Introduction to Nutrigenomics

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Introduction to Nutrigenomics

• Lecture 22
• April 14, 2008
• Dr. Quadro

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Improper diets are risk factors for diseases

• Epidemiological studies associate specific foods
  with incidence and severity of obesity, diabetes,
  cardiovascular, cancer and/or other chronic
  diseases.

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Nutrigenomics

• The study of the effects of diet on the activity
  of individuals genes and health

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• Dietary constituents can affect gene expression
  and/or genome structure

Effects on -Transcription -DNA structure
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Structure of Cells

• Plasma membrane
• Cytoplasm
• Nucleus (compartment where DNA is stored)

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Functions of Nucleus

• Keeps the DNA molecules of eukaryotic cells
  separate from metabolic machinery of cytoplasm
• Makes it easier to organize DNA and to copy it
  before parent cells divide into two daughter
  cells

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Deoxyribonucleic Acid (DNA)
Is the molecule of life It contains all the
information needed to build an organism The
genetic material
(http//siggy.chem.ucla.edu/tim/chemistry/DNA.jpg
)
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Role of the genetic material

• A genetic material must carry out two jobs
  duplicate itself and control the development of
  the rest of the cell in a specific way.
• -Francis Crick

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DNA is a chain of nucleotides

• Nucleotides are composed of
• -Sugar-deoxyribose
• -Phosphate
• -Base-one of four types adenine (A), thymine
  (T)
• guanine (G),
  cytosine (C)

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Structure of DNA
G
C
Two nucleic acid chains running in opposite
directions The two nucleic acid chains are
coiled around a central axis to form a double
helix For each chain the backbone comes from
linking the pentose sugar bases between
nucleotides The bases face inward and pair in a
highly specific fashion with bases in the other
chain A only with T, G only with C Because of
this pairing, each strand is complementary to the
other 5 ACGTC 3 3 TGCAG 5 
A
T
C
G
T
A
G
C
A
T
C
G
T
A
G
C
A
T
C
G
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A gene molecular definition

• A gene is a segment of DNA which codes the
  formation of RNA which in turn directs the
  formation of a protein.

Genotype the genetic information
Phenotype the external features
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RNA is a chain of nucleotides
-Single chain of nucleotides

• -Nucleotides are composed of
• Sugar-ribose
• Phosphate
• Base-one of four types adenine (A), uracile
  (U)
• guanine (G),
  cytosine (C)

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Gene expression the flow of genetic information
from DNA via RNA to protein
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The genetic information is coded by the sequence
of the nucleotides
RNA
Protein
The protein creates the phenotype
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The genetic information is coded by the sequence
of the nucleotides
RNA
Protein
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Nutrigenomics
Diet
Health or Disease
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Molecular nutrition
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Many genes are regulated by dietthrough the
interaction of a given food component with a
specific receptor or set of receptors
Diet plays a crucial role in chronic diseases
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..Again Transcription
Genes are flanked by untranscribed regions called
Promoters. This are DNA sequences near the
beginning of genes that signal RNA polymerase
where to begin transcription
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Transcriptional regulation by vitamin A
RAR
RXR
Gene of interest
RARE
PROMOTER
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Transcription-factor pathways mediating
nutrient-gene interaction
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Functions of PPARs
PPARa
PPARg
PPARb

• Nutrient metabolism
• (lipid, glucose, AAs)
• - Proliferation
• - Inflammation

- Lipid and glucose metabolism - Cell cycle
control - Inflammation
- Lipid metabolism - Keratinocyte
differentiation - Inflammation
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PPARs are ligand activated transcription factors
Function
9 cis retinoic acid
fatty acids
PPAR
Proteinsynthesis
-

PPAR
RXR
DNA transcription
Gene
AGGTCAaAGGTCA
Response element
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Why are PUFAs healthy?
SREBP1SP1/NF-Y
PPAR

-
Fatty acid oxidation genes
Lipogenic genes
FA synthesisTriglyceride synthesis
b-Oxidation
VLDL-TG
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Estrogen Receptors
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Estrogen Receptors

• ER-a
• Uterus, testis, pituitary, ovary, epididymis, and
  adrenal gland.
• ER-b (Kuiper et al. 1996)
• brain, kidney, prostrate, ovary, lung, bladder,
  intestine, and epididymis.
• Membrane localized ER (Pietras and Szego, 1997)
• ER-a and b differ in C-terminal ligand binding
  domains and N-terminal transactivation domains.
  Highest homology in DNA binding domain.

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ER effects on different cell types
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Phytoestrogens
Aherne and OBrien, 2002. Nutrition 1875-81.
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Dietary Sources of Phytoestrogens
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Soy Phytoestrogens

• Genistein, daidzein, coumesterol, and equol bind
  to and transactivate both ER-??and ER-?
  (0.1-10mM)
• Genistetin has a higher affinity for ER?.
• Soy PEs effect cell cycle progression, growth,
  and differentiation. Have antioxidant and
  antiangiogenic activities.

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Phytoestrogens in Human Health

• Cancer prevention
• Post-menopausal supplement
• Prevention of osteoporosis
• Cardiovascular health
• Fertility
• Breast enhancement

References Kurzer, 2003. J. Nutr. 133
1983S-1986S. Benassayag, et al., 2002. J.
Chromatogr.B 777233-248.
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Nutrigenomics

• Nutrigenomics attempts to study the genome-wide
  influences of nutrition.
• From a nutrigenomics perspective, nutrients are
  dietary signals that are detected by the cellular
  sensor systems that influence gene and protein
  expression and, subsequently, metabolite
  production.
• Patterns of gene expression, protein expression
  and metabolite production in response to
  particular nutrients or nutritional regimes can
  be viewed as 'dietary signatures'.
• Nutrigenomics seeks to examine these dietary
  signatures in specific cells, tissues and
  organisms, and to understand how nutrition
  influences homeostasis.
• Nutrigenomics aims to identify the genes that
  influence the risk of diet-related diseases on a
  genome-wide scale, and to understand the
  mechanisms that underlie these genetic
  predispositions.

Müller M,  Kersten S. Nutrigenomics Goals and
Perspectives. Nature Reviews Genetics 4, 315 -322
(2003)
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Nutrigenomics
FoodsNutrition
Target GenesMechanismsPathways
SignaturesProfilesBiomarkers
Molecular Nutrition Genomics
NutritionalSystems Biology

• Identification of dietary signals
• Identification of dietary sensors
• Identification of target genes
• Reconstruction of signaling pathways

• Measurement of stress signatures
• Identification of early biomarkers

Large research consortiaBig money
Small research groupsSmall budgets
Complexity
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• Influence of diet on health depends upon an
  individuals genetic makeup

Personalized nutrition- diets based upon
genotype, nutritional requirements and
status It prevents and mitigate chronic
diseases
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Personalized diets?
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Diet and genes