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Epigenetics & Methylation: The Influence of Our Ancestors by Phyllis D. Light, MA Herbalist (AHG) Epigenetic changes are dependent upon the methylation process. Methylation occurs in many different areas of the body but the majority of methylation takes place in the liver. A healthy liver, along with the right nutrients, contributes to healthy methylation process. To understand epigenetics, it is important to understand methylation and to understand methylation, it is important to understand how the liver work. So, let’s take a look at the liver How the Liver Works

The Liver

• Largest internal organ in the body • Most metabolically complex organ • Weighs about 3 pounds • Liver cells are called lobules • All blood leaving stomach and small intestines must go through liver • More than 500 functions have been identified with liver • Processes everything we eat, drink, breathe or rub on the skin • Two sources of blood: hepatic artery and hepatic portal vein • Hepatic artery brings oxygenated blood to the liver • Hepatic portal vein brings nutrient dense blood from the small intestines • Holds 1 pint or 13% of our blood at any moment • Can regenerate up to 25% loss • A portion of liver can be transplanted and grow • Considered seat of emotions – jealously, anger, greed, courage

Functions of the Liver

• Makes bile to carry away waste and breakdown fat • Makes proteins for blood plasma • Clears blood of drugs and other toxins • Breaks down old or damaged red blood cells • Clears blood of bilirubin – waste from breaking down red blood cells; build-up of

bilirubin causes jaundice • Converts glucose to glycogen for energy storage • Releases glycogen for quick energy • Makes cholesterol • Makes proteins that carry fats through blood • Regulates blood levels of amino acids • Converts ammonia, a poison, to urea. Ammonia is waste product of protein metabolism • Produces immune factors

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• Removes some bacteria from blood • Makes albumin which helps regulate fluid retention in the body • Helps regulate blood clotting • Processes hemoglobin for distribution of iron • Produces, stores, and regulates fat • Produces 25%-50% of lymph fluid • Stores vitamin A – 1-2 year supply • Stores vitamin B12 – 1-3 year supply • Stores vitamin D – 1-4 months supply • Stores copper, iron, vitamin K, vitamin E, copper

Helps Regulate Hormones

• Sex hormones: breakdown and eliminating excess hormones • Thyroid hormones: converts T4 to T3 • Cortisone and other adrenal hormones • Liver depends on growth hormone to operate healthy

Excretions of Liver

• By-products of toxin breakdown leave the body through bile or blood • Toxins in bile leave through the feces • Toxins in blood leave through the kidneys

How the Liver Detoxifies Phase I detox Phase 2 detox Methylation Detoxification • Water soluble outputs from Phase I excreted by kidneys • Fat-soluble intermediates are further processed in Phase 2 • Goal: slow down phase I and speed up phase 2 • If phase 2 is slow, intermediate toxins build up in liver • Thyroid health is important for both phases

Phase I detoxification CYP450 Enzyme Family • Converts through oxidation, reduction, hydrolysis • Enzymatic process • Free radicals are generated • Food additives, drugs, environmental toxins, pollutants, caffeine, alcohol • Includes CYP3A4, CYP1A2, CYP2C19 • Supported by B vitamins, anti-oxidants, choline, bioflavonoids, vitamin C

Nutrients Needed for Phase I • Folate

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• Vitamins B3, B6, B12 (methylated) • Vitamins A, D, E • Vitamin C and citrus bioflavonoids • Calcium • Quercetin • N-acetyl-Cysteine • Magnesium, Iron Speeds Up Phase I detoxification

• Brassica vegetables • Garlic, onions • Nutmeg, cloves • Capsicum, black pepper • St. John’s wort, Ginseng • Fish oil, vitamin E • Carotenoids • Grapefruit juice • Selenium • Manganese

Speeds Up Phase I detoxification

• Alcohol, tobacco, caffeine • Prednisone • Paint, nail polish • Pesticides • Car exhaust • Protein • Citrus fruit • Saturated fats • Vitamins B6, B12 • Heavy metals • Birth control pills, barbiturates

Slows Down Phase I

• Grapefruit juice • Capsaicin, hot peppers • Curcumin, Turmeric • Cloves • Raspberries, blueberries, soft fruits • Cruciferous vegetables • Sesame seed/oil • Hops • Valium, Prozac, Xanax

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• Anti-histamines • Niacin

Phase 2 Conjugation Pathway

• Another substance is added to render it harmless and water soluble • Breaks down intermediates from phase I and most hormones • Glutathione is required • Leaves through urine or bile

• Sulfur containing amino acids: methionine, taurine, cysteine, N-acetyl-cysteine • Non-sulfur amino acids: Glycine, glutamine, ornithine, arginine • Choline and inositol Enhances Phase 2

• Garlic, Onions, Leeks, Shallots • Broccoli, cabbage, Brussels sprouts • Green tea • Red grapes, apples, citrus • Dill, fennel, caraway • Olive oil, sesame oil, ghee, butter • Turmeric • Eggs • Fish oils

Major Phase 2 Pathways • Glutathione • Sulfate • Glycine • Glucuronide conjugations • Glutathione Pathway

Internal antioxidant and liver protector • Metabolizes steroids, thyroid hormone, fat-soluble vitamins, bile acids, bilirubin and

prostaglandins, penicillin, pesticides, petroleum distillates, alcohol, tetracycline • Functions as antioxidant enzymes, detoxifying free radicals and oxidized lipids or DNA • Can be depleted by large amounts of toxins, drugs, infections, starvation, aging, chronic

stress, artificial sweeteners, overuse of antibiotics Glutathione Pathway • Also present in other tissues • Products of glutathione metabolism can be excreted by bile or eliminated in urine • Made from L-cysteine, L-glutamic acid, and glycine • Milk thistle, whey protein, cruciferous vegetables, N-acetyl cysteine (NAC), a-Lipoic

Acid, Vitamins B6, B9, B12, and biotin, selenium, Vitamins C, E

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Sulfate Pathway • Attach sulfates from a sulfur donor to toxin • Plays a major role in drug or toxin breakdown • Role in metabolism of steroids, reproductive hormones, melatonin, thyroid and adrenal

hormones, serotonin, retinol, ascorbate and vitamin D, acetaminophen, phenolic compounds, histamine, dopamine, coumarins

• May also convert pro-carcinogens into carcinogens

Sulfate Pathway • May be used a compensatory phase 2 pathway • Activity limited by supply of inorganic sulfur • Inhibited by catechins, food colorants, flavonoids and phytoestrogens, and environmental

chemicals • Foods that support sulfate pathway include cruciferous vegetables, eggs, onion, garlic,

foods that contain molybdenum • Needs sulfur-containing amino acids: cysteine, taurine, methionine Glycine Pathway • Predominately involved in breakdown of salicylic acid (aspirin), benzoic acid and food

preservatives • Nutrients needed are glycine, B6, magnesium, low salicylate diet • Foods containing glycine: fish, dairy, cheese, meat, beans, soybean, spinach, pumpkin,

kale, cabbage, cauliflower, burdock root, cucumber, kiwi, banana Glucuronide conjugations • Removes used hormones: T4, estrogen, steroid hormones • Metabolizes acetaminophen, NSAIDS, benzodiazepines • Useful nutrients: calcium-d-glucarate, magnesium, zinc, Omega 3 fatty acids, curcumin,

vitamin B complex • Nutrients Needed for Phase 2 • Calcium-d-glucarate • L-glutamine, l-lysine, l-carnitine • Glycine, taurine • N-acetyl-cysteine (NAC)- helps rebuild glutathione levels • MSM (methyl-sulfonyl-methane) Enhances Phase II • Pau d’Arco • Sarsaparilla • Red clover • Milk thistle, Blessed thistle • Barberry, Oregon grape root, Goldenseal, Yellowroot • Licorice

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• Dandelion • Yellow dock • Burdock • Probiotics Slows Down Phase II

• Aspirin • NSAIDs • Low protein • Chronic exposure to toxins • Amount of medications used • Deficiencies of selenium, riboflavin, zinc, folic acid, glutathione, B12, molybdenum,

pantothenic acid, vitamin C • Food dyes

• Alcohol Damage • Fatty liver: more than 5%-10% • Damaged liver cells • Liver inflammation - alcoholic hepatitis • Cirrhosis – permanent scar tissue • Liver cancer • Drink alcohol in moderation – women process alcohol slower than men and are more

susceptible to liver damage Fatty Liver Disease • Linked to poor nutrition, obesity and sedentary lifestyle, medications, alcoholism • Other risk factors include insulin resistance, hyperlipidemia, high blood pressure, and type II

diabetes • Heredity risk • Rapid weight loss Signs of Liver Damage • Yellowing of skin and eyes – jaundice • Excessive fatigue • Dark urine • Pale stools • Retention of fluid in abdomen, feet, ankles, hands due to failure to produce albumin • Easy bruising • Pain in right side and abdomen Tips for a Healthy Liver • Use natural cleaning products in home • Reduce exposure to chemicals in the home – carpet, paint

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• Ventilate your home • Practice safe sex to avoid hepatitis • Avoid contaminated food and water – may carry hepatitis A • Hepatitis B is carried by blood and body fluids • Hepatitis C is carried by blood and body fluids Tips for a Healthy Liver • Don’t combine alcohol and Tylenol (acetaminophen) • Don’t combine medications with alcohol • Read medication information to avoid conflicting food, herbs, or other drugs which might

harm liver • Exercise regularly • Avoid countries with malaria and mosquito borne viruses • Avoid grapefruit, grapefruit juice or supplements with grapefruit bioflavonoids if you are

taking medication • The chemicals in grapefruit (both rind and pulp) can interfere with the liver enzymes that

break down drugs • Avoid recreational or street drugs • Choose a variety of foods from all 4 food groups • Eat lean meats, fish, dried beans, nuts • Eat fresh and organic foods if possible • Wash fruits and veggies before using • Eat veggies from the sulfur-bearing cruciferous family • Exercise on a regular basis • Drink at least 64 oz. of water daily. Herbs for the Liver • Milk thistle – increases glutathione; protects liver from toxins; help repair liver damage;

stimulates production of new liver cells; stimulates bile; may inhibit virus replication • Blessed thistle – increases glutathione; helps breakdown hormones; stimulates bile;

stimulates milk production • Burdock – antioxidant; protects liver from metal toxicity; helps restore damaged cells;

reduces inflammation; supports kidney function • Herbs for the Liver • Dandelion – stimulates production of bile; diuretic; antioxidant; stop bleeding in liver;

helps fatty liver; lowers blood sugar • Chicory – increases bile flow; diuretic, promotes growth of probiotics; antioxidant for

liver • Yellow dock – increases flow of bile; reduces free radicals in liver; increases digestive

enzymes activity; stimulates bowel movements; anti-bacterial; improves iron counts • Artichoke – stimulates and promotes discharge of bile; improves fatty liver; lowers

cholesterol; protects against liver damage; antioxidant; general for gastrointestinal issue; bile duct issues

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• Cayenne – stimulates action of liver; improves liver function; reduces rate of liver fibrosis; lowers triglycerides; does not effect cholesterol levels

• St. John’s wort – speeds toxins and pharmaceuticals through the liver • Goldenseal, Oregon grape root or yellow root – digestive bitter; stimulates flow of bile;

reduces small intestine bacterial overgrowth; reduces inflammation; anti-bacterial; boosts immune activity; targets mucous membrane tissue; anti-fungal

• Fenugreek – protects liver against alcohol-induced damage; reduces effects of fatty liver; increases levels of antioxidants in liver; may protect against pesticides

• Fennel – helps repair liver damage; reduces inflammation in digestive tract • Peppermint – promotes flow of bile; aids in digestion of fats; may lower cholesterol

levels; helps protect liver against toxins • Wild yam – liver cleanser; moves bile; reduces fatty liver; antispasmodic in digestive

tract; reduces inflammation; diuretic; hormonally active • Garlic – activates certain liver enzymes that metabolize toxins; contains sulfur

compounds; may protect against liver cancer; reduces fat accumulation in liver; reduces total cholesterol

• Black walnut – removes parasites; anti-bacterial; anti-fungal; inhibits replication of some viruses; useful in treating liver injury caused by certain environmental toxins such as carbon tetrachloride; lowers cholesterol

• Carrots, pumpkin, winter squashes – beta-carotene; vitamin A; stimulate flow of bile • Raisins – raisin water folk tradition for liver cleanse • Prunes – lowers cholesterol; stimulates bile flow; lowers elevated liver enzymes • Grapefruit – speeds toxins through liver; encourages production of liver enzymes that

remove toxins • Beets – contains betaine which helps liver eliminate toxins; contains pectin which move

toxins from digestive tract; anti-inflammatory • Apples - contains pectin which move toxins from digestive tract • Leafy greens – neutralize metals and toxins; chlorophyll moves toxins • Cruciferous vegetables – sulfur compounds • Walnuts - high in glutathione and omega-3 fatty acids • Avocados – help body produce glutathione

Methylation Key for our health, happiness, longevity, and mental health By Phyllis D. Light, MA, RH Methylation

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• Not one specific reaction that occurs in one location in the body • Many reactions taking place continually in our cells, especially in the liver • Occurs at the end of phase 2 detox in liver • Occurs more than a billion times per second in the body • Happens when one molecule gives a methyl group, which is a carbon atom linked to three

hydrogens, to another molecule • Methyl groups are transferred with enzymes Methylation • Controls sulfur metabolism • Influences glutathione production to control oxidative stress • Plays a role in other sulfur metabolites like cysteine, taurine, and sulfate • Influences the production of ATP • Process is used to make creatine, carnitine, CoQ10, phosphatidylcholine, melatonin, and

other nutrients • Helps make myelin sheath • Lymphocytes and monocytes must be methylated Methylation • Influences the functioning of the brain and the production of neurotransmitters • Affects autism spectrum disorders, ADHD, anxiety, cognitive and behavioral issues,

depression • Affects detoxification processes by liver • Influences histamine breakdown in gut • Helps eliminate heavy metals • Essential to long-term memory formation • Important in neural development Methylation • Detoxify toxins within the cells, repair damaged DNA, and create new cells • Used to metabolize dopamine, serotonin, norepinephrine and epinephrine • Methylate phospholipids, which promote transmission of signals through membranes • Makes embryonic stem cells differentiate irreversibly into different types of body tissue • Suppresses the expression of harmful stretches of DNA Methylation Influenced By • Genetic factors • Epigenetic factors • Psychological/emotional/physical stress • Smoking, alcoholism and other environmental toxins • Diet and nutrition (including supplements), especially B-vitamin and methionine intake • Oxidative stress load Methylation Influenced By

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• Eating processed foods with synthetic folic acid • Decreased stomach acid • Hypothyroidism and other chronic illnesses • Some medications which influence B vitamin use and/or have a detrimental effect on liver DNA Methylation • Regulates gene expression • Turns genes on or off but usually off • Methyl group binds to a gene then changes the way the gene expresses itself • When the methyl group is removed, the reaction stops, which turns off a gene or deactivates

an enzyme • DNA methylation is epigenetics • Affected by environmental factors Methylation Cycle • Methionine, which contains a methyl group, is an amino acid found in protein foods • Using magnesium, methionine becomes SAMe • Then, using ATP (adenosine triphosphate), SAMe travels throughout the body delivering a

methyl group to any number of reactions • When SAMe donates a methyl group, it is attached to the molecule that is being detoxified Methylation Cycle • Homocysteine is the product of this process. It’s left when a methyl group is donated • Vitamins B6, B12, and folic acid are necessary to reduce homocysteine and keep the

methylation process occurring • Homeocysteine is then ready to accept another methyl group which transforms it back into

methionine Methylation Cycle • However, if there are not enough methyl groups to transform the homeocysteine into

methionine, then levels of homeocysteine build in the body • Elevated homeocysteine levels are associated with heart disease, poor circulation, and other

degenerative disorders and inflammatory conditions • Elevated homeocysteine inside vessel walls increases LDL SAMe (S−Adenosyl Methionine) • Primary methyl donor • Donation of the methyl group transforms SAMe into SAH (S−Adenyl Homocysteine) • SAH is potent inhibitor of methylation • The SAMe/SAH ratio can be used as an index of methylation potential in a cell • SAMe is mainly synthesized, utilized, and degraded in the liver • Up to 80% of liver methionine is converted to SAMe, the source of glutathione, which

is required for liver detoxification reactions

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SAMe (natural or supplement) • Protects brains against oxidative stress • Effective for depression • Anti-inflammatory • Aids in sleep • Supplement best taken on empty stomach • Support healthy joints, and muscle and liver function • Helps converts tryptophan amino acid to serotonin and melatonin • Helps converts the amino acid tyrosine to dopamine, noradrenalin and adrenalin Methylation Pathways (donating methyl group) • folate plus B12: homocysteine to methionine: this occurs in all cells • choline-based TMG (trimethylglycine aka glycine betaine): homocysteine to methionine:

this occurs only in the liver: choline can be toxic in large doses as a supplement • DMG (dimethylglycine): homocysteine to methionine: may slow methylation when taken

as supplement • B6 with magnesium: homocysteine to cysteine: makes glutathione and taurine Methylation Cycle Block • A deficiency of any nutrient that affects the methylation cycle can cause a block • Reduce glutathione • Reduction in gene expression, which could be caused by drugs, infections or other

environmental factors • Genetics – build up of homeocysteine • Genetics – folate and B12 Methylation Cycle Block • Type 2 diabetes • Fibromyalgia/Chronic Fatigue Syndrome • Cancer • Pulmonary Embolism • Addictive Behavior, alcoholism • Insomnia • Autism or Down’s syndrome • Frequent miscarriages • Bipolar or manic depression • Allergies or Multiple Chemical Sensitivities • Atherosclerosis

Methylation Cycle Block • Spina Bifida, Cleft Palate, Neural Tube Defects • Multiple Sclerosis • Autoimmune Disorders

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• Hashimoto’s or Hypothyroidism • ADD or ADHD • Dementia/Alzheimer’s • Schizophrenia • Anxiety • Neuropathy • Chronic Viral Infections • Lyme Disease Methylation Cycle Block • The primary measurable sign of a methylation block is high homocysteine • B12 may also be low •

MTHFR About 45% of the population have a variance in this gene

• Provides instructions for making methylenetetrahydrofolate reductase (MTHFR), an enzyme needed to convert folate into useable form

• Genetic variance causes a key enzyme to function at a reduced rate which inhibits methylation

• Those with MTHFR variance produce 30 to 70% less methyl-folate than someone without the mutation

• This may also affect B12 metabolism MTR • Methionine synthase is an enzyme that facilitates transfer of methyl group from 5-

methyltetrahydrofolate to homocysteine using B12 • Mutations in this gene lead to a lack of methionine and the accumulation of homocysteine in

the body • Consider methyl-B12 and SAMe supplementation

MTRR • Enzyme needed for methylation of B12 and activation of methionine synthase (MTR) • Mutations in this gene lead to a lack of methionine and the accumulation of homocysteine in

the body • Consider methyl-B12 and SAMe supplementation • AHCY • Adenosylhomocysteinase is an enzyme involved in the conversion of methionine to

adenosine and homocysteine • Used in the regulation of methyl groups which are added to DNA, RNA, proteins, and lipids

(fats)

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• Variance in gene can lead to excess methionine • Avoid foods high in methionine: nuts, beef, lamb, cheese, turkey, chicken, fish CBS • The enzyme cystathione beta-synthase is dependent on B6 for conversion from

homeocysteine to cysteine • Homeocysteine builds in blood • Increases risk of cardiovascular disease and heart attack • May increase ammonia • Suggested supplements glutiathione and B6 Drugs that Affect Methylation • Acid blockers and antacids – reduces levels of magnesium and B vitamins • Cholesterol binding drugs – uses folate • High doses of niacin • Birth control pills, estrogen containing drugs, HRT – uses magnesium, B6, B2 • Metformin for diabetes • Ibuprofen – uses folate • ACE inhibitors – excrete zinc To Improve Methylation • Optimize digestion and microflora • Avoid synthetic folic acid supplements • Use methylated folate, B6 and B12 if needed • Eat dark, green leafy veggies as a natural folate source • Supplement with calcium, magnesium, zinc, selenium, vitamin C if needed • Good quality omega-3 and omega-6 fatty acids • Avoid processed foods, sugars, and saturated fat • Exercise on a regular basis • Eat pastured raised meat and eggs or wild game Under–over-methylation • Undermethylation – histamine is not methylated and so levels rise in bloodstream. This can

result in low levels of neurotransmitters. • Overmethylation – histamine is quickly methylated leading to low blood histamine and

serotonin, dopamine, and norepinephrine • A person might swing back and forth between the two depending on diet, toxin exposure,

stress, and genetics Undermethylation

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• High histamine reaction – allergies, hives, inflammation • High achievers • High folate or folate overload– may need to limit salads, dark green leafy veggies • High folate may lower levels of dopamine, norepinephrine, and serotonin Undermethylation • Self-motivated for achievement; high accomplishment; competitive in jobs, sports,

relationships • High sex drive • Infrequent or terse speech; shyness • Non-compliance with therapies; can do it better alone • Seasonal allergies; food allergies; hives • Blood histamine may run high Undermethylation • Strong willed • Phobias; addictive behavior • Calm demeanor, high inner tension • Frequent headaches • Large nose and ears; sparse hair growth • Can’t let go past • May be OCD or ODD • Social isolation – an extroverted introvert Undermethylation • Dietary inflexibility • Slenderness • Symptoms of Tourette’s Syndrome • Adverse reaction to benzodiazepines • Responds well to anti-histamines • May do well with SSRIs • Elevated white count Undermethylation • May have depressed calcium, methionine, B6 and excess folic acid • May have high histamine and low serotonin, dopamine and norepinephrine • Beneficial supplements - calcium, methionine, magnesium, zinc, TMG, omega-3 oils, B6,

SAMe, inositol, A, C and E, St. John’s wort • Potentially harmful supplements - folate, choline, DMAE, copper and histidine Overmethylation • Low histamine, folate, B12

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• Elevated serotonin and dopamine • May have elevated copper • Anxiety or panic attacks • Hyperactivity • Low libido • Nervous legs, pacing • Sleep disorder • Dry eyes and mouth Overmethylation • Low motivation during high school • Belief that everyone thinks ill of them • High pain threshold • Frenetic activity during onset of illness • Very few seasonal allergies • Ringing in ears • Upper body, neck, head pain • Food and chemical sensitivities • Low white count Overmethylation • Auditory hallucinations • Adverse reaction to estrogen therapy • History of eczema • Ringing in the ears • Artistic or musical ability • Adverse reaction to anti-histamines, SAMe, SSRIs and methionine • Improvement after lithium Overmethylation • May have depressed folate, B3, B12 and excess copper and methionine • May have low histamine and elevated serotonin, dopamine and norepinephrine • Beneficial supplements: B3, B12, DMAE, folate, choline, manganese, zinc, omega-3 oils, C

and E • Potentially harmful supplements: Methionine, SAMe, inositol, tryptophan, phenylalanine, St.

John’s wort In Summary - Methylation • Affects every tissue and organ system in the body • Healthy methylation reduces our risk for chronic diseases and cancer • Life couldn’t exist without it

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Epigenetics by Phyllis D. Light, MA Nature vs Nurture • Genetics – physical structure of DNA • Genetic mutation – adds or deletes building blocks to DNA • Epigenetics – affects how cells read the genes • Epigenetic change ornaments or tags the building blocks of DNA • Genetic mutation is permanent • Epigenetic change may be reversible • Nature vs Nurture • DNA tells what you can do; static and fixed • Epigenetics determines what you can do with the potential of your DNA • The tag or ornament can cross generations • Potential for disease outcomes – autism, autoimmune disease, cancer, diabetes,

cardiovascular disease, mental health disorders • DNA • Shaped like a helix • The amount of DNA in our bodies would stretch from the earth to the sun 100 times • Inside a cell, DNA is spooled like yarn around blocks of proteins called histones • Histones pack the threads of DNA tight and regulate when and how DNA genes get

translated into proteins DNA • The first step of DNA translation involves unraveling DNA off the histones • Histones have chemical tags that serve as switches to aid the unraveling • Two common tags are acetylation and methylation • Acetylation tags tend to unwind DNA and activate genes • Methyl tags can activate or repress a gene •

Epigenetics • Origins in cell biology and embryology • Darwin theorized that an organism can pass on traits that develop as a product of their

lifestyle (inheritance of acquired characteristics)

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• Jean-Baptiste Lamarck theorized that the environment gives rise to changes in animals – giraffe neck. Also that animals adapt to their environments and these adaptations can be inherited

Epigenetics • C.H. Waddington coined the term epigenetics to explain the different pathways a cell might

take toward differentiation. • How do different adult stem cells know their fate? • Myoblasts can only form muscle cells

• Keratinocytes only form skin cells • Hematopoetic cells only become blood cells • But all have identical DNA sequences

Epigenetics • Epigenetic information provides additional instruction on how, when and where this

information should be used • This information influences your ability to be different • Epigenetic patterns are easily altered by the environment Epigenetics • The epigenetic landscape is non-linear and incorporates the effects of chance and

environment • Relationship between a person’s set of genes (genotype) and an individual’s observable

traits (phenotype) are not deterministic • Provides a general molecular mechanism for all the non-genetic factors that influence an

individual’s phenotype Epigenetics • In biology, refers to mechanisms of gene regulation that determine the state of a cell and

that are heritable through cell divisions • Do not involve changes in DNA sequence • Refer to chemical modifications (such as methylation) of DNA • Can be stably inherited from one cell to another Types of Epigenetic Changes • DNA Methylation - epigenetic signaling that can fix genes in the “off” position; direct

modification • Histone modification - histone proteins act to package DNA, which wraps around the

eight histones, into chromosomes; direct modification • Non-coding RNA – does not encode proteins; not a direct modification of DNA;

interfering RNA bind to messenger RNA and prevent translation into protein

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Methylation • Can activate or inactivate genes • May silence (imprint) a gene from one parent which can be expressed in the offspring • May contribute to disease such as lupus, immune disorders, cancer, facial abnormalities Methylation • Not one specific reaction that occurs in one location in the body, but many reactions

taking place continually in our cells, especially in the liver • A methyl group consists of one carbon atom connected to three hydrogen ones which are

passed around a group of molecules in a cycle. • Two of DNA’s four bases can be methylated: cytosine and adenine Mechanisms of Action • Methylation of cytosine nucleotides (building blocks) in DNA • Modification of histone proteins – proteins that organize the genetic material • Histones have high amount of amino acids which gives it a positive charge • DNA has negative charge • Thyroid, stress and inflammatory hormones influence gene expression by binding with

specific proteins and creating tags Epigenetic Tags • Cloned - genetically identical but different colors – calico color on X chromosome • Identical Twins with Different Hair Color Epigenetics and Cancer • DNA repair is a critical process in genetic health • Inability to repair DNA may be a major contributor to the development of cancer • Hypermethylation of promoter regions has a silencing effect on tumor suppressor genes

which normally function to protect cells from turning cancerous • Hypermethylation is an increase in the epigenetic methylation of cytosine and adenosine

residues in DNA Epigenetics and Cancer • ~13% of sporadic breast cancers and 5-30% of ovarian cancers present with

hypermethylation of the BRCA1 gene • 40-90% of sporadic colorectal cancer has hypermethylation of the MGMT gene • Hypomethylation is implicated in cancers of the prostate, lymphocytic leukemia, cervical

cancers, breast ductal carcinomas • Hypomethylation refers to unmethylated DNA that should be methylated • Environment can influence epigenetic changes

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Dutch Famine Study • German’s blocked food to the Dutch in the winter of 1944. • Calorie consumption dropped from 2,000 to 500 per day for 4.5 million. • Children born or raised in this time were small, short in stature and had many diseases

including edema, anemia, diabetes and depression. • Those children, as adults, had higher levels of cardiovascular disease and obesity due to less

DNA methylation of the insulin-like growth factor II gene. Dutch Famine Study • As adults, also had higher rates of schizophrenia. • The Dutch Famine Birth Cohort study showed that women living during this time had

children 20-30 years later with the same problems despite being conceived and born during a normal dietary state.

Överkalix Study • Retrospective study conducted in Överkalix, Sweden • Divided population into three cohorts: 1890, 1905, 1920 • Assessed each cohort for access to food supply during slow growth period (SGP) of

adolescence (8-10 girls, 9-12 boys) • Summary, shortage of food for grandfather resulted in lower cardiovascular disease for

offspring Överkalix Study • When the father or mother was exposed to a famine during SGP, offspring exhibited

protection against cardiovascular causes of death. • If the paternal grandfather lived through a famine during his SGP it tended to protect

grandchildren from diabetes (P=0.09). • If the paternal grandfather had an abundance of food during their SGP, their grandchildren

had a four-fold increased risk for death of diabetes mellitus. Överkalix Study • Paternal grandfather’s food supply linked to grandson’s mortality • Paternal grandmother's food supply to granddaughter's mortality • Sharp change in food supply of paternal grandmother linked to increased cardiovascular

mortality in granddaughters Avon Longitudinal Study of Parents and Children (ALSPAC) • Began in 1991; still ongoing in Bristol, UK • The earlier the father started smoking, the greater the BMI at 9 ears of sons, but not

daughters • Daughters showed a reduction in total lean mass Barker • Barker, a scientist in the UK during the 1980s found the highest rates of heart disease were

actually in the lowest-income communities

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• People with the highest risk of early heart attack, before the age of 65, were people who were born at the lowest birth weight

• If the nutritional status during pregnancy is poor, epigenetic mechanisms are triggered in the developing baby to hoard calories because the baby senses that it’s being born into an environment of scarcity

Influencing Factors • Phytoestrogens • Prescription drugs • Synthetic estrogens • Endocrine disruptors • Diet • Nutrient level • Environmental Toxins • Stress Phytoestrogens • Excess phytoestrogen intake of coumestrol and equol may cause hypermethylation of

certain genes (clover, alfalfa, beans) • Genistein can have a protective effect in prostate cancer & breast cancer via histone

demethylation and/or acetylation and chromatin remodeling of tumor suppressor genes, resulting in their activation (soy, beans)

• Prescription Drugs • Synthetic estrogens, combined oral contraceptive pills, fluoroquinolone antibiotics, beta-

blockers, statins, cox-2 inhibitors, neuroleptics, SSRIs, Ritalin, Adderall, chemotherapeutics and general anesthetics

Estrogens • Critical period of estrogen effect on human reproductive tracts between 2nd and 3rd

trimester of development • Perinatal or neonatal exposure of rats lead to “imprinting” of reproductive tracts

associated with increased proliferation, inflammation, and dysplastic changes in later life • Developmental exposure to estrogens can be shown to be associated with permanent

defects in reproductive system • These defects can be transmitted to 2nd generation • This is epigenetic imprinting through DNA methylation Environmental Influences • Neonatal exposure to estrogen and bisphenol increases risk of prostate cancer -

reprograms and over-expressed the PDE4D4 gene – African Americans have higher risk with exposure

• Neonatal exposure to DES, a synthetic estrogen, increases risk of uterine cancer

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Environmental Influences • Association between DNA methylation and environmental metals, including nickel,

cadmium, lead, and particularly arsenic • Exposure to black carbon (BC), a marker of traffic particles, was also associated with

decreased DNA methylation • Other Chemicals • In utero exposure to the common traffic-related air pollutants, polycyclic aromatic

hydrocarbons (PAHs), is a risk factor for development of childhood asthma Stress and Emotional Influence • Studies found that fear and social deprivation were major causes of DNA methylation • Stress or trauma and the resulting release of hormones can create tags • Our attitude helps dictate epigenetic influence Stress and Emotional Influence • Stress affects methylation of gene that regulates glucocorticoids and their effect on

behavior • Affects methylation of genes that influence inflammation • Affects hypermethylation of genes that related to the development of cancer Six Types of Fear • Fear of loss of money or security • Fear of criticism or loss of self-esteem • Fear of sickness or fatal disease • Fear of loss of love of those held dear • Fear of growing old and what old age brings • Fear of death The Mind • Subconscious mind is programmed by age 6 or 7 • Subconscious mind controls conscious actions • Character of life is printout of subconscious mind • Victim mentality is common • Reprogram mind; recognize your role in your life Nutrients • B vitamins – folate, B12, B6 • Zinc • Selenium • Amino acids – methionine, cysteine, tyrosine • Calcium, magnesium • Choline • Resveratrol • Calorie restriction

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Lifestyle • Alcohol limits methyl transfer reactions • Cigarette smoking has a broad impact on genome-wide methylation that, at many loci,

persists many years after smoking cessation (at least 5 years) • Exercise creates methylation changes and new methylation patterns and an increase in

gene expression Lifestyle • Processed sugar can cause epigenetic changes if hyperglycemia lasts longer than six

hours. • Glucose restriction may enhance tumor suppressor genes • Poor methylation may result in altered gene transcription, leading to impaired vitamin D

synthesis associated with severe disease activities Thanks for coming!!!!