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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
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
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
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
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
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?
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