Epigenomics and Nutrition

Oleh:
Christina Rusli
Pembimbing:
dr. Agussalim Bukhari, M.Med., Ph.D, Sp.GK(K)
 ABSTRACT

Epigenomics or epigenetics refers to the modification of DNA that can

influence the phenotype through changing gene expression without altering
the nucleotide sequence of the DNA. Two examples are methylation of
DNA and acetylation of the histone DNA-binding proteins. Dietary
components – both nutrients and nonnutrients – can influence these
epigenetic events, altering genetic expression and potentially modifying
disease risk. Some of these epigenetic changes appear to be heritable.
Understanding the role that diet and nutrition play in modifying genetic
expression is complex given the range of food choices, the diversity of
nutrient intakes, the individual differences in genetic backgrounds and
intestinal physiological environments where food is metabolized, as well as
the impact on and acceptance of new technologies by consumers.
 NUTRIGENOMICS
Covers the interaction of diet with DNA, chromatin or RNA expression

Varying levels of bioactivity and

bioavailability
Functions
Diet Protective Nonprotective
(mixture of
nutrients) Nonnutritive
bioactives or The risk of developing disease or
food components ill-health

There is considerable diversity in the genome (polymorphisms) and

in its expression → Genomic variation can occur in:
• Single nucleotides [either as single nucleotide polymorphisms or as point
mutations]
• Insertion or deletion of a few up to several hundred bases
• Through gross chromosomal rearrangements like those occurring in Down’s
syndrome
 NUTRIGENETICS AND NUTRIGENOMICS
Nutrigenetics

• The nutrient response at the level of the single gene and is

concerned with the effects of specific gene variants on an
individual’s response to diet

Nutrigenomics

• The response to nutrients at the level of the whole genome

or how diet affects genetic expression across the whole
genome
 NUTRIGENETICS
Individual’s genetic background Respond differently to
with recognition that there are bioactives from foods.
allelic variations in genes

Genetic polymorphisms may influence the nutrient or

bioactive response in several ways
• Genetically based differences in absorption, disposition, metabolism
and excretion
• Nutrient-gene interactions – an individual’s genetic background can
determine which gene products are expressed that modulate the
physiological response to specific nutrients
• Nutrients may affect gene expression and thus the tissue or cellular
level of a protein that is part of the causal pathway of a disease
and, as such, could modify an individual’s susceptibility to that disease
 Epigenomics
Traditionally Epigenetics/genomics
Nucleotide
sequence was
the sole driver of Modification of the DNA and DNA-binding
Phenotypic traits
heredity. proteins that can influence the phenotype
were determined
solely by genetic without altering the nucleotide sequence of
mutations and the DNA.
recombinations
RNA-associated interference with gene
expression (e.g. small interfering RNAs

Epigenetic • Heritable
• Associated with different disease states
changes • Modifiable by dietary factors
DNA METHYLATION
 DNA METHYLATION
Aging

Epigenetic drift
with aberrant
methylation of ↑ tissue ↑ incidence of
CpG islands in vulnerability to several cancers,
the promoter neoplastic such as colorectal
regions of DNA transformation cancer
repair and tumor
suppressor genes
 DNA METHYLATION

Alzheimer’s disease has been associated with different

patterns of DNA methylation

DNA hypomethylation has been reported in the

genetic regions associated with the expression of
amyloid precursor protein, presenilin 1 and -
secretase

Hypomethylation could theoretically lead to

increased transcription with the net result being
elevated expression of these proteins that appear to
be central to the development of Alzheimer’s disease
 DIET AND DNA METHYLATION

Methionine Vitamin
B12 Riboflavin

Folate Choline

Pyridoxine Zinc
Methyl Cofactors
donors

Methionine cycle
 Diet and DNA Methylation

Affect the activity

Tea of DNA
polyphenols methyltransferase
or its gene

Influence Influence
genetic predisposition
expression towards
disease
Affect DNA
Selenium methylation
status
 Diet and DNA Methylation
Programming of Methylation state Further
DNA methylation Fetal programming
• Transmitted through interaction
(genetic
mitosis imprinting)
and meiosis
•• Occur
DNA in utero through
maternal diet
•• Possible
Transmitted
with postnatal
environmental factors
methylation • Determined over
prior to generations
birth
Net effect
Affect disease
Epigenetic events • To ‘reset’ the basal
Additional
risk expression of genes epigenetic events
 Diet and DNA Methylation
Diabetes Dietary
Epigenetic environment
programming of ancestors
• During critical
The Barker times (germ
hypothesis: cell and early
Fetal embryo
malnutrition development)
Heart Metabolic Influencing
disease syndrome genetic
expression
today
 HISTONE MODIFICATION
Acetylation • Acetyl functional group is transferred from one
molecule to one another
2nd • Methyl groups are added to DNA
Methylation
epigenomic
mechanism:
Determine the
modification of Phosphorylation • transcription
Attachment of a phosphate group onto aof genes
protein
histone proteins
(mediate the • Attachment of ubiquitin to lysine residues on substrate
Ubiquitination
folding of DNA protein or itself
into chromatin
which supports
PolyADP-
ribosylation protein
Referred to as the
• Addition of one or more ADP-ribose moieties to a
and influences histone or chromatin
• Analogous to ubiquitination, addition of small
genomic
transcript)
Sumoylation code
ubiquitin-like modifiers

Biotinylation • The proses of covalently attaching biotin to a protein,

nucleid acid or other molecule
 HISTONE MODIFICATION
Highly alkaline proteins
found in eukaryotic cell
nuclei that package and
order the DNA into structural Five major
units called nucleosomes families of
histones
Histones H2A, H2B, H3 and
exist: H1/H5,
H4 → core histones
H2A, H2B, H3,
Histones H1 and H5 → the
and H4
linker histones

Histone proteins consist of a globular C-terminal domain and a

flexible N-terminal tail. The amino terminus protrudes from the
nucleosomal surface – lysines, arginines, serines and glutamates in the
N-terminus are targets for the modifications mentioned above.
 HISTONE MODIFICATION
The 2 most common epigenetic
Important for events
• DNA methylation
Regulation of • Histone modification
Reversible chromosome
segregation during
cell division (both
Enzymically meiosis and mitosis)
driven
Can interact and appear to be
DNA repair interdependent in some instances such that
methylation of DNA can trigger local histone
modifications
 DIET AND HISTONE MODIFICATION
Biotin
Folate
• Cofactor in fatty acid
synthesis by carboxylase
Zinc Choline enzymes
• Required for histone
biotinylation
Methyl donors
for histone Tryptophan and
Riboflavin methylation Methionine niacin
• Supply NAD for
polyADP-ribosylation of
Vitamin Vitamins histones (NAD is also
B12 B6 required for class III
HDACs)
 GENOMIC INSTABILITY

↑ the risk of some diseases

• DNA is potentially a target for damage Role in prevention
Dietary • Lead
of DNA to genomic instability and to
damage
factors and genome
its repairdamage
Conception

Lead to a
Uracil is mutagenic lesion
Methyl group incorporated into (by predisposing Damage to the
donors are low or DNA instead of that region to the DNA
unavailable thymine formation of
double-strand
breaks in the DNA)
 Genomic Instability
Breakage
Genome damage
mainly caused by Associated
Loss
faulty DNA
metabolism and
repair
with ↑
Nutrient
deficiency
Translocation
Strand breaks Cancer
in DNA
incidence
Oxidative
Chromosomal Linked to
stress
Amplification DNA
misrepair Degenerative diseases
• Excess
Alzheimer’s disease
Apoptosis • calories
Parkinson’s disease
Mitotic • Diabetes
malfunction • Vascular disease
Necrosis
 Genomic Instability
More
research
Associations between the
Protect against Elevate different measures of
genome genomic genomic damage
damage damage
Actual risk of developing
• Folate • Biotin specific diseases
• Nicotinic acid
• Calcium The identification of food
components that are
potentially protective
DIET AND NUTRITION CONSIDERATIONS/IMPACTS
To identify foods,
nutrients or bioactives • Critical to understand the effect of food
components on gene expression and genome
that can prevent or stability
delay the onset of • Critical to understand the impact of genetic
disease in population diversity within that population.
groups

• Need to determine the levels of genetic damage,

To personalize a • Need to determine the capability and extent of
dietary approach for genetic repair
an individual • Need to obtain a measure of that person’s genetic
background and the extent of epigenetic changes
 Diet and Nutrition Considerations/Impacts
Vast range of foods and Carcinogen
beverages consumed both metabolism (e.g.
across and within populations fiber)
Nutrition or diet
is an Signal DNA damage
exceedingly Differences in food transduction (e.g. (e.g. heterocyclic
preparation and processing phytoestrogens) amines)
complex
environmental
factor even Nutrients or
Varying amounts of protective bioactives
before we or potentially damaging can affect
consider the bioactives present with
complex varying bioavailabilities in Cell
interactions foods proliferation DNA repair (e.g.
with the (e.g. resveratrol) folate)
genome
Cell cycle and
Nutrient-nutrient interactions apoptosis (e.g.
within the human body butyrate, n–3
fatty acids)
Diet and Nutrition Considerations/Impacts
Per Genetics of the human host and
the profile of the gut microflora

person Interspecies interaction

To develop
dietary
1–2 kg of Nutrient-gene
and potential
Cross-feeding
approaches
bacteria gene-gene
to improve
health and
(500 interactions Quorum sensing
lower
species of disease risk
colonic Interaction with dietary substrates
microflora) The products released and their
relationships with the host’s
mucosal layer and immune system
 Diet and Nutrition Considerations/Impacts
Example of the link between microflora and epigenetic effects
To develop foods that may be protective against disease
Affect histone Influencing
acetylation gene
Need to become
Bacteria in themore innovative with delivery mechanisms
Producing expression
colon butyrate Elimination of
Promote
of the intestine wherecells
In order to deliver bioactives to targeted sitesapoptosis theirwith DNA
release will maximize the physiological response damage

Microencapsulation Protect the bioactive until a trigger releases

its payload at the desired site

Examples:
Promote apoptosis
Resists some upper intestinal digestion and
Butyrate starch ester reaches the colon where the butyrate is
released where it may help to Potentially minimize
the risk of developing
colorectal cancer
Diet and Nutrition Considerations/Impacts
Genetic differences in sensory sensitivities
Dietary
behaviors
Influence what is consumed

Diet or
food Attitudes and beliefs
Cultural
issues
Food Lifestyle
choices factors
Impinge on the acceptance of these new
biomic technologies and foods developed
from our greater understanding of
nutrition at the molecular level
Diet and Nutrition Considerations/Impacts
Protective
Nutrients effect Depend on the genetic
background of the individual
Nutrients or Nonprotective
bioactives effect

To tailor diets for specific genetic backgrounds of

individuals
• Need to be able to have the appropriate cost-effective
diagnostics and the accompanying capabilities and technologies
to predict disease susceptibility and identify individuals who need
more or less of particular nutrients or bioactives.
 CONCLUSION
Dietary intake
Specific • For the prevention and even
treatment
→ more of aof different
nutrigenomic
• A complex social and bioactive mixture
not always better
disease states
potentially protective nutrient is

approaches
Different genetic polymorphisms

• Affect disease risk → dietary recommendations may need to be modified

accordingly
• It is increasingly unlikely that
One thing
Individual that
measures oneepigenetic
(genetic variation, set ofchanges
dietary
&
is emerging recommendations
genome stability, nutrient metabolism & gut flora populations) is going to

suitdiets,
• We should have tailored preventative allespecially
of usifinourthe
diet isfuture
likely to affect
gene expression and hence health outcomes of our successors.