1. Introduction to Nutrigenomics
Lecture 26
April 27, 2015
Dr. Quadro

2. 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.

3. Nutrigenomics The study of the effects of diet on the activity of
individual’s genes
and health

4. From Dawson KAS, 2007

5. From Dawson KAS, 2007

6. From Dawson KAS, 2007

7. CH3-DNA DNA mRNA Proteins Genomic Transcription and translation
Epigenomic
CH3-DNA
Genomic Transcription and translation
DNA
mRNA
Proteins
Enzymes, structural,
transport, signaling caused by phosphorylation, glycosylation, etc.
Bioactive
Food
Components

8. Effects on: -Transcription -DNA structure
Dietary constituents can affect gene expression and/or genome structure
Effects on:
-Transcription
-DNA structure

9. Structure of Cells
Plasma membrane
Cytoplasm
Nucleus (compartment where DNA is stored)

10. 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

11. Deoxyribonucleic Acid (DNA)
Is the molecule of life
It contains all the information
needed to build an organism
The genetic material (

12. 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

13. DNA is a chain of nucleotides
Nucleotides are composed of:
-Sugar-deoxyribose
-Phosphate group
-Base-one of four types: adenine (A), thymine (T)
guanine (G), cytosine (C)

14. Structure of DNA C T G A
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’ 

15. RNA is a chain of nucleotides
-Single chain of nucleotides
-Nucleotides are composed of:
Sugar-ribose
Phosphate group
Base-one of four types: adenine (A), uracile (U)
guanine (G), cytosine (C)

16. Gene expression: the flow of genetic
information from DNA to protein via RNA

17. 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

18. The protein creates the phenotype
The genetic information is coded by the sequence of the nucleotides
DNA
RNA
Protein
The protein creates the phenotype

19. The genetic information is coded by the sequence of the nucleotides
expression
Transcription
DNA
RNA
Protein
Translation

20. Nutrigenomics
Diet
Genotype
Health or Disease
Phenotype

21. Molecular nutrition

22. Genes → Metabolism → Function
Key Points:
Everyone has the same genes in slightly different
versions, called “gene variants”
It’s these variations that distinguish one person from another
Different variations (gene variants) lead to different metabolism
and function between individuals due to different nutrient
requirements that result from the specific gene variants one has

23. Many genes are regulated by diet through the interaction of a given food component with a specific receptor or set of receptors
Diet plays a crucial role in chronic diseases

24. …..Again Transcription
Genes are flanked by untranscribed regions called Promoters.
These are DNA sequences near the beginning of genes that signal RNA polymerase where to begin transcription.
Gene of interest
PROMOTER
Beginning of transcription
RNA Polymerase

25. Transcriptional regulation by vitamin A
CoA
HAT RA
NCoR
Sin3A
HDAC
RAR
RXR
Gene of interest
RARE
PROMOTER

26. Transcription-factor pathways mediating nutrient-gene interaction

27. 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

28. PPARs are ligand activated transcription factors
Function
fatty acids
9 cis retinoic acid
PPAR
Protein synthesis - +
PPAR
RXR
Gene
DNA transcription
AGGTCAaAGGTCA
Response element

29. Fatty acid oxidation genes FA synthesis Triglyceride synthesis
Why are PUFAs healthy?
SREBP1 SP1/NF-Y
PPAR + -
PPRE
Fatty acid oxidation genes
Lipogenic genes
FA synthesis Triglyceride synthesis
b-Oxidation
VLDL-TG

30. Estrogen Receptors
Two Different Estrogen Receptors Recent studies have revealed the existence of two distinct estrogen receptors in our bodies: ERa and ERb. While they both bind estrogen as well as other agonists and antagonists, the two receptors have distinctly different localizations and concentrations within our body. Structural differences also exist between the two. allowing for a wide range of diverse and complex processes to take place. The following diagram, adapted from the Gustafsson review (1999), shows the distribution of ERa and ERb

31. Estrogen Receptors ER-a ER-b (Kuiper et al. 1996)
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.

32. ER effects on different cell types

33. Phytoestrogens
Aherne and O’Brien, Nutrition 18:75-81.

34. Dietary Sources of Phytoestrogens

35. 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.

36. Phytoestrogens in Human Health
Cancer prevention
Post-menopausal supplement
Prevention of osteoporosis
Cardiovascular health
Fertility
Breast enhancement

37. Other examples Omega-3 downregulation of cytokine genes
Glucosinolate upregulation of Phase II enzymes
Cruciferous vegetables are relatively unique in our diet as a source of glucosinolates, a series of plant secondary metabolites derived from amino acids with a thioglucose and an N-sulfate moiety.

38. Diet May Influence Epigenetics
Epigenetics: the study of heritable changes in gene expression that occur without a change in DNA sequence.
DNA methylation- CpG islands
Histone posttranslational modifications:
Acetylation of lysines
Methylation of lysines and arginines
Phosphorylations of serines and threonines
ADP-ribosylation of glutamic acids
Ubiquitination of lysine residues
Sumolyation of lysine residues
Biotinylation of lysines
Recently, in human cells small-interfering RNAs (siRNAs) have been shown to mediate transcriptional gene silencing (Morris KV, Cell Mol. Life Sci. 62: , 2005).

39. Maternal supplementation with
LTR Hypomethylated
LTR Hypermethylated
Maternal supplementation
with
zinc
methionine
betaine
choline,
folate
B12
Yellow Mouse
Agouti Mouse
High risk cancer, diabetes, obesity & reduced lifespan
Lower risk of cancer, diabetes, obesity and prolonged life
Cooney et al. J Nutr 132:2393S (2002)

40. From Dawson KAS, 2007

41. From Dawson KAS, 2007

42. From Dawson KAS, 2007

43. Transcriptomic Studies Are Providing Clues About Molecular Targets for Specific Food Components
Corn Oil Fish Oil Olive Oil
Davidson et al., Cancer Res. 64: , 2004

44. 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'.
Müller M,  Kersten S. Nutrigenomics: Goals and Perspectives. Nature Reviews Genetics 4, (2003)

45. Nutrigenomics
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, (2003)

46. Nutrigenomics Foods Nutrition Target Genes Mechanisms Pathways
Signatures Profiles Biomarkers
Molecular Nutrition & Genomics
Nutritional Systems 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
Small research groups Small budgets
Large research consortia Big money
Complexity

47. From Dawson KAS, 2007

48. Influence of diet on health depends upon an individual’s genetic makeup
“Personalized nutrition”- diets based upon genotype, nutritional requirements and status
It prevents and mitigates chronic diseases

49. Personalized diets?

50. Diet and genes Changing the environment can change outcomes by
influencing the goodness-of-fit of a genotype for that
particular environment

51. Climate change=Diet change
Diet and genes
Jurassic
Climate change
Extinction
Climate change=Diet change