Choline, Other Methyl-Donors and Epigenetics

Choline dietary intake varies such that many people do not achieve adequate intakes. Diet intake of choline can modulate methylation because, via betaine homocysteine methyltransferase (BHMT), this nutrient (and its metabolite, betaine) regulate the concentrations of S-adenosylhomocysteine and S-adenosylmethionine. Some of the epigenetic mechanisms that modify gene expression without modifying the genetic code depend on the methylation of DNA or of histones; and diet availability of choline and other methyl-group donors influences both of these methylations. Examples of methyl-donor mediated epigenetic effects include the changes in coat color and body weight in offspring when pregnant agouti mice are fed high choline, high methyl diets; the changes in tail kinking in offspring when pregnant Axin(Fu) mice are fed high choline, high methyl diets; the changes in Cdkn3 methylation and altered brain development that occurs in offspring when pregnant rodents are fed low choline diets. When choline metabolism is disrupted by deleting the gene Bhmt, DNA methylation is affected (especially in a region of chromosome 13), expression of specific genes is suppressed, and liver cancers develop. Better understanding of how nutrients such as choline and methyl-donors influence epigenetic programs has importance for our understanding of not only developmental abnormalities but also for understanding the origins of chronic diseases

A Grand Challenge for Nutrigenomics

The low hanging fruit in genetics research has mostly been harvested, and now the work of studying genes as part of systems biology is well underway. Metabolism and nutrition seem to be an ideal complex system in which to apply the knowledge and methods of genetics and genomics. Diet is perhaps the most important environmental factor we are exposed to. Nutritional factors are thought to be the cause of 30–60% of cancers (similar in magnitude to smoking; Doll, 1992), diabetes is a nutritional/metabolic disorder, we are all familiar with the cholesterol–cardiovascular disease relationship, and obesity is a pressing nutritional problem, with a majority of Americans overweight and expanding rapidly (Ogden et al., 2007). If genetic scientists are looking for a complex system to step up to and address, what better choice? Hence, the developing discipline of nutrigenomics

Dietary choline deficiency causes DNA strand breaks and alters epigenetic marks on DNA and histones

Dietary choline is an important modulator of gene expression (via epigenetic marks) and of DNA integrity. Choline was discovered to be an essential nutrient for some humans approximately one decade ago. This requirement is diminished in young women because estrogen drives endogenous synthesis of phosphatidylcholine, from which choline can be derived. Almost half of women have a single nucleotide polymorphism that abrogates estrogen-induction of endogenous synthesis, and these women require dietary choline just as do men. In the US, dietary intake of choline is marginal. Choline deficiency in people is associated with liver and muscle dysfunction and damage, with apoptosis, and with increased DNA strand breaks. Several mechanisms explain these modifications to DNA. Choline deficiency increases leakage of reactive oxygen species from mitochondria consequent to altered mitochondrial membrane composition and enhanced fatty acid oxidation. Choline deficiency impairs folate metabolism, resulting in decreased thymidylate synthesis and increased uracil misincorporation into DNA, with strand breaks resulting during error-prone repair attempts. Choline deficiency alters DNA methylation, which alters gene expression for critical genes involved in DNA mismatch repair, resulting in increased mutation rates. Any dietary deficiency which increases mutation rates should be associated with increased risk of cancers, and this is the case for choline deficiency. In rodent models, diets low in choline and methyl-groups result in spontaneous hepatocarcinomas. In human epidemiological studies, there are interesting data that suggest that this also may be the case for humans, especially those with SNPs that increase the dietary requirement for choline

Nutritional Genomics: Defining the Dietary Requirement and Effects of Choline

As it becomes evident that single nucleotide polymorphisms (SNPs) in humans can create metabolic inefficiencies, it is reasonable to ask if such SNPs influence dietary requirements. Epidemiologic studies that examine SNPs relative to risks for diseases are common, but there are few examples of clinically sized nutrition studies that examine how SNPs influence metabolism. Studies on how SNPs influence the dietary requirement for choline provide a model for how we might begin examining the effects of SNPs on nutritional phenotypes using clinically sized studies (clinical nutrigenomics). Most men and postmenopausal women develop liver or muscle dysfunction when deprived of dietary choline. More than one-half of premenopausal women may be resistant to choline deficiency-induced organ dysfunction, because estrogen induces the gene [phosphatidylethanolamine-N-methyltransferase (PEMT)] that catalyzes endogenous synthesis of phosphatidylcholine, which can subsequently yield choline. Those premenopausal women that do require a dietary source of choline have a SNP in PEMT, making them unresponsive to estrogen induction of PEMT. It is important to recognize differences in dietary requirements for choline in women, because during pregnancy, maternal dietary choline modulates fetal brain development in rodent models. Because choline metabolism and folate metabolism intersect at the methylation of homocysteine, manipulations that limit folate availability also increase the use of choline as a methyl donor. People with a SNPs in MTHFD1 (a gene of folate metabolism that controls the use of folate as a methyl donor) are more likely to develop organ dysfunction when deprived of choline; their dietary requirement is increased because of increased need for choline as a methyl donor

Genetic polymorphisms in methyl-group metabolism and epigenetics: Lessons from humans and mouse models

Choline is an essential nutrient that is critical during fetal brain development. Choline deficiency, through disturbing methyl metabolism, may alter DNA methylation and thereby influence neural precursor cell proliferation and apoptosis. This results in long term alterations in brain structure and function, specifically memory function. A recommended dietary intake for choline in humans was set in 1998, and a portion of the choline requirement can be met via endogenous de novo synthesis of phosphatidylcholine catalyzed by phosphatidylethanolamine N-methyltransferase (PEMT) in the liver. Though many foods contain choline, many humans do not get enough in their diets. When deprived of dietary choline, most adult men and postmenopausal women developed signs of organ dysfunction (fatty liver, liver or muscle cell damage). However, only a portion of premenopausal women developed such problems. The difference in requirement occurs because estrogen induces expression of the PEMT gene and allows premenopausal women to make more of their needed choline endogenously. In addition, there is significant variation in the dietary requirement for choline that can be explained by common genetic variants (single nucleotide polymorphisms; SNPs) in genes of choline and folate metabolism. Some of these increase the risk of choline deficiency many fold. These variations in choline requirement could have important implications for brain development

Is maternal diet supplementation beneficial? Optimal development of infant depends on mother’s diet

There are periods during perinatal development in which specific nutrients are required for optimal development, and there is growing evidence that optimal dietary intake of these nutrients, which include iodine, docosahexaenoic acid, choline, and folate, is important. Lessons in how these nutrient effects were identified can help us to broaden our approaches for finding other critical nutrients: we are looking for nutrients for which there is a wide range of dietary intake, that have no or marginal pathways for biosynthesis, and that are needed by dividing progenitor cells. For some of the nutrients discussed, such as iodine and folate, the effects in humans are abundantly clear; for others, animal data are the most convincing. More human studies need to be conducted. We need a better understanding of diet and diet supplement intake during pregnancy and lactation and of whether diets are particularly low in some nutrients. Also, we need to understand how common genetic variations influence nutrient requirements during these periods. If we are going to supplement maternal and infant diets, first we must understand much more about the risks of having too much of a critical nutrient. Whatever the limitations of our current state of knowledge, it is apparent that pregnancy and lactation are periods during which good nutrition is exceptionally important. The infant is not protected from the inadequate diet of the mother

A Conceptual Framework for Studying and Investing in Precision Nutrition

Nutrients and food-derived bioactive molecules must transit complex metabolic pathways, and these pathways vary between people. Metabolic heterogeneity is caused by genetic variation, epigenetic variation, differences in microbiome composition and function, lifestyle differences and by variation in environmental exposures. This review discusses a number of these sources of metabolic heterogeneity and presents some of the research investments that will be needed to make applications of precision nutrition practical

Nutrigenomics and metabolomics will change clinical nutrition and public health practice: insights from studies on dietary requirements for choline

Science is beginning to understand how genetic variation and epigenetic events alter requirements for, and responses to, nutrients (nutrigenomics). At the same time, methods for profiling almost all of the products of metabolism in a single sample of blood or urine are being developed (metabolomics). Relations between diet and nutrigenomic and metabolomic profiles and between those profiles and health have become important components of research that could change clinical practice in nutrition. Most nutrition studies assume that all persons have average dietary requirements, and the studies often do not plan for a large subset of subjects who differ in requirements for a nutrient. Large variances in responses that occur when such a population exists can result in statistical analyses that argue for a null effect. If nutrition studies could better identify responders and differentiate them from nonresponders on the basis of nutrigenomic or metabolomic profiles, the sensitivity to detect differences between groups could be greatly increased, and the resulting dietary recommendations could be appropriately targeted. It is not certain that nutrition will be the clinical specialty primarily responsible for nutrigenomics or metabolomics, because other disciplines currently dominate the development of portions of these fields. However, nutrition scientists' depth of understanding of human metabolism can be used to establish a role in the research and clinical programs that will arise from nutrigenomic and metabolomic profiling. Investments made today in training programs and in research methods could ensure a new foundation for clinical nutrition in the future

Importance of methyl donors during reproduction 1-4

Evidence is growing that optimal dietary intake of folate and choline (both involved in one-carbon transfer or methylation) is important for successful completion of fetal development. Significant portions of the population are eating diets low in one or both of these nutrients. Folates are important for normal neural tube closure in early gestation, and the efficacy of diet fortification with folic acid in reducing the incidence of neural tube defects is a major success story for public health nutrition. Similarly, maternal dietary choline is important for normal neural tube closure in the fetus and, later in gestation, for neurogenesis in the fetal hippocampus, with effects on memory that persist in adult offspring; higher choline intake is associated with enhanced memory performance. Although both folates and choline have many potentially independent mechanisms whereby they could influence fetal development, these 2 nutrients also have a common mechanism for action: altered methylation and related epigenetic effects on gene expression

Metabolic crosstalk between choline/1-carbon metabolism and energy homeostasis

There are multiple identified mechanisms involved in energy metabolism, insulin resistance and adiposity, but there are here-to-fore unsuspected metabolic factors that also influence these processes. Studies in animal models suggest important links between choline/1-carbon metabolism and energy homeostasis. Rodents fed choline deficient diets become hypermetabolic. Mice with deletions in one of several different genes of choline metabolism have phenotypes that include increased metabolic rate, decreased body fat/lean mass ratio, increased insulin sensitivity, decreased ATP production by mitochondria, or decreased weight gain on a high fat diet. In addition, farmers have recognized that the addition of a metabolite of choline (betaine) to cattle and swine feed reduces body fat/lean mass ratio. Choline dietary intake in humans varies over a >three-fold range, and genetic variation exists that modifies individual requirements for this nutrient. Although there are some epidemiologic studies in humans suggesting a link between choline/1-carbon metabolism and energy metabolism, there have been no controlled studies in humans that were specifically designed to examine this relationship