Nutrition, Epigenetics And Health

Graham Burdge, Karen Lillycrop

• Publisher: WSPC
• Year: 2016
• eBook ISBN: 9789813143326
• Topic: Medicine
• Subtopic: Nutrition, Dietics & Bariatrics

Epigenetics is emerging as an important factor in risk of diseases of global importance including obesity, cardiovascular disease and cancer. Unlike gene polymorphisms which have been the focus of understanding the role of inherited disease susceptibility

CHAPTER 1

Basic Mechanisms in Epigenetics

Karen A. Lillycrop

Centre for Biological Sciences, University of Southampton,
IDS Building (MP 887), Southampton General Hospital,
Tremona Road, Southampton, SO16 6YD, UK

Abbreviations

5mC, 5 methyl cytosine;

5hmC, 5 hydroxy methyl cytosine;

5fC, 5-formylcytosine;

5caC, 5-carboxylcytosine;

CBX, chromobox-domain protein;

C/EBP_α, CCAAT/Enhancer Binding Protein;

CRE, cAMP response element;

CpG, cytosine and guanine nucleotides linked by phosphate;

CTCF, CCCTC-Binding Factor (Zinc Finger Protein);

Dnmt, DNA methyltransferase;

EED, embryonic ectoderm development;

ES, embryonic stem;

EZH2, enhancer of zeste homolog 2;

HATs, histone acetyl transferases;

HDACs, histone deacetylases;

HMTs, histone methyl transferases;

JMJD2, Jumonji domain 2;

IAP, intracisternal A-particles;

ICR, Imprinting control region;

IGF-2, insulin like growth factor-2;

LINE, long interspersed nuclear elements;

lncRNAs, long non-coding RNAs;

LSD, lysine-specific demethylase 1;

LTR, Long terminal repeats containing endogenous retroviruses;

MBD, methyl binding domain;

MeCP2, methyl CpG binding protein 2;

miRNAs, microRNAs;

ncRNAs, non-coding RNA;

NRF-1, Nuclear respiratory factor 1;

PARP, poly-ADP-ribose polymerases;

piRNA, Piwi-interacting RNA;

PGC1α, peroxisome proliferator- activated receptor gamma, coactivator 1 alpha;

PRC, polycomb repressive complex;

PPAR, peroxisomal proliferator-activated receptor;

O-GlcNAc, β-N-acetylglucosamine;

O-GlcNAcase, β-N-acetylglucosaminidase;

SAM, s adenosyl methionine;

SINE, short interspersed nuclear elements;

SIRT1, Sirtuin1;

SUZ12, suppressor of zeste 12;

RISC, RNA-induced silencing complex;

TET, Ten-eleven translocation proteins;

YY1, Yin Yang 1;

XCI, X chromosome inactivation;

Xist, X-inactive specific transcript

Introduction

It has been widely recognized that the sequence of bases (A,C,G,T) within DNA determine phenotype. However, recent research has shown that gene sequence is not the sole determinant of phenotype, but epigenetic processes can also influence phenotypic traits. Epigenetic processes regulate the accessibility of genes to the cellular proteins that regulate gene transcription, determining where and when a gene is switched on, and its level of activity. Epigenetic processes not only play a central role in regulating gene expression but also allow an organism to adapt to the environment. A growing body of evidence has shown that a number of environmental factors such as nutrition, body composition or social environment can all influence these epigenetic processes, often with long-term consequences on metabolism and disease risk. In this first chapter, the basic mechanisms of the three main epigenetic processes, DNA methylation, histone modification and non-coding RNAs will be discussed.

Introduction to Epigenetics

Conrad Waddington (1905–1975) first introduced the term “epigenetics” in the 1940s. He used it to define “the branch of biology which studies the causal interactions between genes and their products, which bring the phenotype into being”.¹ However, with our increased understanding of the mechanisms underlying gene regulation and cell specification, the definition of epigenetics has narrowed and in 2007, Adrian Bird defined epigenetics as “the structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states”. But there was much controversy over how stable the changes induced by such epigenetics processes needed to be to fit the definition of epigenetic and so in 2008, a consensus definition was produced and epigenetics was defined as “stably heritable phenotypes resulting from changes in a chromosome without changes in gene sequence”.² Epigenetic processes include: DNA methylation, histone modifications, and non-coding RNAs. These processes regulate all aspects of gene expression by controlling access to the underlying DNA sequence. Epigenetic mechanisms also provide both variability and rapid adaptability that allow organisms to respond to the environment both in the short and long term.

DNA Methylation

DNA methylation is a common modification in eukaryotic organisms. In mammals, DNA methylation occurs primarily on the 5^th position of the cytosine (5mC) base within a CpG dinucleotide. In humans, this dinucleotide is present at only 5 to 10% of its predicted frequency with a total 28 million CpGs within the human genome, of which 70 to 80% are methylated.³ These CpG dinucleotides are not uniformly distributed across the genome but are clustered at the 5′ promoter or control regions of genes. This cluster of CpGs is often referred to as a CpG island. CpG islands are defined as a sequence with a G+C content of greater than 60% and ratio of CpG to GpC of at least 0.6.⁴ Genes which contain CpG islands are usually “housekeeping” genes which are constitutively expressed and where the CpG islands are largely unmethylated. Methylated CpG islands are however found in the promoters of developmental genes^5,6 suggesting that DNA methylation is an important regulatory mechanism in regulating cell fate. Other sequences that are heavily methylated in mammals includes repetitive DNA sequences such as those within the centromeric and pericentromeric regions of chromosomes or in the endogenous transposable elements such as the long interspersed nuclear elements (LINEs), short interspersed nuclear elements (SINEs) and long terminal repeat (LTR)-containing endogenous retroviruses.³

DNA Methylation Regulates Gene Transcription

The observation that low levels of DNA methylation in the promoter or control regions of genes are generally associated with transcriptional activity, while high levels of promoter methylation are associated with transcriptional silencing, led to the suggestion that DNA methylation may modulate the level of gene transcription.³ Subsequent studies support this hypothesis and have shown that DNA methylation can affect gene transcription through two main mechanisms. Firstly, DNA methylation can influence transcription factor binding. In the vast majority of cases, DNA methylation within the binding site of a transcription factor has been shown to block binding of the transcription factor to the DNA. Examples of transcription factors whose binding is inhibited by DNA methylation include NRF-1,⁷ YY1, MYC and AP1.⁸ But there are exceptions, for example, methylation of the CRE sequence enhances the DNA binding of C/EBPa, which in turn activates a set of promoters specific for adipocyte differentiation.^9,10

The second mechanism by which DNA methylation can affect gene transcription is through the recruitment of histone modifying enzyme complexes to the DNA which leads to transcriptional repression.¹¹ Methyl CpG binding protein 1 (MeCP1) recognizes and binds to methylated CpGs but requires at least seven methylated CpGs for efficient DNA binding and so recruitment of MeCP1 may be important for the repression of genes with CpG islands,^12,13 while MeCP2 binds to a single methylated CpG and may be responsible for repression from CpG sparse promoters.¹⁴

However, DNA methylation is also found within the bodies of genes, and here higher levels of intragenic methylation correlate with higher levels of gene expression.^15–17 The functional significance of gene body methylation is less clear and a number of potential roles have been suggested, including regulation of alternative transcription initiation sites¹⁷ or regulation of splicing.¹⁸ DNA methylation in mammals is often increased at exons relative to introns, leading to the suggestion that DNA methylation may mark exon/intron boundaries.¹⁹ It has been proposed that DNA methylation may modulate the binding of DNA-binding factors such as CTCF, which could induce a local pausing of the RNA polymerase and favor the co-transcriptional assembly of the spliceosome at splice sites.²⁰

Non-CpG Methylation

In mammals, non-CpG methylation has also been reported. This occurs primarily at CpA dinucleotides and is most prevalent in embryonic stem (ES) cells, oocytes and in neuronal cells in the brain. Non-CpG methylation is enriched at certain genomic features and co-occurs w...

Table of contents

• Cover Page
• Title
• Copyright
• Contents
• Preface
• Chapter 1: Basic Mechanisms in Epigenetics
• Chapter 2: Nutrition, Epigenetics and the Early Life Origins of Disease: Evidence from Human Studies
• Chapter 3: The Early Life Nutritional Environment, Epigenetics and Developmental Programming of Disease: Evidence from Animal Models
• Chapter 4: Lipids and Epigenetics
• Chapter 5: Circadian Biology: Interaction with Metabolism and Nutrition
• Chapter 6: Nutrition, Epigenetics and Aging
• Chapter 7: Nutrition and Epigenetics: Evidence for Multi- and Transgenerational Effects
• Chapter 8: Epigenetic Biomarkers and Global Health
• Chapter 9: Nutrition, Epigenetics and Health: Evolutionary Perspectives
• Chapter 10: The Body Politic: Epigenetics and Society
• Index