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Content What are the evidence from epigenetics science? Diseases & conditions linked to epigenetics • • • • • • • • • • • 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”.