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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 Oxidative stress Aging … Previous generations experiences behavior, nutrition Epigenetics CH3 CH3CH3 Genotype Oscillatory, circadian, seasonal rhythms perturbation Metabolic, neuronal malprogramming Mitochondrial dysfunction Chromosome/ DNA damage Epigenetic programming dynamics Environmental transient / permanent impacts IG Transposons Genes Gametes Methylation Embryoadult cells, tissues Somatic Zygote tissues Genes, transposons Aging Gastrula Blastocyst ExtraEmbryonic tissues Primordial germ cellsgametes Methylation Zygote Gametes Imprinted genes Primordial Gonadal ridge germ cells (Gallou-Kabani & Junien Diabetes 2005) I CIRCADIAN-LIFELONG epigenetic deteriorations Pr. Claudine Junien - Inserm U781, Hôpital Necker-Enfants Malades, Paris France Circadian nutritional epiphenotype ? The epigenetic connection Oscillatory, circadian, seasonal rhythms Sleep-wake Feeding-fasting Thermogenesis • Circadian rhythms in H3 acetylation and RNA pol II binding of the core clock • Clock coHAT p300 (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) with EZH2 polycomb, •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) Gene-specific aberrant methylation Age-related diseases Normal colon Atherogenesis: IFN PDGFA MMP2-7-9 TIMP ICAM ERa-b EC-SOD HSD11B2 P53… (Issa et al. PNAS 1996) (Hiltunen & Yla-Herttuala ATVB 2003) Genome-wide methylation Age- and diet-related diseases Human arteries Apoe-/mice arteries Apoe-/mice WT 4-weeks old 6-months old (Hiltunen & Yla-Herttuala ATVB 2003) (Lund et al. JBC 2004) Genetic basis for epigenetic instability Susceptibility to environment/ diets ? CIMP : CpG island methylator phenotype MTHFR DNMT ? Etc… II : DOAD Developmental Origin of Adult Diseases Pr. Claudine Junien - Inserm U781, Hôpital Necker-Enfants Malades, Paris France DOAD : Diet and/or specific dietary component Diet Protein restriction Carbohydrate-rich Lipid-rich Amino-acids Thr, Met, gly Tau etc.. Sugar Glucose, fructose Fatty acids SAT, MUFA, PUFA TFA LP/C C HFD/LFD/C suckling LP/C HHC HFD/LFD/C weaning HFD/C HHC/C HFD/LFD/C Lifespan Hypertension Glucose Metabolism Liver methyl. Pancreas devel Membrane FA. Hyperinsulinism Obesity Preference (CH/F) Hyperinsulinism Hypertension Obesity Preference (CH/F) gestation Outcome (Armitage et al, J. Physiol 2004) 1 - Can we identify epigenetic alterations responsible for nutritional malprogramming ? 2 - Are they reversible ? How : diet? drugs? lifestyle? … Sex-specific adaptive resistance to a high fat diet Crossing and diet scheme F0 Mating F1HF F1 Gestation-Lactation weaning 83% Rˇsistante Sensible n=87 n=106 Adult HFD Mating F2 17% F2HF Gestation 57% 1er trim. 2e trim. Lactation Weaning HFD Adult p= 0.001 n=35 (Gallou-Kabani et al 2006) HFD n=47 43% A « satiety » phenotype Plausible candidates for adaptation ? Imprinted genes ? Coevolution: Placenta and Imprinting (mammals) Monoallelic Expression Maternal allele silenced 0 - 10 % Paternal allele expressed 90 - 100 % Fetal and placental growth Brain development - behaviors Postnatal nutritional adaptation Co-adaptation mother-infant (evolution) Epigenetic lability by nutrients Non-expression Biallelic expression 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) Satiety phenotype 1 - Custom microarrays Dgat 1 Gata 3 60 Imprinted genes « Epigenetics energy homeostasis » 500 genes Decorin Esx1 Acads Gata 1 Decorin Esx1 Igf 2 Riken cDNA Pparg Igf 2 Riken cDNA Grb10 Grb10 Nr1h3 Slc2a5 Kcnq 1 Slc2a5 Placenta Nnat Nr1h3 Ube3a Liver (Vigé et al CGR 2005) Nnat Satiety phenotype 2 - Candidate gene approach Q-RT-PCR Females 0,6 stomach, muscle, adipose tissue, hypothalamus, liver Peg3 0,4 0,3 Peg1 & Peg 3: 0,2 Paternally expressed 0,1 0 FN F1C F1HF F1HF F2HF sen F2HF res F2-S F2-R Imprinted genes increased in DIO 60 Peg1: 50 Peg1 Unitˇ arbitraire 28 genes Unitˇ arbitraire 0,5 Adipocyte size marker 40 30 20 10 0 FN F1C F1HF F1HF F2HF sen F2HF res F2-S F2-R (Moraes et al 2003; Takahashi et al 2004; Curley et al 2004) Satiety phenotype DNA methylation Candidate genes : Bisulphite-Pyrosequencing - Liver : Scd1, Snrpn = no difference..so far - Adipose tissue : Lep, Peg1, Peg3 = no difference 70 % de méthylation 3 - Epigenetic signatures? Femelles Peg1_MSP6 Tissu Adipeux 80 60 F1N F1HF F2HF Res F2HF Sen 50 40 30 20 10 0 Position 1 Position 2 Position 3 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 0,15 F1N F1HF F2HFR F2HFS Histones alterations Candidate genes: Chromatin ImmunoPrecipitation(ChIP) Genome-wide: ChIP (Karimi et al, Epigenetics, 2006, Umlauf et al, Nat Genet, 2006) Can we identify placental markers for early events of malprogramming, tracing back the in utero nutritional and metabolic course? DBA/2 X C57B/6 C57B/6 X DBA/2 MetS : Placental markers of nutritional and metabolic epigenetic malprogramming E 0.5 Control vs ≠ diets E 15.5 Maternally expressed Slc22a3 Paternally expressed Rtl1 (Peg11) Epigenetic signatures III Transgenerational effects Pr. Claudine Junien - Inserm U781, Hôpital Necker-Enfants Malades, Paris France Modes of transmission Paternal Maternal Germ cells Developmental Germ cells Gametes programming Gametes Male transmission on 4 generations Endocrine disruptors & fertility: Apoptosis Sperm - number - mobility Methylation : 25 sequences (Anway et al Science 2005) Maternal effect Gestation-postnatal/lactation First generation High-carbohydrate diet during suckling Hyperinsulinism (Srinivasan et al Diabetes 2003) Second generatiion Control diet (HC mother) T2D, mortality : only paternal grandparents ! XX XY GP Y X (Kaati et al 2002; Pembrey et al, 2005) GM (Kaati et al 2002) Acknowledgements Bioinformatics -statistics JP Jais (Hôp.Necker SBIM) U383-U781 Beta oxydation fatty acids C Gallou-Kabani, A Vigé, F. Djouadi, J. Bastin E Boudadi, H Pilet, MS Gross, (Inserm U393, Paris) Desaturation index ,FFA A Belaid, C. Junien 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) Financing INRA, ATC- INSERM, PRNH T. Ekstrom (Karolinska, Suède INSERM, AFD, AFERO I.B. Delessert, Lab Fournier, Nestlé 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) 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) Epigenetic patterns Involvement of an imprinted gene ? Promotor ? Differentially methylated Region (DMR) Proportional to the adipocyte size ? Adaptation to caloric intake heritable ? -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? Plausible candidates for resistance to HFD ? Spatiotemporal windows ? Markers ? Placenta ? WBC? -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?