Lillycrop opac2013


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Lillycrop opac2013

  1. 1. Epigenetic mechanisms linking early life dietand cancer riskDr Karen A LillycropInstitute of Developmental SciencesCentre for Biological SciencesUniversity of Southampton
  2. 2. Disease SusceptibilityPhenotype+Genotype(CVD, obesity, type II diabetes, cancer)
  3. 3. Genes are surely not everything?1. Large regional variations in disease risk2. Identical twins are discordant for some diseases3. Rapid rise in rates of obesity and T2D over the pasttwo decades
  4. 4. 4GenotypePhenotype+Disease susceptibility(CVD, obesity, type II diabetes, cancer)EnvironmentEpigeneticsGhosts in our genes – a second code
  5. 5. Rainbow Carbon CopyThe cloned cat shows the importance of epigenetics
  6. 6. EpigeneticsLiterally means ‘on top of genetics’Definition: Processes that induced long term stable changes in gene activitywithout a change in gene sequenceGenes = hardwareEpigenetics =softwareThe major epigenetics processes areDNA methylation,Histone modificationnon coding RNAs
  7. 7. Unmethylated promoterMethylated promoterCpG islandCpG islandCH3mRNAProteinTranscription TranslationCytosine is methylated to 5-methyl cytosinethe majority of methylated cytosine is found as a dinucleotide CpGCpGs are not randomly distributed throughout the genome but areclustered at the 5’ ends of genes (CpG islands)DNA methylation
  8. 8. Tissue differentiationOnce established, these methylation patterns are then stablymaintained throughout the life of an organismDNA methylation is established during early lifemuscleskinadipocytenervebloodGerm Cells Embryos Santos F , Dean W Reproduction 2004;127:643-651
  9. 9. Role of epigenetic processes in CancerhCancer is caused both by genetic and epigenetic alterations
  10. 10. Epigenetic dysregulation and cancerGlobal DNA hypomethylationaltered histone codeglobal loss of monoacetylated& trimethylatd histone H4Gene specific hypermethylationCancer cells Altered miRNAexpression
  11. 11. Degree of hypomethylation increases as the cancerprogressesEsteller et al., 2008
  12. 12. Profiles of hypermethylation of tumour suppressor genes are specific toeach cancer type
  13. 13. Epigenetic silencing plays a seminal role in cancer initiationEg methylation of P16INK4a is one of the earliest epigenetic mediatedlosses of tumour suppressor function in human cancers– silencing begins in the preinvasive stages of cancersJones & Baylin 2007
  14. 14. Early life environment can alter the epigenomeThe epigenome is particularly susceptible to environmental influencesat certain life stagesPrenatal Neonatal Puberty Aging
  15. 15. Early life environmentPersistent changes in gene expressionAltered metabolism and physiologyAltered disease risk(CVD, obesity, T2D &Some forms of cancer)Altered epigenetic gene regulationDevelopmental origins of adult diseaseMortality from coronary heart diseasebefore 65 years in 15,726 men andwomen in Hertfordshire<5.55.5-6.56.5-7.57.5-8.58.5-9.5>9.5050100MenWomenBirth weight (lbs)Standardisedmortalityratio
  16. 16. Nutrition can also alter the epigenomeHDACs?Folate
  17. 17. 18Bee (Apis mellifera) phenotype is controlled bynutritionQueenGenome+ Royal jelly - Royal jellyKucharski 2008nutrition can profoundly affect developmental fates and suggests thatnutrition may modulate phenotype through DNA methylationSiRNA Dnmt
  18. 18. Maternal diet can alter DNA methylation in the offspringcoat colour in mice is determined by the methylation status of the5’ end of the agouti genehypomethylation Gene active Yellow coathypermethylation Gene inactive Brown coatSupplementation of maternal diet with dietary methyl donors(folic acid, B12, choline and betaine) shifted the coat colour of theoffspring from yellow to brown
  19. 19. PPARα expression Β oxidationAOX expressionPPARα methylationternal protein restriction induces the hypomethylation of PPARα promoter20Lillycrop et al., 2005,.2007PPARα methylationvs. expression2 3 4 501234Methylation (normalised Ct)mRNAexpression(normalisedCt)Plasma β-hydroxybutyrateconcentration vs. PPARα methylation2 3 4 50200400600Methylation (normalised Ct)β-Hydroxybutyrateconcentration(µmol/l)R2=0.49 R2=0.50
  20. 20. 1 2+1 +251 +944 +1031-306-380+259-537CpG Island2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17050100150200* * * *CpGMethylation(%RelativetoControl)Maternal diet alters methylation of specific CpGs in the PPARα promoterDay 34juvenileDay 80adult2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17050100150200 Control PR* * * *SP1 AHRCREBSP1 HESFUSBPax9NRF1ZFSFEGRGCPBP WHNFCpGMethylation(%RelativetoControl)Lillycrop et al. 2007
  21. 21. conception birth weaning Growth maturation agingFolic acidEpigenomeProteinrestrictionGR, PPAR, PEPCKHNF4,ATR1GR, PPARaOver feedingFADS2Long term changesin gene expression& metabolismAltered disease riskGlobalrestrictionHighfatFADS2 POMC
  22. 22. The Dutch Hunger WinterA period of severe food shortage in theNetherlands in 1944.Energy intakes dropped from 1800 to between400 and 800 kcal per day (equivalent 100 -200g pasta).Individuals born to women exposed to famineduring pregnancy have an increased risk ofCVD, T2D and obesity in later lifeTobi et al., 2009Alterations in DNA methylation has been shown in individuals from mothers whoWere exposed to famine during pregnancy compared to their non exposed siblingsIL10 GNASAS IGF2 Lep ABCA1 MEG3
  23. 23. Is there a link between early life nutritionAnd cancer risk?* Studies from the DHW have shown that women born to mothers exposedto famine are at an increased risk of breast cancer (Painter 2008)*Animal models show maternal diet an important determinant of cancersusceptibility in the offspringMaternal protein restrictionMaternal high fat feeding (De Assis (2006)Maternal folic acid supplementation (Ly et al. 2011)Peripubertal folic acid supplementation(D.S.Fernandez-Twinn et al.,2006),Increase in mammarytumourigenesis in offspringIncrease in mammary tumours
  24. 24. Does Folic acid supplementation lead to changes in the epigenome?To determine the effect of folic acid intake during the juvenile-pubertal period on the long term expression and epigeneticregulation ofBRCA1Oct-42mg/kg FA5mg/kg FA2mg/kg FAJuvenile-pubertalperiodPN28PN56 PN84BRCA1 & Oct4mRNA expressionBRCA1 & Oct-4 promotermethylation2mg/kg FA1x BDR2.5 xBDR
  25. 25. Implicationsconception birth weaning Growth maturation agingPrenatal Neonatal PubertalNutritional exposuresEpigenetic changes p17 Increased cancer riskBRCA1Oct-4DNA repair?Stem cell number?Folic acidHigh fatProteinrestrictionp16
  26. 26. Epigenetic marks as biomarkers?In humans limited tissue availability?Available tissues: Umbilical cordCord bloodPlacentabuccal cellsBlood
  27. 27. Are methylation marks at birth associated with latermetabolic capacity?Extracted DNA from 115 umbilical cords from babies within thenormal birth weight rangeAssociations between methylation of CpGs and outcomeconfirmed by bisulfite sequencing (Sequenom)Correlated methylation levels to adiposity of the children age 9
  28. 28. Values are means + SEMMethylation at the retinoid X receptor α (RXRA) promoterat birth vs child’s fat mass-40-60-8080≥345678Umbilical cord RXRA methylationr= 0.32 P=0.009n=64Childsfatmassageandsexadjusted(kg)PAH children age 9 yrs-40-60-8080≥3456Umbilical cord RXRA methylationr= 0..20 P=0.002n=239Childsfatmassageandsexadjusted(kg)SWS children age 6 yrsGodfrey et al., 2011
  29. 29. Potential epigenetic biomarkers of cancer risk?Methylation of ATM (Ataxia telangiectasia mutated) in prediagnosticperipheral blood samples associated with increased breast cancer riskBrennan et al., 2012No association seen between the time from blood collection to diagnosisand level of methylation suggesting findings not explained by preclinical diseaseHypermethylation of ATM representsa stable marker of breast cancerpredisposition
  30. 30. Summary1. Cancer is caused by both genetic and epigenetic alterations2. The epigenome is susceptible to a number of environmental factors in early life3. Epigenetic processes are central to the mechanism by which early life environmentaffect future disease risk including cancer susceptibility4. Detection of epigenetic marks in early life may have utility in predicting futuredisease risk
  31. 31. How & whentointervene?Whattissues touse?What are the periods ofsusceptibilityEpigeneticvs geneticsSexdifferencesWhat makes one CpG stable over timeanother plastic?Many challenges remain….What does achange inmethylationmean?EpigeneticsBiomarkers?Epigenetictargets?Need more mechanistic studies and longitudinal cohortStudies to answer these questionsAre thesemethylationchanges reallycausal?
  32. 32. Genes are not our destiny…
  33. 33. Southampton Developmental Epigenetics groupGraham BurdgeKeith GodfreyMark HansonTeejal BhattNicki IrvineElisoe CookLeanie GrenfellBecki ClarkePaula CostelloMark BurtonDanya AgfaJordan PriceRob MurrayEmma GarrattSam HoileCharlie SimmonsNew ZealandPeter GluckmanSingaporeJoanna HolbrookWalter StrunkelAustraliaRaeChi HuangLeidenBas ZwaanPlymouthTerry WilkinJo Hosking