Lorena Bouzas Alfonsín Advanced Genetics 2017-2018 NUTRIGENOMICS Lorena Bouzas Alfonsín Advanced Genetics 2017-2018

Contents Introduction. Nutritional genomics Nutrigenetics Nutritional epigenomics Nutrigenomics Nutrigenomics tools: present and future

NUTRITIONAL EPIGENOMICS Nutritional genomics Interactions genes - nutrients survival and reproduction NUTRIGENETICS NUTRIGENOMICS NUTRITIONAL EPIGENOMICS

greater risk of lung cancer Nutrigenetics Genetic changes influence the response to nutrients Example reduce incidence of cancer Polymorphism at codon 198 Substitution of proline to leucine Pro/Pro Pro/Leu 80% greater risk of lung cancer Leu/Leu 130%

Nutritional epigenetics Nutrients cause modifications in the genome that don’t involve changes in the DNA sequence Example Vitamins B12, B6, niacin, riboflavin and minerals Methylated DNA gene expression is silenced Nutrients involved in DNA methylation SAM for genome methylation Nutritional deficiencies alter methylation patterns Alteration of gene expression

Nutrigenomics Nutrigenomics Nutrients influence gene expression, mainly through transcriptions factors (TFs)

preventative against cardiovascular disease Nutrigenomics Peroxisome proliferation activated receptors (PPARs) - Fatty acid metabolism - Ketogenesis - Gluconeogenesis - Amino acid metabolism influence expression of genes involved in ω-3 and ω6 fatty acids Vitamin A derivates Fatty acid synthesis Fatty acid oxidation lipoproteins cholesterol Modulate genes involved in the metabolism of Fibrates plasma triglycerides HDL cholesterol preventative against cardiovascular disease Kauwell, G. P. A., 2005. Emerging concepts in nutrigenomics: a preview of what is to come. Nutrition in Clinical Practice, 20(1), pp. 75-87.

Nutrigenomics Müller, M. and Kersten, S., 2003. Nutrigenomics: goals and strategies. Nature Reviews Genetics, 4(4), pp. 315-322.

Nutrigenomics Natural compounds have effects on cancer cells through targeting multiple cellular signalling pathways Akt NF-κB Wnt MAPK AR ER Notch p53 Examples Epigallocatechin gallate (EGCG) a polyphenol presents in green tea Inhibits phosphorylation of: - Her-2/neu receptor - Epidermal growth factor receptor (EGFR) Reduce NF-κb pathway associated with breast cancer

Inhibitory effects on cancer cell growth Nutrigenomics Indol-3 carbinol (I3C) from glucosinolates of family Cruciferae Modulate genes related to: control of cell proliferation cell cycle apoptosis signal transduction oncogenesis Curcumin presents in turmeric Antiinflammatory and antioxidant effects Cancer chemopreventive agent Resveratrol phytoalexin present in grapes, mulberries and peanuts Lycopene present in tomatoes Inhibitory effects on cancer cell growth Inhibit growth of various cancer cells - Induce apoptotic cell death

A traditional hypothesis-driven approach A system biology approach Nutrigenomic tools Genomic tools can be used in two complementary strategies: A traditional hypothesis-driven approach A system biology approach Genome wide discovery of target genes and the regulatory pathways through which diet influences homeostasis Identify molecular biomarkers associated with early changes of homeostatic control

Nutrigenomic tools Present Main investigate strategies to discover dietary target genes and the pathways affected: Transgenic and knockout mouse models In vitro experiments - Inducible expression systems - RNA interference (RNAi) - Transdominant negative adenoviral constructs (tdnAd) Modulate expression levels and functionality of nutrient-sensor systems Müller, M. and Kersten, S., 2003. Nutrigenomics: goals and strategies. Nature Reviews Genetics, 4(4), pp. 315-322.

Nutrigenomic tools Future Collect “healthy” diet-related expression signatures Compare with stress signatures derived from experiments Identify early biomarkers that could warn about future serious conditions Design dietary interventions to: - prevent these conditions in risk groups regain homeostatic control Müller, M. and Kersten, S., 2003. Nutrigenomics: goals and strategies. Nature Reviews Genetics, 4(4), pp. 315-322.

References DeBusk, R., 2010. The role of Nutritional Genomics in Developing an Optimal Diet for Humans. Nutrition in Clinical Practice, 25(6), pp. 627-633. Farhud, D. D. and Zarif Yeganeh, D., 2010. Nutrigenomics and Nutrigenetics. Iranian Journal of Public Health, 39(4), pp. 1-14. Kauwell, G. P. A., 2005. Emerging concepts in nutrigenomics: a preview of what is to come. Nutrition in Clinical Practice, 20(1), pp. 75-87. Müller, M. and Kersten, S., 2003. Nutrigenomics: goals and strategies. Nature Reviews Genetics, 4(4), pp. 315-322. Sarkar, F. H., Yiwei, L., Li, Y., Wang, Z., Kong, D., 2009. Cellular signaling perturbation by natural products. Cellular signaling, 21(11), pp. 1541-1547. Singh-Dang, T., Walker, M., Ford, D. and Valentine, R. A., 2014. Nutrigenomics: the role of nutrients in gene expression. Periodontology 2000, 64, pp. 154-160.