Overview of nutrigenomics and epigenomics: mechanisms and relevance

Abstract

Advances in nutrigenomics and epigenomics are providing new understanding of mechanisms underlying the nutritional regulation of growth, development and health. Nutrition affects the structure and function of biological systems at all life-stages, with profound implications for health and disease. These effects are mediated by changes in expression of multiple genes and associated regulatory networks. Responses to nutrition are in turn affected by individual variability in target genes, including mutations, single nucleotide polymorphisms (SNPs) and copy number variants (CNVs). An important layer of regulation is provided by the epigenome: nutrition is one of many epigenetic regulators that modify gene expression without changes in DNA sequence. They play a key role in development and enable a given genotype to express a wide range of cell-specific and age-related phenotypes. Although epigenetic events can be stable and heritable, they can also be reversible, highlighting their critical role in health and disease. Nutrition can act directly on gene expression, or indirectly via hormones, growth factors and signalling molecules. These actions often involve epigenetic mechanisms, including DNA methylation, histone modifications and non-protein-coding RNAs. Understanding of mechanisms underlying nutrition-gene interactions depends in part on a comparative approach across a wide range of species. Thus, findings in mammals on the role of epigenetics in early-life nutrition programming of adult health and disease are highly relevant to avian species. Future progress in nutrigenomics and epigenomics is critical to advancing understanding of optimal avian growth, development and health.

Full text

MJD REVIEW 1: FACTA Avian Nutrigenomics Course, Campinas, Brazil: 27-28 May 2014
Overview of nutrigenomics and epigenomics: mechanisms and relevance
M. J. Dauncey
Wolfson College, University of Cambridge, UK
ABSTRACT: Advances in nutrigenomics and epigenomics are providing new understanding of
mechanisms underlying the nutritional regulation of growth, development and health. Nutrition
affects the structure and function of biological systems at all life-stages, with profound implications
for health and disease. These effects are mediated by changes in expression of multiple genes and
associated regulatory networks. Responses to nutrition are in turn affected by individual variability
in target genes, including mutations, single nucleotide polymorphisms (SNPs) and copy number
variants (CNVs). An important layer of regulation is provided by the epigenome: nutrition is one of
many epigenetic regulators that modify gene expression without changes in DNA sequence. They
play a key role in development and enable a given genotype to express a wide range of cell-specific
and age-related phenotypes. Although epigenetic events can be stable and heritable, they can also be
reversible, highlighting their critical role in health and disease. Nutrition can act directly on gene
expression, or indirectly via hormones, growth factors and signalling molecules. These actions often
involve epigenetic mechanisms, including DNA methylation, histone modifications and non-
protein-coding RNAs. Understanding of mechanisms underlying nutrition-gene interactions
depends in part on a comparative approach across a wide range of species. Thus, findings in
mammals on the role of epigenetics in early-life nutrition programming of adult health and disease
are highly relevant to avian species. Future progress in nutrigenomics and epigenomics is critical to
advancing understanding of optimal avian growth, development and health.
1. INTRODUCTION
Nutrition can profoundly alter the phenotypic expression of a given genotype, with major
implications for growth, development, metabolism, health and disease (Dauncey et al., 2004;
Dauncey and White, 2004; Dauncey, 2009, 2012, 2013a, b). The effects of nutrition on gene
expression are exerted throughout the life-cycle, with prenatal and early postnatal life being
especially critical periods for optimal development. These effects may be dynamic and short-term,
stable and long-term, and even heritable between cell divisions and across generations. A critical
layer of regulation is provided by the epigenome; nutrition is one of many epigenetic regulators that
modify gene expression without changes in DNA sequence. Figure 1 presents an overview of key
mechanisms involved in nutrition-gene interactions.
The field of nutrigenomics is accompanied by a wide range of terminologies and definitions. The
term 'nutrigenomics' is often used interchangeably with 'nutritional genomics' and involves the
study of nutrition-gene interactions. This includes both the effects of nutrition on gene expression
('nutrigenomics') and the effects of genetic variability on responses to nutrition ('nutrigenetics')
(Dauncey and Astley, 2006; Fenech et al., 2011; de Godoy and Swanson, 2013; Phillips, 2013).
Advances in nutrigenomics are critical for optimal avian health, welfare and production. They are
relevant to numerous parameters including: development, growth and function of cells, tissues and
systems; resilience to environmental and physiological stress; breeder fertility; quality and
production of eggs and broiler meat.
The role of nutrition in health and disease is highly complex because, as with all aspects of
nutrition, it is multifactorial. The concern is not with a single chemical but with numerous nutrients,

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metabolites and interacting factors that together affect multiple genes and associated regulatory
networks. Moreover, gene variability significantly modifies the effects of nutrition on gene
expression. Individual responses to nutrition are due in part to gene variants in numerous protein-
coding and non-coding regions of the genome. These can involve either single nucleotides or large
sections of genomic DNA i.e. single nucleotide polymorphisms (SNPs) and copy number variants
(CNVs), respectively.
Figure 1. Overview of key interactions between nutrition and genes; modified from (Dauncey, 2012)
This short review aims to increase understanding of the complex interactions between nutrition,
genes and health. It highlights the importance of the One Health comparative approach to
nutrigenomics and its importance to avian biology. The focus of this review is on recent advances in
genomics and epigenomics, especially in relation to underlying mechanisms and relevance to avian
health, welfare and production.
2. COMPARATIVE NUTRIGENOMICS
The One Health approach aims to optimize health in humans, animals and the environment (Ducrot
et al., 2011; Dauncey, 2013b). Studies in comparative biology and medicine are advancing
understanding of health and disease across species: advances in animals are relevant to humans and
findings in humans have important implications for animal health. Numerous studies have identified
the importance of this approach to cellular and molecular mechanisms underlying many aspects of
biology including growth, development, metabolism and endocrinology (Dauncey, 1995; Dauncey
et al., 2001; Dauncey et al., 2004). Important comparisons can be made in relation to cells, tissues,
organs and systems, including gastrointestinal, muscular, adipose, cardiac and neurological.
In relation to comparative nutrigenomics it is essential to take account of the many similarities and
differences between species. These include nutrition and diet, ambient temperature and humidity,
activity, age, stage of development at birth, body size, life-span, and metabolic, digestive, endocrine
and neurological systems. In many respects, not only does the chicken make a valuable model for
the human infant, but advances in human nutrition and development are relevant to avian species.
Indeed, recent advances in many species including honey bees, rodents, swine and humans are
increasing knowledge of development, growth, metabolism, welfare and production in poultry.

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3. NUTRITION, GENOMICS AND EPIGENOMICS
The genome is extremely sensitive to its nutritional environment. Specific food components and
overall energy status profoundly influence the action of numerous genes implicated in health and
disease (Dauncey and Astley, 2006; Dauncey, 2012; de Godoy and Swanson, 2013; Dauncey,
2014a, b). By contrast with single-gene disorders, many chronic diseases are polygenic:
cardiovascular disease, diabetes and cancers frequently involve many genes and gene variants that
interact with multiple environmental factors.
Two complementary and equally valid approaches are being used to investigate nutrition-gene
interactions. First, specific genes can be investigated in depth, using established techniques of
molecular and cell biology (Ekmay et al., 2013). This approach has led to numerous important
findings. Second, the more recent development of high-throughput technologies has enabled
genome-wide analysis in which numerous genes are investigated simultaneously (Brennan et al.,
2013; de Oliveira et al., 2013). This approach is also enabling considerable progress in
nutrigenomics. Initially, the focus of genome-wide analysis was on protein-coding regions of the
genome and messenger-RNAs (mRNAs). More recently, progress in methodology has enabled
assessment of the entire genome, thus enabling evaluation of multiple non-protein-coding RNAs
that play a key role in regulating gene expression (Dauncey, 2013a).
Recent advances in DNA sequencing technology have revolutionized understanding of the
mechanisms underlying regulation of growth and development in health and disease (Liu, 2011;
Kilpinen and Barrett, 2013). Compared with methods used by the Human Genome Project, modern
sequencers are 50,000-fold faster and have dramatically reduced the cost of DNA sequencing by a
factor of more than 50,000. These new technologies are thus enabling major advances in
understanding of genomics and epigenomics and their relevance to nutritional regulation of health
and disease (Dauncey, 2013a).
4. NUTRITIONAL REGULATION OF GENE EXPRESSION
Nutrition has both direct and indirect effects on gene expression, with indirect effects being exerted
via cell signalling pathways (Dauncey et al., 2001; Dauncey et al., 2004; Dauncey and White, 2004;
Gomez-Pinilla, 2008; Dauncey, 2009, 2012). In relation to direct effects, many nutrients and
metabolites are ligands for nuclear receptors/transcription factors e.g. vitamin A (retinoic acid
receptor, RAR), vitamin D (vitamin D receptor, VDR), vitamin E (pregnane X receptor, PXR),
calcium (calcineurin), zinc (metal-responsive transcription factor 1, MTF1), fatty acids (peroxisome
proliferator activated receptors, PPARs; sterol regulatory element binding proteins, SREBPs).
An example of the indirect effects of nutrition on genes is given by fatty acids: their metabolism
alters intracellular energy balance, leading to changes in cellular NAD homeostasis, which is
associated with alterations in chromatin remodelling, DNA function and gene regulation.
Carbohydrates, amino acids and energy status also have profound effects on signalling molecules
and their receptors, with important consequences for health and disease. Energy status, for example,
influences numerous hormones and growth factors. Polypeptide hormones including growth
hormone, insulin-like growth factors (IGFs), insulin and brain-derived neurotrophic factor (BDNF)
act on plasma membrane-bound receptors to trigger gene transcription via intracellular signalling
pathways. Lipophilic hormones, including thyroid hormones and glucocorticoids, act on their
nuclear receptors to regulate transcription of multiple genes via DNA binding and chromatin
remodelling (Dauncey, 2014a). Epigenetic mechanisms are thus clearly involved in these responses
and these are discussed in the following section.

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5. EPIGENETICS IN DEVELOPMENT, HEALTH AND DISEASE
Nutrition affects gene expression at levels of transcription, translation and post-translational
modifications. Epigenetic mechanisms play a key role in some of these responses (Mathers et al.,
2010; Pham and Lee, 2012; Dauncey, 2013a; Murrell et al., 2013; Dauncey, 2014a, b). They are
fundamental to normal development, and enable cell-specific and age-related gene expression.
Although epigenetic events can be highly stable, they can also be reversible, emphasizing critical
roles for nutrition in modulation of health and disease. Many nutritional components have both
immediate and long-term effects on the epigenome, including energy status and dietary methyl
donors such as folate, vitamin B12, choline and methionine.
5.1. Epigenetic mechanisms
The term epigenetics means 'above genetics' and includes mechanisms that alter gene expression
without changes in DNA sequence. Precise definitions vary widely: depending on the area of study,
investigators may be concerned with transient or stable effects, with the latter sometimes involving
heritable changes between generations. Epigenetic mechanisms often involve chemical marking of
chromatin i.e. the form in which DNA is packaged with histone proteins in the cell nucleus.
Epigenetic marks can induce chromatin remodelling and related changes in gene expression. They
include DNA methylation, which reduces gene activity, and histone modifications such as
acetylation, which increases gene activity. Figure 2 illustrates the changes induced in chromatin and
gene expression by histone acetylation changes. Additional epigenetic mechanisms involve non-
protein-coding RNAs (ncRNAs), RNA editing, telomere control and chromosomal position effects.
Figure 2. Histone acetylation increases gene expression via changes in chromatin remodelling;
for details, see (Dauncey et al., 2001; Dauncey et al., 2004; Dauncey, 2013a)
Although protein-coding genes are the subject of many functional studies, most of the genome gives
rise to ncRNAs that nevertheless play key roles in development, health and disease (Li et al., 2012)
(Qureshi and Mehler, 2012; Dauncey, 2013a; Wang et al., 2013). Numerous studies have revealed a
central role for ncRNAs as regulators of transcription, epigenetic processes and gene silencing
(Derrien et al., 2012; Dunham et al., 2012; Rinn and Chang, 2012). Moreover, there are key
interactions between ncRNAs and environmental factors such as nutrition (Dauncey, 2013a, 2014a).
Multiple gene variants in protein-coding and non-coding regions of the genome add a further level
of control and these are discussed in section 6 of this review.

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5.2. Early-life nutrition programming of later health and disease
Nutrition-gene interactions are critical for growth, development and function throughout life.
Especially important is early-life experience: in human adults the incidence of numerous diseases is
related in part to early nutrition (Lucas, 1994; Barker, 1995; Dauncey, 1997; Dauncey and Bicknell,
1999; Dauncey, 2004, 2009, 2012). Programming is the phenomenon whereby an insult, such as
malnutrition, acting during a critical period has long-term or permanent effects on structure and
function. Both the timing and type of insult are important to later health and disease. Critical
periods of development occur prenatally and in early postnatal life, indicating that optimal nutrition
is especially important during these stages of the life-cycle.
Both prenatal and postnatal nutrition can affect health and disease in later life, and these effects may
even be passed between generations. Epigenetic mechanisms are implicated in the programming of
many human diseases. These include metabolic disorders such as obesity and diabetes, cancers, and
neurodevelopmental disorders (Dauncey, 2012, 2013a). Moreover, maternal environment can
critically affect both immediate and long-term development of the offspring (Waterland and Jirtle,
2003; Dauncey, 2014a, b; Rush et al., 2014). Changes are related to energy status and specific
nutrients. For example, maternal dietary methyl supplements alter the phenotype of rat offspring by
methylating the epigenome. Similarly, avian maternal and embryonic nutrition can have long-term
and transgenerational effects on growth, development, welfare and production, in part via changes
in epigenetic regulation (Uni et al., 2005; Fresard et al., 2013).
Epigenetic marks can be stable and heritable, suggesting a mechanism for programming of later
health or disease and transgenerational inheritance. However, it should be stressed that epigenetic
mechanisms are plastic and reversible. Thus, environment and lifestyle can alter the early-life
environmental and genetic determination of phenotype. The possibility is that, in humans, optimal
infant and adult nutrition could be used to ameliorate or reverse the adverse effects of early-life
experience. In avian production, if early nutrition is modified to optimize later performance, then
care must be taken to ensure that an adverse postnatal and adult environment does not harm these
early advantages.
6. NUTRIGENETICS: GENE VARIABILITY AND RESPONSES TO NUTRITION
Differences in DNA sequence can influence gene expression, phenotype, responses to environment
and risk of disease (Dauncey and Astley, 2006; Dauncey, 2009, 2012). Gene variants include
relatively rare mutations, and more common single nucleotide polymorphisms (SNPs) and DNA
copy number variants (CNVs). These have the ability to markedly affect the extent to which
nutrition influences the expression of multiple genes.
Mutations involve a change in DNA sequence that can result in a loss or change in gene function.
They are sometimes linked with rare single gene disorders, such as phenylketonuria. By contrast,
common gene variants involving a change of a single nucleotide in at least 1% of the population are
termed SNPs. They have a key role in individual responses to nutrition and are linked with many
polygenic common disorders in humans: the combined action of alleles from several genes
increases the risk of obesity, diabetes, cancers, cardiovascular disease and brain disorders. Genome-
wide association studies on large numbers of individuals are significantly advancing understanding
of the role of SNPs in responses to nutrition. For example, a physically active life-style is associated
with a 40% reduction in the genetic predisposition to obesity (Li et al., 2010). This finding resulted
from genotyping 12 SNPs in obesity-associated loci, in a study involving more than 20,000 people.
Numerous SNPs also have key roles in avian responses to nutrition. IGF1 and lysine (K)-specific
histone demethylase 5A (KDM5A) have important roles, respectively, in growth and epigenetic

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regulation of genes in the cell cycle, respectively. Recent findings demonstrated that several
polymorphisms in the IGF1 and KDM5A genes are associated with performance, fatness and
carcass traits (Boschiero et al., 2013). For example, body weight, feed intake and abdominal fat
were affected by significant interactions between genotype and gender.
By contrast with SNPs, CNVs are structural gene variants that involve multiple copies or deletions
of large parts of the genome, and can affect from 1 kb to many megabases of DNA per event
(Redon et al., 2006). CNVs can be inherited or result from de novo mutation, and occur in genes,
parts of genes and outside genes. Changes in a gene or its regulatory region can profoundly affect
RNA and protein expression. These common insertions or deletions are often linked with genes
involved in molecular-environment interactions. The extent to which CNVs are involved in
multifactorial common diseases is the focus of considerable interest (Morrow, 2010; Guffanti et al.,
2013).
Genome-wide study of different chicken breeds reveals large-scale variations in SNPs and CNVs
(Fan et al., 2013). In relation to DNA copy number, array comparative genomic hybridization
(aCGH) using blood DNA from a wide range of chicken breeds revealed 3154 CNVs, grouped into
1556 CNV regions (Crooijmans et al., 2013). The average size of the CNVs was 46.3 kb, with the
largest being 4.3 Mb. Approximately 75% were copy number losses, relative to the Red Jungle
Fowl reference genome. Genome coverage was found to be 60 Mb i.e. almost 5.4% of the chicken
genome. Many of the CNVs are line-specific and probably related to the causative mutation of
phenotypic variants. Overall, these findings are highly significant to avian nutrigenomics. Many
CNVs probably affect qualitative and quantitative traits that are of economic importance, global
characterisation of CNVs will help to identify relevant structural variations in the chicken genome,
and results will complement knowledge about SNPs. This should provide new information on the
molecular basis of phenotypic variation and disease; genes relevant to growth, appetite and
metabolism; and the role of gene variability in responses to nutrition.
7. CONCLUSIONS
Nutrition-gene interactions are important throughout life, with prenatal and early postnatal
development being especially susceptible to nutrition. Effects may be beneficial or harmful, and
have both immediate and long-term consequences. Knowledge of individual gene variability and
epigenetic mechanisms underlying gene expression is critical to the understanding of nutritional
regulation of optimal and sub-optimal growth, development and health. Interactions between
nutrition and other environmental factors add a further level of control and these are discussed in a
related review article (Dauncey, 2014a).
Progress in nutrigenomics and epigenomics is relevant to numerous aspects of avian health, welfare
and production. These include the growth and function of cells, tissues, organs and systems, stress
resilience, breeder fertility, quality and production of eggs and broiler meat, and feed efficiency and
costs. Significant advances are dependent on comparative studies in a wide range of species,
including worms, insects, rodents, pigs and humans.
Future advances depend in part on very large-scale investigations of the whole genome and the
epigenomes of specific cell types, together with their highly complex regulatory networks.
Technological progress combined with innovative approaches should result in significant advances
in the understanding of nutritional genomics and its role in optimal health and prevention or
amelioration of disease.

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ACKNOWLEDGEMENTS
This review is based on MJD Lecture 1 for the FACTA Avian Nutrigenomics Course, Brazil 2014.
I thank many colleagues world-wide for valuable discussion; the organizers and sponsors of the
Course, especially Professor Marcos Macari, for inviting me to lecture at this prestigious event;
computing and library staff at the University of Cambridge for expert advice. Parts of the article are
based on previous publications including (Dauncey et al., 2001; Dauncey et al., 2004; Dauncey and
White, 2004; Dauncey, 2009, 2012, 2013a, b); additional references can be found in these articles.
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