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Nutritional epigenomics of the metabolic syndrome Periconceptual, fetal, neonatal, lifelong and transgenerational

Nutritional epigenomics of the metabolic syndrome Periconceptual, fetal, neonatal, lifelong and transgenerational . Pr. Claudine Junien - Inserm U781, Hôpital Necker-Enfants Malades, Paris France . Developmental, environmental origin of the MetS. Indulgent lifestyle Energy imbalance

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Nutritional epigenomics of the metabolic syndrome Periconceptual, fetal, neonatal, lifelong and transgenerational

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  1. Nutritional epigenomics of the metabolic syndrome Periconceptual, fetal, neonatal, lifelong and transgenerational Pr. Claudine Junien - Inserm U781, Hôpital Necker-Enfants Malades, Paris France

  2. Developmental, environmental origin of the MetS Indulgent lifestyle Energy imbalance Oxidative stress Aging … Epigenetics CH3 CH3 CH3 Previous generations experiences behavior, nutrition Metabolic, neuronal malprogramming Oscillatory, circadian, seasonal rhythms perturbation Chromosome/DNA damage Mitochondrial dysfunction Genotype

  3. Epigenetic programming dynamics Environmental transient / permanent impacts IG Develop- -ment. Amino acid medium Diet-induced obesity Carcinogenes Maternal care FCS medium M16 medium Synth diets Transposons Litter size Folates Folates Agouti Crop TGE Genes Zygote Gametes Methylation Gonadal ridge Primordial germ cells-gametes Primordial germ cells Imprinted genes Somatic tissues Zygote Gametes Embryo- adult cells, tissues Methylation Aging Genes, transposons Gastrula Extra- Embryonic tissues Blastocyst ? Adult Implantation Lactation Fertlization Weaning Puberty Birth SGP Peri- conception (Gallou-Kabani & Junien Diabetes 2005)

  4. I CIRCADIAN-LIFELONG epigenetic deteriorations Pr. Claudine Junien - Inserm U781, Hôpital Necker-Enfants Malades, Paris France

  5. The epigenetic connection • Circadian rhythms in H3 acetylation and RNA pol II binding of the core clock • Clock co- with EZH2 polycomb, HAT p300 • Rythmic gene expression : ± 10% or > genes : • Temporal coactivator recruitment and HAT-dependent chromatin remodeling on the promoter of clock controlled genes (Curtis et al 2004; Etchegaray et al 2003, 2006) Circadian nutritional epiphenotype ? Oscillatory, circadian, seasonal rhythms Sleep-wake Feeding-fasting Thermogenesis (Staels B Nat Med 2006) (Turek et al 2005; Rudic et al 2004; Oishi et al 2005; Shimba et al 2005; Inoue et al 2005; Zvonic et al 2006; Kreier F 2003)

  6. Atherogenesis: IFN PDGFA MMP2-7-9 TIMP ICAM ERa-b EC-SOD HSD11B2 P53… (Hiltunen & Yla-Herttuala ATVB 2003) Gene-specific aberrant methylation Age-related diseases Normal colon (Issa et al. PNAS 1996)

  7. Genome-wide methylation Age- and diet-related diseases Apoe-/- mice WT 4-weeks old Human arteries Apoe-/- mice arteries 6-months old (Hiltunen & Yla-Herttuala ATVB 2003) (Lund et al. JBC 2004)

  8. Genetic basis for epigenetic instability Susceptibility to environment/ diets ? CIMP : CpG island methylator phenotype MTHFR DNMT ? Etc…

  9. II : DOAD Developmental Origin of Adult Diseases Pr. Claudine Junien - Inserm U781, Hôpital Necker-Enfants Malades, Paris France

  10. Amino-acids Thr, Met, gly Tau etc.. Sugar Glucose, fructose Fatty acids SAT, MUFA, PUFA TFA HFD/LFD/C LP/C C HFD/LFD/C LP/C HHC HFD/LFD/C HFD/C HHC/C Lifespan Hypertension Glucose Metabolism Liver methyl. Pancreas devel Membrane FA. Hyperinsulinism Hypertension Obesity Preference (CH/F) Hyperinsulinism Obesity Preference (CH/F) • DOAD : • Diet and/or specific dietary component Diet Lipid-rich Carbohydrate-rich Protein restriction gestation suckling weaning Outcome (Armitage et al, J. Physiol 2004)

  11. 1 - Can we identify epigenetic alterations responsible for nutritional malprogramming ? 2 - Are they reversible ? How : diet? drugs? lifestyle? …

  12. F1HF n=87 83% n=106 HFD • p = 0.001 17% F2HF 57% 43% HFD HFD n=35 n=47 Sex-specific adaptive resistance to a high fat diet   Crossing and diet scheme F0 Mating F1 Gestation-Lactation weaning Adult Mating F2 Gestation Lactation Weaning A « satiety » phenotype Adult (Gallou-Kabani et al 2006)

  13. Monoallelic Expression Maternal allele silenced 0 - 10 % Paternal allele expressed 90 - 100 % Biallelic expression Non-expression Plausible candidates for adaptation ? Imprinted genes ? Coevolution: Placenta and Imprinting (mammals) Fetal and placental growth Brain development - behaviors Postnatal nutritional adaptation Co-adaptation mother-infant (evolution) Epigenetic lability by nutrients Non erasing of epigenetic marks (except gametes) Altered imprinting syndromes and obesity, T2D Buffering or « rheostat » System (Pembrey M. 1996, Junien C. 2000, Beaudet A. 2002, Pembrey M. 2002)

  14. Dgat 1 Gata 3 Acads Gata 1 Decorin • Esx1 Igf 2 Riken cDNA 60 Imprinted genes Igf 2 Riken cDNA Pparg Grb10 Nr1h3 Nnat Slc2a5 Kcnq 1 Slc2a5 Ube3a Decorin • Esx1 Grb10 Nr1h3 Nnat Satiety phenotype 1 - Custom microarrays « Epigenetics - energy homeostasis » 500 genes Placenta Liver (Vigé et al CGR 2005)

  15. F1C F1HF F2-S F2-R F1C F1HF F2-S F2-R Satiety phenotype 2 - Candidate gene approach Q-RT-PCR Females 28 genes stomach, muscle, adipose tissue, hypothalamus, liver Peg3 Peg1 & Peg 3: Paternally expressed Imprinted genes increased in DIO Peg1: Adipocyte size marker Peg1 (Moraes et al 2003; Takahashi et al 2004; Curley et al 2004)

  16. P = 0.02 P = 0.03 Hypomethylation 0,45 0,4 0,35 Genome-wide: Luminometric Methylation Assay (LUMA) Satiety phenotype, liver : Hypomethylation F1HF -> adaptation F2 0,3 0,25 Hypermethylation 0,2 F1N F1HF F2HFR F2HFS 0,15 Histones alterations • Candidate genes: • Chromatin ImmunoPrecipitation(ChIP) • Genome-wide: • ChIP Satiety phenotype 3 - Epigenetic signatures? DNA methylation Candidate genes : Bisulphite-Pyrosequencing - Liver : Scd1, Snrpn = no difference..so far - Adipose tissue : Lep, Peg1, Peg3 = no difference (Karimi et al, Epigenetics, 2006, Umlauf et al, Nat Genet, 2006)

  17. Can we identify placental markers for early events of malprogramming, tracing back the in utero nutritional and metabolic course?

  18. DBA/2 C57B/6 X C57B/6 X DBA/2 E 0.5 Control vs ≠ diets E 15.5 Maternally expressed Slc22a3 Paternally expressed Rtl1 (Peg11) Epigenetic signatures MetS : Placental markers of nutritional and metabolic epigenetic malprogramming

  19. III Transgenerational effects Pr. Claudine Junien - Inserm U781, Hôpital Necker-Enfants Malades, Paris France

  20. Maternal Paternal Developmental programming Germ cells Gametes Germ cells Gametes Modes of transmission

  21. Methylation : • 25 sequences Male transmission on 4 generations Endocrine disruptors & fertility: • Apoptosis • Sperm • - number • - mobility • (Anway et al Science 2005)

  22. First generation High-carbohydrate diet during suckling Second generatiion Control diet (HC mother) Hyperinsulinism • Maternal effect • Gestation-postnatal/lactation (Srinivasan et al Diabetes 2003)

  23. XX XY Y X T2D, mortality : only paternal grandparents ! GP GM (Kaati et al 2002; Pembrey et al, 2005) (Kaati et al 2002)

  24. Acknowledgements Network ATC-Nutrition – PRNH Inserm Inra Coord C. Junien C Junien (Inserm Paris) J. P. Jaïs (SBIM, Paris), H. Vidal (Inserm, Lyon) D. Langin (Inserm, Toulouse) K. Clément (Inserm, Paris) J.D.Zucker (Paris XIII) Bioinformatics -statistics JP Jais (Hôp.Necker SBIM) Beta oxydation fatty acids F. Djouadi, J. Bastin (Inserm U393, Paris) Desaturation index ,FFA P.Gambert (Inserm, Dijon) Lipid fraction analysis J. Fruchart (Inserm, Lille) LDL, HDL, TG, C. Boileau, J.P. Rabès (Biochimie Hôp.A. Paré, Boulogne) Absorptiometry P. Letteron, B. Fromenty (Hôp.Bichat CERFI Paris) Microarray fabrication L.Talini, M.C. Pottier (Genescore, ESPCI,Paris) Energy metabolism (Ind Calorimetry) P. Even, D. Tomé, C. Larue (INA-PG, Paris) Methylation by pyrosequençing/LUMA I Gut, J. Tost (CNG, Evry) T. Ekstrom (Karolinska, Suède U383-U781 C Gallou-Kabani, A Vigé, E Boudadi, H Pilet, MS Gross, A Belaid, C. Junien Placenta network Coord C. Junien (Paris) F. Andreelli (Paris) C. Levy-Marchal (Paris) MA Charles (Villejuif) A Vambergue (Lille) I Fajardy (Lille) D Vieau (Villeneuve d’Asq) B. Reusens (Louvain) G.Moore (Londres) R. Frydman (Paris) Y. Dumez (Paris) D. Vaiman (paris) J Tost (Evry) Financing INRA, ATC- INSERM, PRNH INSERM, AFD, AFERO I.B. Delessert, Lab Fournier, Nestlé

  25. Promotor ? Proportional to the adipocyte size ? Differentially methylated Region (DMR) Adaptation to caloric intake heritable ? Epigenetic patterns Involvement of an imprinted gene ?

  26. -Validity of epigenetic mechanisms as causative agents in the development of nutritionally linked chronic disease? • -How are additional models developed, when and how do we study them? • -What will be the effective methodologies in terms of culture models and molecular techniques for determining epigenetic marks? • -How do we explore the nutritional factors and their effects on C1 metabolism? • -Can human cell-based models be used effectively to study epigenetic programming in vitro? • -What kind of environmental variables initiate the emergence of an epigenetic phenotype? • -Is there a genetic basis to epigenetic inheritance? Are certain genotypes more prone to epigenetic programming? • -What kind of epigenetic modifications could be physiologically advantageous? • -How do you identify epigenetic biomarkers? • -What are some simple model systems? Phenotype? • -How do you determine the modes of transmission of some epigenetic phenomena? • -What are the molecular methods that can most efficiently identify epigenetic changes? • In utero vs. postnatal impacts?

  27. Plausible candidates for resistance to HFD ? Spatiotemporal windows ? Markers ? Placenta ? WBC?

  28. -Is there a genetic basis to epigenetic inheritance? Are certain genotypes more prone to epigenetic programming? • -How do you determine the modes of transmission of some epigenetic phenomena? • -What kind of environmental variables initiate the emergence of an epigenetic phenotype?

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