivery, poor growth of the placenta and uterus, and intrauterine growth retardation. Several complex diseases, including cancer, cardiovascular diseases and autism have also been linked to maternal folate status. Based on animal studies it has been hypothesized that reduced folate intake could increase the risk of neural tube defects by reducing the amount of methylated DNA during cranial neural tube closure. Recently it was discovered that folate protection from congenital heart defects is linked to epigenetics and Wnt signaling. Multiple environmental factors target the Wnt signaling pathway during embryogenesis and can cause misregulation of the pathway. Folic acid metabolism generates SAM, thereby altering the methylation states of histones H3K9, H3K4, and H3K27 and genetically altering Wnt signaling.