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Epigenetic mechanisms linking early life diet
and cancer risk
Dr Karen A Lillycrop
Institute of Developmental Sciences
Centre for Biological Sciences
University of Southampton
Disease Susceptibility
Phenotype
+
Genotype
(CVD, obesity, type II diabetes, cancer)
Genes are surely not everything?
1. Large regional variations in disease risk
2. Identical twins are discordant for some diseases
3. Rapid rise in rates of obesity and T2D over the past
two decades
4
Genotype
Phenotype
+
Disease susceptibility
(CVD, obesity, type II diabetes, cancer)
Environment
Epigenetics
Ghosts in our genes – a second code
Rainbow Carbon Copy
The cloned cat shows the importance of epigenetics
Lillycrop opac2013
Epigenetics
Literally means ‘on top of genetics’
Definition: Processes that induced long term stable changes in gene activity
without a change in gene sequence
Genes = hardware
Epigenetics =software
The major epigenetics processes are
DNA methylation,
Histone modification
non coding RNAs
Unmethylated promoter
Methylated promoter
CpG island
CpG island
CH3
mRNA
Protein
Transcription 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 are
clustered at the 5’ ends of genes (CpG islands)
DNA methylation
Tissue differentiation
Once established, these methylation patterns are then stably
maintained throughout the life of an organism
DNA methylation is established during early life
muscle
skin
adipocyte
nerve
blood
Germ Cells Embryos Santos F , Dean W Reproduction 2004;127:643-651
Role of epigenetic processes in Cancer
hCancer is caused both by genetic and epigenetic alterations
Epigenetic dysregulation and cancer
Global DNA hypomethylation
altered histone code
global loss of monoacetylated
& trimethylatd histone H4
Gene specific hypermethylation
Cancer cells Altered miRNA
expression
Degree of hypomethylation increases as the cancer
progresses
Esteller et al., 2008
Profiles of hypermethylation of tumour suppressor genes are specific to
each cancer type
Epigenetic silencing plays a seminal role in cancer initiation
Eg methylation of P16INK4a is one of the earliest epigenetic mediated
losses of tumour suppressor function in human cancers
– silencing begins in the preinvasive stages of cancers
Jones & Baylin 2007
Early life environment can alter the epigenome
The epigenome is particularly susceptible to environmental influences
at certain life stages
Prenatal Neonatal Puberty Aging
Early life environment
Persistent changes in gene expression
Altered metabolism and physiology
Altered disease risk
(CVD, obesity, T2D &
Some forms of cancer)
Altered epigenetic gene regulation
Developmental origins of adult disease
Mortality from coronary heart disease
before 65 years in 15,726 men and
women in Hertfordshire
<
5
.5
5
.5
-
6.5
6
.5
-
7
.5
7
.5
-
8
.5
8.5
-
9.5
>
9
.5
0
50
100
Men
Women
Birth weight (lbs)
Standardisedmortalityratio
Nutrition can also alter the epigenome
HDACs
?
Folate
18
Bee (Apis mellifera) phenotype is controlled by
nutrition
Queen
Genome
+ Royal jelly - Royal jelly
Kucharski 2008
nutrition can profoundly affect developmental fates and suggests that
nutrition may modulate phenotype through DNA methylation
SiRNA Dnmt
Maternal diet can alter DNA methylation in the offspring
coat colour in mice is determined by the methylation status of the
5’ end of the agouti gene
hypomethylation Gene active Yellow coat
hypermethylation Gene inactive Brown coat
Supplementation of maternal diet with dietary methyl donors
(folic acid, B12, choline and betaine) shifted the coat colour of the
offspring from yellow to brown
PPARα expression Β oxidationAOX expressionPPARα methylation
ternal protein restriction induces the hypomethylation of PPARα promoter
20
Lillycrop et al., 2005,.2007
PPARα methylation
vs. expression
2 3 4 5
0
1
2
3
4
Methylation (normalised Ct)
mRNAexpression(normalisedCt)
Plasma β-hydroxybutyrate
concentration vs. PPARα methylation
2 3 4 5
0
200
400
600
Methylation (normalised Ct)
β-Hydroxybutyrate
concentration(µmol/l)
R2
=0.49 R2
=0.50
1 2
+1 +251 +944 +1031-306-380
+259-537
CpG Island
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
0
50
100
150
200
* * * *
CpG
Methylation(%
Relativeto
Control)
Maternal diet alters methylation of specific CpGs in the PPARα promoter
Day 34
juvenile
Day 80
adult
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
0
50
100
150
200 Control PR
* * * *
SP1 AHR
CREB
SP1 HESF
USB
Pax9
NRF1
ZFSF
EGRG
CPBP WHNF
CpG
Methylation(%
Relativeto
Control)
Lillycrop et al. 2007
conception birth weaning Growth maturation aging
Folic acid
Epigenome
Protein
restriction
GR, PPAR, PEPCK
HNF4,ATR1
GR, PPARa
Over feeding
FADS2
Long term changes
in gene expression
& metabolism
Altered disease risk
Global
restriction
High
fat
FADS2 POMC
The Dutch Hunger Winter
A period of severe food shortage in the
Netherlands in 1944.
Energy intakes dropped from 1800 to between
400 and 800 kcal per day (equivalent 100 -
200g pasta).
Individuals born to women exposed to famine
during pregnancy have an increased risk of
CVD, T2D and obesity in later life
Tobi et al., 2009
Alterations in DNA methylation has been shown in individuals from mothers who
Were exposed to famine during pregnancy compared to their non exposed siblings
IL10 GNASAS IGF2 Lep ABCA1 MEG3
Is there a link between early life nutrition
And cancer risk?
* Studies from the DHW have shown that women born to mothers exposed
to famine are at an increased risk of breast cancer (Painter 2008)
*Animal models show maternal diet an important determinant of cancer
susceptibility in the offspring
Maternal protein restriction
Maternal 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 mammary
tumourigenesis in offspring
Increase in mammary tumours
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 epigenetic
regulation of
BRCA1
Oct-4
2mg/kg FA
5mg/kg FA
2mg/kg FA
Juvenile-pubertal
period
PN28
PN56 PN84
BRCA1 & Oct4
mRNA expression
BRCA1 & Oct-4 promoter
methylation
2mg/kg FA
1x BDR
2.5 xBDR
Implications
conception birth weaning Growth maturation aging
Prenatal Neonatal Pubertal
Nutritional exposures
Epigenetic changes p17 Increased cancer risk
BRCA1
Oct-4
DNA repair?
Stem cell number?
Folic acidHigh fatProtein
restriction
p16
Epigenetic marks as biomarkers?
In humans limited tissue availability?
Available tissues: Umbilical cord
Cord blood
Placenta
buccal cells
Blood
Are methylation marks at birth associated with later
metabolic capacity?
Extracted DNA from 115 umbilical cords from babies within the
normal birth weight range
Associations between methylation of CpGs and outcome
confirmed by bisulfite sequencing (Sequenom)
Correlated methylation levels to adiposity of the children age 9
Values are means + SEM
Methylation at the retinoid X receptor α (RXRA) promoter
at birth vs child’s fat mass
-40
-60
-80
80
≥
3
4
5
6
7
8
Umbilical cord RXRA methylation
r= 0.32 P=0.009
n=64
Child'sfatmass
ageandsexadjusted(kg)
PAH children age 9 yrs
-40
-60
-80
80
≥
3
4
5
6
Umbilical cord RXRA methylation
r= 0..20 P=0.002
n=239
Child'sfatmass
ageandsexadjusted(kg)
SWS children age 6 yrs
Godfrey et al., 2011
Potential epigenetic biomarkers of cancer risk?
Methylation of ATM (Ataxia telangiectasia mutated) in prediagnostic
peripheral blood samples associated with increased breast cancer risk
Brennan et al., 2012
No association seen between the time from blood collection to diagnosis
and level of methylation suggesting findings not explained by preclinical disease
Hypermethylation of ATM represents
a stable marker of breast cancer
predisposition
Summary
1. Cancer is caused by both genetic and epigenetic alterations
2. The epigenome is susceptible to a number of environmental factors in early life
3. Epigenetic processes are central to the mechanism by which early life environment
affect future disease risk including cancer susceptibility
4. Detection of epigenetic marks in early life may have utility in predicting future
disease risk
How & when
to
intervene?
What
tissues to
use?
What are the periods of
susceptibility
Epigenetic
vs genetics
Sex
differences
What makes one CpG stable over time
another plastic?
Many challenges remain….
What does a
change in
methylation
mean?
Epigenetics
Biomarkers?
Epigenetic
targets?
Need more mechanistic studies and longitudinal cohort
Studies to answer these questions
Are these
methylation
changes really
causal?
Genes are not our destiny…
Southampton Developmental Epigenetics group
Graham Burdge
Keith Godfrey
Mark Hanson
Teejal Bhatt
Nicki Irvine
Elisoe Cook
Leanie Grenfell
Becki Clarke
Paula Costello
Mark Burton
Danya Agfa
Jordan Price
Rob Murray
Emma Garratt
Sam Hoile
Charlie Simmons
New Zealand
Peter Gluckman
Singapore
Joanna Holbrook
Walter Strunkel
Australia
RaeChi Huang
Leiden
Bas Zwaan
Plymouth
Terry Wilkin
Jo Hosking

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Lillycrop opac2013

  • 1. Epigenetic mechanisms linking early life diet and cancer risk Dr Karen A Lillycrop Institute of Developmental Sciences Centre for Biological Sciences University of Southampton
  • 3. Genes are surely not everything? 1. Large regional variations in disease risk 2. Identical twins are discordant for some diseases 3. Rapid rise in rates of obesity and T2D over the past two decades
  • 4. 4 Genotype Phenotype + Disease susceptibility (CVD, obesity, type II diabetes, cancer) Environment Epigenetics Ghosts in our genes – a second code
  • 5. Rainbow Carbon Copy The cloned cat shows the importance of epigenetics
  • 7. Epigenetics Literally means ‘on top of genetics’ Definition: Processes that induced long term stable changes in gene activity without a change in gene sequence Genes = hardware Epigenetics =software The major epigenetics processes are DNA methylation, Histone modification non coding RNAs
  • 8. Unmethylated promoter Methylated promoter CpG island CpG island CH3 mRNA Protein Transcription 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 are clustered at the 5’ ends of genes (CpG islands) DNA methylation
  • 9. Tissue differentiation Once established, these methylation patterns are then stably maintained throughout the life of an organism DNA methylation is established during early life muscle skin adipocyte nerve blood Germ Cells Embryos Santos F , Dean W Reproduction 2004;127:643-651
  • 10. Role of epigenetic processes in Cancer hCancer is caused both by genetic and epigenetic alterations
  • 11. Epigenetic dysregulation and cancer Global DNA hypomethylation altered histone code global loss of monoacetylated & trimethylatd histone H4 Gene specific hypermethylation Cancer cells Altered miRNA expression
  • 12. Degree of hypomethylation increases as the cancer progresses Esteller et al., 2008
  • 13. Profiles of hypermethylation of tumour suppressor genes are specific to each cancer type
  • 14. Epigenetic silencing plays a seminal role in cancer initiation Eg methylation of P16INK4a is one of the earliest epigenetic mediated losses of tumour suppressor function in human cancers – silencing begins in the preinvasive stages of cancers Jones & Baylin 2007
  • 15. Early life environment can alter the epigenome The epigenome is particularly susceptible to environmental influences at certain life stages Prenatal Neonatal Puberty Aging
  • 16. Early life environment Persistent changes in gene expression Altered metabolism and physiology Altered disease risk (CVD, obesity, T2D & Some forms of cancer) Altered epigenetic gene regulation Developmental origins of adult disease Mortality from coronary heart disease before 65 years in 15,726 men and women in Hertfordshire < 5 .5 5 .5 - 6.5 6 .5 - 7 .5 7 .5 - 8 .5 8.5 - 9.5 > 9 .5 0 50 100 Men Women Birth weight (lbs) Standardisedmortalityratio
  • 17. Nutrition can also alter the epigenome HDACs ? Folate
  • 18. 18 Bee (Apis mellifera) phenotype is controlled by nutrition Queen Genome + Royal jelly - Royal jelly Kucharski 2008 nutrition can profoundly affect developmental fates and suggests that nutrition may modulate phenotype through DNA methylation SiRNA Dnmt
  • 19. Maternal diet can alter DNA methylation in the offspring coat colour in mice is determined by the methylation status of the 5’ end of the agouti gene hypomethylation Gene active Yellow coat hypermethylation Gene inactive Brown coat Supplementation of maternal diet with dietary methyl donors (folic acid, B12, choline and betaine) shifted the coat colour of the offspring from yellow to brown
  • 20. PPARα expression Β oxidationAOX expressionPPARα methylation ternal protein restriction induces the hypomethylation of PPARα promoter 20 Lillycrop et al., 2005,.2007 PPARα methylation vs. expression 2 3 4 5 0 1 2 3 4 Methylation (normalised Ct) mRNAexpression(normalisedCt) Plasma β-hydroxybutyrate concentration vs. PPARα methylation 2 3 4 5 0 200 400 600 Methylation (normalised Ct) β-Hydroxybutyrate concentration(µmol/l) R2 =0.49 R2 =0.50
  • 21. 1 2 +1 +251 +944 +1031-306-380 +259-537 CpG Island 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 0 50 100 150 200 * * * * CpG Methylation(% Relativeto Control) Maternal diet alters methylation of specific CpGs in the PPARα promoter Day 34 juvenile Day 80 adult 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 0 50 100 150 200 Control PR * * * * SP1 AHR CREB SP1 HESF USB Pax9 NRF1 ZFSF EGRG CPBP WHNF CpG Methylation(% Relativeto Control) Lillycrop et al. 2007
  • 22. conception birth weaning Growth maturation aging Folic acid Epigenome Protein restriction GR, PPAR, PEPCK HNF4,ATR1 GR, PPARa Over feeding FADS2 Long term changes in gene expression & metabolism Altered disease risk Global restriction High fat FADS2 POMC
  • 23. The Dutch Hunger Winter A period of severe food shortage in the Netherlands in 1944. Energy intakes dropped from 1800 to between 400 and 800 kcal per day (equivalent 100 - 200g pasta). Individuals born to women exposed to famine during pregnancy have an increased risk of CVD, T2D and obesity in later life Tobi et al., 2009 Alterations in DNA methylation has been shown in individuals from mothers who Were exposed to famine during pregnancy compared to their non exposed siblings IL10 GNASAS IGF2 Lep ABCA1 MEG3
  • 24. Is there a link between early life nutrition And cancer risk? * Studies from the DHW have shown that women born to mothers exposed to famine are at an increased risk of breast cancer (Painter 2008) *Animal models show maternal diet an important determinant of cancer susceptibility in the offspring Maternal protein restriction Maternal 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 mammary tumourigenesis in offspring Increase in mammary tumours
  • 25. 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 epigenetic regulation of BRCA1 Oct-4 2mg/kg FA 5mg/kg FA 2mg/kg FA Juvenile-pubertal period PN28 PN56 PN84 BRCA1 & Oct4 mRNA expression BRCA1 & Oct-4 promoter methylation 2mg/kg FA 1x BDR 2.5 xBDR
  • 26. Implications conception birth weaning Growth maturation aging Prenatal Neonatal Pubertal Nutritional exposures Epigenetic changes p17 Increased cancer risk BRCA1 Oct-4 DNA repair? Stem cell number? Folic acidHigh fatProtein restriction p16
  • 27. Epigenetic marks as biomarkers? In humans limited tissue availability? Available tissues: Umbilical cord Cord blood Placenta buccal cells Blood
  • 28. Are methylation marks at birth associated with later metabolic capacity? Extracted DNA from 115 umbilical cords from babies within the normal birth weight range Associations between methylation of CpGs and outcome confirmed by bisulfite sequencing (Sequenom) Correlated methylation levels to adiposity of the children age 9
  • 29. Values are means + SEM Methylation at the retinoid X receptor α (RXRA) promoter at birth vs child’s fat mass -40 -60 -80 80 ≥ 3 4 5 6 7 8 Umbilical cord RXRA methylation r= 0.32 P=0.009 n=64 Child'sfatmass ageandsexadjusted(kg) PAH children age 9 yrs -40 -60 -80 80 ≥ 3 4 5 6 Umbilical cord RXRA methylation r= 0..20 P=0.002 n=239 Child'sfatmass ageandsexadjusted(kg) SWS children age 6 yrs Godfrey et al., 2011
  • 30. Potential epigenetic biomarkers of cancer risk? Methylation of ATM (Ataxia telangiectasia mutated) in prediagnostic peripheral blood samples associated with increased breast cancer risk Brennan et al., 2012 No association seen between the time from blood collection to diagnosis and level of methylation suggesting findings not explained by preclinical disease Hypermethylation of ATM represents a stable marker of breast cancer predisposition
  • 31. Summary 1. Cancer is caused by both genetic and epigenetic alterations 2. The epigenome is susceptible to a number of environmental factors in early life 3. Epigenetic processes are central to the mechanism by which early life environment affect future disease risk including cancer susceptibility 4. Detection of epigenetic marks in early life may have utility in predicting future disease risk
  • 32. How & when to intervene? What tissues to use? What are the periods of susceptibility Epigenetic vs genetics Sex differences What makes one CpG stable over time another plastic? Many challenges remain…. What does a change in methylation mean? Epigenetics Biomarkers? Epigenetic targets? Need more mechanistic studies and longitudinal cohort Studies to answer these questions Are these methylation changes really causal?
  • 33. Genes are not our destiny…
  • 34. Southampton Developmental Epigenetics group Graham Burdge Keith Godfrey Mark Hanson Teejal Bhatt Nicki Irvine Elisoe Cook Leanie Grenfell Becki Clarke Paula Costello Mark Burton Danya Agfa Jordan Price Rob Murray Emma Garratt Sam Hoile Charlie Simmons New Zealand Peter Gluckman Singapore Joanna Holbrook Walter Strunkel Australia RaeChi Huang Leiden Bas Zwaan Plymouth Terry Wilkin Jo Hosking