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

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Presentation on theme: "Nutritional epigenomics of the metabolic syndrome Periconceptual, fetal, neonatal, lifelong and transgenerational lifelong and transgenerational Pr. Claudine."— Presentation transcript:

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

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

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

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

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

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

7 (Lund et al. JBC 2004) 4-weeksold 6-months old old WTApoe-/-mice ( Hiltunen & Yla-Herttuala ATVB 2003) Apoe-/-micearteries Humanarteries Genome-wide methylation Age- and diet-related diseases

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

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

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

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

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

13 Buffering or « rheostat » System (Pembrey M. 1996, Junien C. 2000, Beaudet A. 2002, Pembrey M. 2002) 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 Maternal allele Maternal allelesilenced % Paternal allele Paternal alleleexpressed % Monoallelic Expression Biallelic expression Non-expression Plausible candidates for adaptation ? Imprinted genes ?

14 Liver DecorinEsx1 Nr1h3NnatGrb10 Igf 2Riken cDNA Slc2a5 Dgat 1Gata 3Acads Esx1Decorin Igf 2Riken cDNA Gata 1 Nr1h3NnatGrb10 Kcnq 1Slc2a5Ube3a Pparg Placenta Satiety phenotype 1 - Custom microarrays 60 Imprinted 60 Imprintedgenes (Vigé et al CGR 2005) « Epigenetics - energy homeostasis » 500 genes

15 Satiety phenotype 2 - Candidate gene approach Q-RT-PCR (Moraes et al 2003; Takahashi et al 2004; Curley et al 2004) 28 genes stomach,muscle, adipose tissue, hypothalamus,liver : Peg1 & Peg 3: Paternally expressed Imprinted genes increased in DIO : Peg1: Adipocyte size marker Peg1 Peg3 FemalesF2-SF1CF1HFF2-R F2-SF1CF1HFF2-R

16 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) Histones alterations Candidate genes: Chromatin ImmunoPrecipitation(ChIP) Genome-wide: ChIP Genome-wide: Luminometric Methylation Assay (LUMA) Satiety phenotype, liver : Hypomethylation F1HF -> adaptation F2 0,15 0,2 0,25 0,3 0,35 0,4 0,45 P = 0.03 P = 0.02 F1NF2HFRF1HFF2HFS Hypomethylation Hypermethylation

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

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

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

20 Germ cells GametesPaternalMaternal Gametes Developmental programming Modes of transmission

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

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

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

24 Acknowledgements 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 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) Financing INRA, ATC- INSERM, PRNH INSERM, AFD, AFERO I.B. Delessert, Lab Fournier, Nestlé 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) U383-U781 C Gallou-Kabani, A Vigé, E Boudadi, H Pilet, MS Gross, A Belaid, C. Junien

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

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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