Transcript Epigenetics seminar 9-7-2014x

Content
What are the evidence from
epigenetics science?
Diseases & conditions linked to epigenetics
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Obesity
● Insulin resistance
Heart disease
● Rare genetics syndromes
Various cancers
● Asthma
Autism
neurodegenerative disorders,
bipolar disorder,
schizophrenia,
atherosclerosis,
hypertension,
SLE,
kidney diseases,
Genetic Susceptibility to Complex Disorders
•Genome wide association studies (GWAS) have been
used to study common complex disorders (diabetes &
coronary artery disease)
•Reseachers looked for replicable associations between
genetic variation & a given disorder.
•But variants (SNP) identified in this way tend only to
account for a small % of the heritable component of such
disorders.
•Does 'missing heritability' suggest that we have
overestimated the genetic component of complex
disorders?
•Or GWAS was focusing on DNA differences but
overlooking the dynamic & responsive aspects of genes in
action
•‘Non-coding regions’ stretches of DNA between genes
were once thought of as ‘junk’, but it is now found to have
important roles in regulating how, where, & when genes are
expressed.
•An NIH study found large number of disease-associated
GWAS variants located in regulatory DNA regions that are
active during foetal development suggesting that
environmental exposures during this period could influence
risk for a large number of diseases.
•Researchers found that lifestyle factors
such as
diet,
obesity,
physical activity,
tobacco smoking,
alcohol consumption,
environmental pollutants,
psychological stress &
even working on night shifts
might modify epigenetic patterns through
DNA methylation
• Understanding how & when environmental
exposures affect gene regulation may provide
insights into ways to prevent disease by reducing
exposures early in life, instead of treating the
disease when symptoms occur in adulthood
Diabetes & Exercise
•A study evaluated genome-wide methylation in
adipose tissue in healthy men with & without a family
history of Type II Diabetes.
•They participated in 3 hours exercise a week
(average 1.8 hr), without changing their diet or daily
activity for 6 months.
•waist-hip ratio ↓ with ↑methylation of a gene
previously associated with waist-hip ratio,
•significant methylation changes were also observed
in 18 candidate genes previously associated with
obesity &
•21 genes associated with Type II Diabetes
Obesity
•Another study of Amish volunteers found that two
copies of FTO gene ‘fattening’ variant made them 67%
more likely to be 7 lbs heavier than others.
•Researchers found that a natural way to control
genes, is through exercise! "We can nurture nature"
•Most physically active people were able to stay within
a normal BMI range, despite their genetic
predisposition
•Meta analysis of data from 45 studies in adults & 9
studies in children—nearly 240,000 people were also
carried out.
•Found those who carried 2 FTO ‘fattening’ gene
variants had a 23% higher risk of obesity than those
who did not. But once again, being physically active
lowered the risk by 30%. Genes are not destiny!
•Another study of 38,759 Europeans for variants of
FTO gene identified an obesity risk.
•Carriers of 1 copy of the allele weighed on average
1.2 kg more than people with no copies.
•Carriers of 2 copies (16% of the subjects) weighed 3
kg more & had a 1.67-fold higher rate of obesity than
those with no copies.
•The association was observed in ages 7 & upwards
Pregnancy
• Epigenetics control how & when certain
genes are turned on & off to help the body
grows & develops into various tissues
forming different organs at embryological
development
• Periods of developmental plasticity are from
early on in embryological development, up
to mid childhood but especially the first 2
years of life
Epigenetics in normal human development
3 generations at
once are exposed to
the same
environmental
conditions (diet,
toxins, hormones,
etc.).
University of Utah Genetics Science Learning Centre Website
Epigenetics Reprogramming
University of Utah Genetics Science Learning Centre Website
•Cambridge researchers funded by Wellcome Trust
found that some rare methylation can ‘escape’ the
reprogramming process & can thus be passed on to
offspring – revealing how epigenetic inheritance
could occur.
•“Our research demonstrates how genes could
retain some memory of their past experiences,
revealing that one of the big barriers to the theory of
epigenetic inheritance – that epigenetic information
is erased between generations – should be
reassessed”.
Effects of famines
•Effects of famines in Holland in the 1940s, in
China in the 1950s & in USA over a century ago
showed that they have changed the lifespan &
obesity rates in subsequent generations.
•Epigenetic marks may be particularly vulnerable
during the very early embryological stage of
mammalian development, which is a crucial period
for establishing & maintaining epigenetic marks
•Early-life environmental conditions can cause
epigenetic changes in humans that persist
throughout life.
The Dutch Hunger winter
In1944 Nazi imposed rationing
on Dutch population as
punishment for the resistance
movement.
Energy intakes dropped from
1800 to (400-800) kcal/day
Lasted for 7 months until
Holland was liberated
Despite famine, details of birth
records were maintained.
Slide :Dr. Graham Burdge,
Southampton University
Picture:University of Leiden ‘Traces of Dutch 'Hunger Winter' in genetic material’
Slide :Dr. Graham
Burdge, Southampton
University
Average methylation (exposed vs unexposed
(difference %)
60 years later , persistent epigenetic differences
associated with prenatal exposure to famine in Dutch
hunger winter in 1944
Conceived early famine
Insulin like growth factor 2
(IGF2) gene
Conceived late famine
Heijmans et al. Proc Natl Acad Sci USA (2008)
•Children of pregnant women exposed to famine
were more susceptible to diabetes, obesity,
cardiovascular disease, kidney problems & others
•Children affected in second trimester of their
mother's pregnancy found to have an increased
incidence of schizophrenia & other neurological
defects.
•Children of women who were pregnant during
famine were smaller, as expected.
•However, surprisingly, when these children grew up
& had children those children were also smaller than
average (3rd generation).
• Health & DNA methylation of people in rural
Gambia was found to be affected by the season
in which they were conceived.
• People whose mothers went hungry during the
rainy season when conceived had a poorer
outcome for future health.
• They switched on genes that increased the
accumulation of body fat in times of plenty, in
order to improve survival chances in times of
famine.
• This suggests that either
Children’s stem cells carried these methylation
changes
or the famine could have changed the children’s
hormone response levels for life.
Smoking, Obesity &
Child Abuse
The Avon Longitudinal Study of Parents and
Children (ALSPAC) (Children’s of the 90s)
•A cohort of 14,000 pregnant women, most children & their
fathers were followed since 1991-2
•Fathers who smoked as pre-adolescents have increased
their sons BMI at 9 years of age, but not their daughters.
•Slow growth period is in mid childhood ( 9-12 years in
boys, 8-10 years for girls). This is the time when
environmental factors have larger impact on the body.
•Studies have assessed paternal smoking &
obesity on markers of DNA damage or instability in
cord blood of their offspring.
•They tested parental blood cells, spermatozoa &
cord blood from 39 family trios & identified
transgenerational DNA alterations in the unexposed
offspring of smoking-exposed fathers.
•Hypomethylation at IGF2 (Insulin like growth factor
2) gene in umbilical cord blood have been
associated with paternal obesity.
•This suggests a pre-conceptional impact of obesity
(and/or exposures related to it) on the
reprogramming of methylation marks during
spermatogenesis.
British Birth Cohort of 1958, of 45 year old men
chosen from extreme Socio Economic Position
(Marcus Pembrey)
Adult DNA carries distinct DNA methylation patterns
associated with
•child socio-economic position,
•prenatal tobacco exposure
•child abuse
•Studies of hippocampus from suicide victims who
had known histories of childhood abuse showed
higher methylation when compared with those who
were not abused.
•Another study found a dosage-dependent
association of paternal betel quid use with early
metabolic syndrome in the adult offspring who
had never chewed betel quid
Twin Studies
•A study compared DNA methylation patterns from 39
sets of monozygotic & 40 dizygotic twins found that
identical twins had more similar methylation patterns,
suggesting that these patterns are inherited
•Another study revealed that epigenetics pattern in MZ
twins became different as they got older. 1/3 had
differences in DNA methylation & histone modification.
•Rates of disease phenotype discordance in MZ twins
are usually well over 50%, even for highly heritable
disease suggesting that epigenetics can contribute
significantly to MZ twin phenotype discordance
Stress
• Avon Longitudinal Study of Parents & Children’s
(ALSPC) found that women who suffer higher
levels of stress while pregnant are more likely to
have children with lower IQs & greater emotional
difficulties.
•Epigenetics effects of post-traumatic stress
disorder in babies of mothers exposed to the
World Trade Centre attacks during pregnancy
•Lower cortisol levels were observed in both mothers &
their 1 year old babies who developed PTSD
compared with mothers who did not
•It was most apparent in babies whose mothers were
exposed in 3rd trimesters.
•Potential hypothesised mechanisms
early social regulation
glucocorticoid programing in utero
and/or shared underlying genetic susceptibility
•Another study showed that rat pups that are
neglected by their mothers in the nest grow up to
be timid adults.
 A gene that regulates response to stress was
methylated resulting in ‘permanent anxiety’
state.
 This prepares the rats for a tough environment
by making them risk averse.
•Another study found maternal grooming behaviour
in rats effected glucocorticoid receptor expression
in the brain of their offspring.
 High grooming mothers produced less fearful
offspring who showed better physiological
stress control.
Diet
Mother's diet during pregnancy & DNA methylation
at birth is associated with child’s later adiposity
•Researchers looked for "epigenetic
markers of increased methylation” in
umbilical cord blood
•Mothers with early pregnancy diets low in carbohydrates
had children with these markers which were strongly linked
with child's obesity at ages 6 & 9
•It explains 25% of the difference in the fatness
•The effect was "considerably greater" than birth weight
& did not depend on how thin or fat the mother was.
•The developing baby tries to predict the
environment it will be born into, taking cues from
its mother & adjusting its DNA.
•This study provided the most compelling
evidence yet that just focusing on
interventions in adult life will not reverse
the epidemic of chronic diseases
Nutrition & the epigenome
•Both mice & human have the
agouti gene, when it is
completely unmethylated the
mouse has yellow coat colour, is
obese & prone to diabetes &
cancer
•When the agouti gene is
methylated (as in normal mice)
the coat colour is brown & the
mouse has a low disease risk.
•When researchers fed
• Fat yellow mice & brown
pregnant yellow mice a methyl skinny mice are genetically
rich diet, most of the resulting identical.
pups were brown & healthy &
•Some researchers have argued
stayed that way for life.
that the effect is ameliorated in
later generations
Nutritional & environmental chemical effects during
development
Institute of Environmental Health Sciences, NIH
•Nutritional health before pregnancy, during
pregnancy & the first 2 years of life has a significant
impact on the development of chronic diseases in
children, adolescents & adults
•Reducing exposure to environmental chemicals,
especially those with endocrine disrupting activities
during this period & perhaps longer, is likely to have a
significant impact on the development of chronic
diseases in children, adolescents & adults.
Risk of chronic diseases
Child development is the most important
time to intervene to prevent disease
Fixed genetics
contribution to risk
Life course
How nutrition alters gene expression
•Histones can "hug" DNA (with its TSG) so tightly that it
becomes "hidden from view for the cell“, it cannot be
utilised
Too much histones will "turn off" these cancer suppressors,
& allow cancer cells to proliferate.
•Certain foods, such as broccoli & other cruciferous
vegetables, garlic, & onions contain substances that act
as histone inhibitors, allowing the tumour suppressor genes
to activate & fight cancer.
•By regularly consuming these foods, we are naturally
supporting our body’s ability to fight cancer.
•So having a "cancer program" in our DNA does not
automatically mean we're destined to get cancer. Far from
it.
The nutrients that affect our epigenome & the foods
they come from
Nutrient
Methionine
Folic Acid
Vitamin B12
Vitamin B6
SAM-e (SAM)
Choline
Betaine
Food Origin
Sesame seeds, brazil nuts,
fish, peppers, spinach
Leafy vegetables,
sunflower seeds, baker's
yeast, liver
Meat, liver, shellfish, milk
Meats, whole grain
products, vegetables, nuts
Epigenetic Role
SAM synthesis
Methionine synthesis
Methionine synthesis
Methionine synthesis
Enzymes transfer methyl
Popular dietary supplement
groups from SAM directly
pill; unstable in food
to the DNA
Egg yolks, liver, soy,
cooked beef, chicken, veal Methyl donor to SAM
and turkey
Break down the toxic
Wheat, spinach, shellfish,
byproducts of SAM
and sugar beets
synthesis
Nutrient
Food Origin
Epigenetic Role
Removes acetyl groups
from histones, improving
Resveratrol
Red wine
health (shown in lab
mice)
Increased methylation,
Genistein
Soy, soy products
cancer prevention,
unknown mechanism
Increased histone
Sulforaphane
Broccoli
acetylation turning on
anti-cancer genes
Increased histone
A compound produced in acetylation turning on
Butyrate
the intestine when
'protective' genes,
dietary fiber is fermented
increased lifespan
(shown in the lab in flies)
Increased histone
Diallyl sulphide (DADS)
Garlic
acetylation turning on
anti-cancer genes
Epigenetics & Cancer Therapy
•Both gene mutations & epigenetic abnormalities can
drive the development of cancer.
•Epigenetics disturbances are the Achillies heel of
certain cancers
•Unlike genetic mutations, epigenetic changes are
reversible & restoring epigenetic balance represent
exciting potential therapeutic targets for cancer.
•More than 100 agents are in various stages of
development & the field of epigenetics holds exciting
implications for cancer detection, treatment &
prognosis.
Scientists Reprogram Cancer Cells with
Low Doses of Epigenetic Drugs
Release Date: 03/29/2012
•Azacitidine (AZA) & decitabine (DAC), have
antitumor responses in breast, lung, and colon
cancers.
•Low doses of AZA and DAC may re-activate
genes that stop cancer growth without causing
immediate cell-killing or DNA damage.
•Several drugs with epigenetic effects are already
on the market & tens more are in development. A
putative replacement, adjuvant or enhancers of
current cancer treatment (radiation &
chemotherapy).
•Scientists also used non-toxic peptides & amino
acids known as antineoplastons, which act as
genetic switches that turn the tumour suppressor
genes “on”.