Nutritional Epigenomics

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• Publisher: Academic Press
• Year: 2019
• eBook ISBN: 9780128173107
• Topic: Medicine
• Subtopic: Genetics in Medicine

Nutritional Epigenomics offers a comprehensive overview of nutritional epigenomics as a mode of study, along with nutrition's role in the epigenomic regulation of disease, health and developmental processes. Here, an expert team of international contributors introduces readers to nutritional epigenomic regulators of gene expression, our diet's role in epigenomic regulation of disease and disease inheritance, caloric restriction and exercise as they relate to recent epigenomic findings, and the influence of nutritional epigenomics over circadian rhythms, aging and longevity, and fetal health and development, among other processes. Disease specific chapters address metabolic disease (obesity and diabetes), cancer, and neurodegeneration, among other disorders. Diet-gut microbiome interactions in the epigenomic regulation of disease are also discussed, as is the role of micronutrients and milk miRNAs in epigenetic regulation. Finally, chapter authors examine ongoing discussions of race and ethnicity in the social-epigenomic regulation of health and disease. - Empowers the reader to employ nutritional epigenomics approaches in their own research - Discusses the latest topics in nutritional epigenomics in the regulation of aging, circadian rhythm, inheritance and fetal development, as well as metabolism and disease - Offers a full grounding in epigenetic reprogramming and nutritional intervention in the treatment and prevention of disease, as informed by population-based studies

Section VII

Macro- and micronutrients as epigenomic regulators of health and disease

Outline

Chapter 19. B-vitamins & one-carbon metabolism: impacts on the epigenome during development

Chapter 20. Food bioactives in the epigenomic regulation of metabolic disease

Chapter 21. Stilbenoids as dietary regulators of the cancer epigenome

Chapter 22. Regulation of non-coding RNAs by phytochemicals for cancer therapy

Chapter 23. Short chain fatty acids as epigenetic and metabolic regulators of neurocognitive health and disease

Chapter 19

B-vitamins & one-carbon metabolism

Impacts on the epigenome during development

Karilyn E. Sant ^a , and Olivia S. Anderson ^{b a} San Diego State University School of Public Health, San Diego, CA, USA ^b University of Michigan School of Public Health, Ann Arbor, MI, USA

Abstract

The embryonic and fetal periods of development are times of substantial programming and growth, which establish a foundation for health throughout the life-course. During this time, DNA methylation is substantially remodeled, giving rise to distinct cellular- and organ-level epigenetic signatures. Dietary methyl group donors and cofactors are instrumental for the biochemical basis of these methylation changes, contributing to a pathway known as one carbon metabolism (OCM). These dietary nutrients, specifically folate, choline, betaine, and vitamin B12, have been widely implicated in altered DNA methylation. This chapter reviews the OCM pathway, and the scientific basis for this nutrient-epigenetic relationship during development.

Keywords

DNA methylation; One-carbon metabolism; Folate; Vitamin B12; Choline; Betaine; Embryo; Mammalian development

1. Introduction

Mammalian development is a period of dynamic cellular and molecular change, relying on specific environmental inputs to guide the processes of proliferation and differentiation. In mammals, there are two discrete periods of development—embryonic and fetal. During this embryonic period of mammalian development, pluripotent embryonic stem cells are differentiated into unique cells, germ layers, and tissues. The placenta is not yet functional during embryogenesis, and therefore the mammalian embryo must rely on processes such as maternal deposition of yolk granules and/or histiotrophic uptake of essential nutrients via the yolk sac in order to sustain this rapid growth [1,2]. Pharmacological inhibition of these processes in rodent models has been shown to reduce global DNA methylation in embryos [3].

Once the placenta is functional, the embryo enters the fetal period of development—the peak time of organogenesis. The placenta provides a reliable source of maternally-supplied nutrition, enabling rapid growth and tissue maturation. Because the placenta is a metabolically-active tissue, it serves as both a toxicological barrier and nutritional regulator of the fetal environment. Therefore, the nutritional environment is key to the supply of adequate essential nutrients for proper development throughout the embryonic and fetal periods.

1.1. The early epigenome

Epigenetics is the study of mitotically heritable yet potentially reversible, molecular modifications to DNA and chromatin without change of the underlying DNA sequence. The field of epigenetics has vastly expanded over the past decade; between 2007 and 2017, the number of publications mentioning the term “epigenetic” increased by more than 600%. DNA methylation is the most widely studied epigenetic mechanism. DNA methylation is implicated in diseases ranging from birth defects to cancers, and susceptible to conditions such as environment, behavior, or nutrition. DNA methylation is the modification of genomic cytosine residues with a methyl group (

CH₃) in the carbon-5 position of the nucleotide, yielding 5-methylcytosine. Methylation typically occurs on cytosine residues located directly adjacent to guanine residues (5′-CG-3′), known as CpG sites. Embryonic epigenomes, however, also commonly contain 5-methylcytosine at non-CpG loci—namely during the pre-implantation stage ([4], reviewed in Ref. [5]). Therefore, it is important to assess the holistic embryonic methylation landscape throughout development.

DNA methylation is dynamically remodeled throughout development, directing processes such as differentiation and organogenesis (reviewed in Ref. [6]). Progenitor cells in a developing embryo undergo extensive DNA demethylation and gradual remethylation later during gametogenesis, though the timing of these events may be sex-specific. These events are a crucial quality control for the progenitor cell epigenome prior to mammalian conception. Once fertilization has occurred, embryonic DNA methylation is substantially modified. The pre-implantation embryo erases the majority of its DNA methylation in the inner cell mass prior to the implantation (blastocyst) stage [corresponding with days 4, 6, and 9 in mouse, rat, and human development, respectively] [7]. This DNA demethylation of embryonic stem cells establishes a pluripotent “blank canvas”, providing a foundation for de novo methylation throughout embryogenesis. It is important to note that not all loci in the pre-implantation genome are erased, as imprinted loci retain their methylation marks throughout embryonic development. However, the majority of the epigenome is demethylated during the pre-implantation stage and undergoes de novo methylation during embryogenesis.

1.2. One-carbon metabolism

One-carbon metabolism (OCM) is the metabolic process by which S-adenosylmethionine (SAM), the ultimate biochemical methyl donor for processes such as DNA methylation, is generated [8] (Fig. 19.1). During OCM, methionine is metabolized to SAM by the methionine adenosyltransferase (MAT) family of enzymes (I, II, and III), supplying all of the methyl groups required for processes including DNA methylation, protein post-translational modifications such as histone methylation, and Phase II biotransformation. MAT II, encoded by the MAT2A/B genes, is expressed in almost every tissue, including embryonic and fetal cells. Decreased MAT II enzyme specific activity in mammalian embryos is associated with decreased global DNA methylation [3]. MAT I and MAT III are expressed primarily in the mature liver, and are both isozymes expressed from the MAT1A gene. While MAT2A sequence is highly conserved, there are several deleterious human polymorphisms of MAT1A that have been associated with hypermethioninemia and homocysteinemia in infants and children [9–14].

Fig. 19.1 One-carbon metabolism is a crucial biochemical pathway for the generation of methyl donors from dietary nutrients. Dietary provisions of choline, betaine, folate, and vitamin B12 are metabolized to recharge intracellular methionine stores.
Credit: Karilyn E. Sant and Olivia S. Anderson.

The product of enzymatic extraction of the methyl group from SAM is S-adenosylhomocysteine, which is ultimately converted to homocysteine. Homocysteine can then be “recycled” to methionine to propagate OCM. This process requires the bioavailability of specific dietary nutrients that can serve as methyl donors and enzymatic cofactors for this homocysteine to methionine metabolic step, namely choline, betaine, or folate (vitamin B9) and the water soluble enzymatic cofactor vitamin B12 (cobalamin). During deficiencies of these substrates and cofactors, homocysteine can become elevated intracellularly, which is highly cytotoxic. In these instances, homocysteine is typically exported into the blood for removal via excretion to avoid toxicity, which may reduce OCM [15].

Intracellular homocysteine can also be shunted toward the production of cysteine in the Transsulfuration pathway, a primarily hepatic pathway that generates intracellular cysteine and ultimately glutathione—two abundant cellular antioxidants important for the mitigation of reactive oxygen species. Under normal conditions, both OCM and Transsulfuration are propagated by homocysteine. Cells and tissues experiencing oxidative stress, however, are metabolically compelled to prioritize the Transulfuration pathway in order to sustain necessary antioxidant concentrations [16]. Therefore, it is expected that increased cellular oxidative stress would reduce the efficiency of OCM and generation of SAM, and may potentially have epigenetic co...

Table of contents

• Cover image
• Title page
• Table of Contents
• Translational Epigenetics Series
• Copyright
• Contributors
• About the editor
• Section I. Introduction
• Section II. Epigenetic regulators
• Section III. Epigenomic regulation of disease
• Section IV. Nutrition, epigenetics and transgenerational inheritance
• Section V. Nutritional epigenomics and the circadian clock
• Section VI. Carloric restriction and exercise in the epigenomic regulation of aging and disease
• Section VII. Macro- and micronutrients as epigenomic regulators of health and disease
• Section VIII. Diet, epigenetics and the microbiome
• Index