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Epigenetics 101 Why Grandmothers are Important

Photo from: welcomebooks.com

Dian Baker PhD, APRN, PNP

dibaker@csus.edu

Learning Objectives • Describe the basic concepts behind epigenetics

• Discuss why the epigenome is sensitive to maternal (and maybe paternal), nutrition stress, and environmental exposures

• Explain why epigenetics may provide a mechanism for prevention of behavioral disorders

To meet our objectives:

1. Review basics of DNA, genes, genomes 2. Overview of epigenetics

3. How might epigenetics impact behavior and

development?

4. What does the future hold?

Contact information: Dian Baker dibaker@csus.edu

What is everyone talking about?

Epigenetics

I am the beneficiary of a lucky break in

the genetic sweepstake

Isaac B. Singer

OR NOT?

Photo from:

http://www.europarl.europa.eu/comparl/tempcom/genetics/graphics/genetics.jpg

Overview of the Basics

• What’s a gene? What is DNA? – 3 billion chemical based pairs

• What’s a genome?

– 25, 000 to 30,000 indentified genes – Except for Red Blood Cells all human cells have a complete

genome – 99% of all nucleotide bases are the same in all humans

• What’s epigenetic? “in addition to the genome”

www.ornl.gov/sci/tachresources/human-genome/project

Overview of the Basics

• Double Helix

DNA and GENES

• Instructions to grow and live reside in the nucleus of every cell

• These instruction are in a molecule – DNA – your human blueprint

• Twisted ladder – double helix

• 4 letter alphabet – A always pairs with T, and C always pair with G

– G Guanine A adenine T thymine C cytosine

DNA

• We have about 3 meters of DNA in each cell, how does it fit? It turns and twist in a ladder

• DNA information is packed into chromosomes

• Chromosomes are tightly packed DNA with a protein wrapper (histone)

• Humans have 46 chromosomes, one set of 23 each from mom and dad

What is a gene?

www.montana.edu/wwwai

• Instruction manual made up of DNA molecules

• Provide directions for building all the proteins in our bodies

• About 30,000 genes – each with special sets of instructions – • not all are used, all the

time in fact, most are not!

Genes – special set of instructions

• Each cell makes use of its genetic materials in a different way – that is why the heart is the heart, and the ear is the ear

• Functional genes turn on and turn off certain parts of the DNA materials

• Housekeeping genes keep things in order

www.ornl.gov/sci/tachresources/human-genome/project

Telomeres and Aging

• Ends of chromosomes – telomeres

• Telomeres protect our genetic data

• Like the plastic tip of a shoelace, protect the gene from fraying and sticking together

• Each time the cell divides the telomeres get shorter and less protective – this process is assoc with certain cancers and aging

What does it look like really?

What about Epigenetics?

“Epigenetic changes influence the

phenotype without altering the genotype.”

- Benjamin Lewin

Photo from: stochasticsscientist.blogspot.com/2010/05/grandmotherfavorite

Epigenetics

• Waddington – 1942 – Intersection of ecology,

development, evolution and genetics

– Can change the phenotype without alteration of the genome – but changes can persist across generations

– Environment can drive alteration in the epigenome • 3 mechanism

– DNA methylation – Histone modification – Non-coding, duplication RNA

Ho & Burggren J of Exp Biology. 2010, 21, 3-16

Photo from:christs.cam.uk/cms/misc/images

Epigenetics

• Turn on and off the tape players

• Currently know of 3 knobs on the controls

– RNA

– Nucleosome

– DNA methylation

DNA + histones make Chromatin

Repair of DNA

Imagine from: publications.nigms.nih.gov/.../RepairingDNA.htm

Red Dots – Epigenetic Methylation sites in the genome

Photo from: Nova Ghost in your Genes

• The Epigenome at a Glance2

• http://learn.genetics.utah.edu/content/epigenetics/intro/

An example – epigenetics at work The Agouti Sisters – Twin Mice

Jirtle & Waterland Duke University

Next set of Agouti Sister slides and

photos from

http://learn.genetics.utah.edu/

Agouti Gene

• http://learn.genetics.utah.edu/

What happens in stressful situations? Stress and Epigenetics

Stress Circuit – HPA Axis

(hypothalamus-pituitary-adrenal)

http://learn.genetics.utah.edu/

Nurturing Mothers

• When mothers lick their pups and nurture them, epigenetics come into to play

• More receptor sites to stabilize stress hormones are established in the “licked” rats

• The increase in receptor sites passes to the next generations

http://learn.genetics.utah.edu/

Is it inherited?

• Just as the genome is passed along from parents to their offspring, the epigenome can also be inherited.

• The chemical tags found on the DNA and histones of eggs and sperm can be conveyed to the next generation.

Imitating Nature with Science

http://learn.genetics.utah.edu/

Epigenetics at work Important environmental flexibility

• Reaction to stress can be a good thing, it depends on the environment

• Stressful environments make “stressed, less nurturing moms” but the offspring may need to have excellent stress reaction – “be alert and anxious”

Jirtle & Waterland http://learn.genetics.utah.edu/

Epigenetics are intergenerational Its your grandmother !

• Part of the genome get turned on and off for the eggs developing inside the young female

• Environment, hereditary, stress, nutrition, etc. during your grandmother’s pregnancy with your mom affect you!

Grandpa & Dad’s role in epigenetics

• Still not clearly understood

• Environment does matter

• Boys ages 9-12 have a slow growth period and ready for spermatogenesis – Nutrition ( and possibly stress) during this time –

correlation to grandchildren’s life span – diabetes and heart disease

Photo from: Learn.genetics.utah.edu/ epigenetics/twins

Epigenetics and Disease

• MOST epigenetic changes are harmless • However current research projects are examining

epigenetics and genomic links for hundreds of diseases (PudMed - 37,194 hits) – Cancer – Leukemia – has active trials ongoing – Obesity – Irritable Bowel Syndrome – Personality Disorders (Maladaptive Disorders) – Schizophrenia – multiply studies – Autism – Muscle Disorders – Mitochondrial Disorders – Dental Disease – Addiction

Just some epigenetics disease

From: nature.com/nated

Epigenetics and Behavior

• Mental health – semaphorins and the frontal cortex

• Advancing paternal and maternal age & cognitive function

– Reichenberg (2010) Cog Neuropsy, 14(4), 337

• Suicide and child abuse – McGowan et al. (2009) –compared brains of suicide victims

with those that died in car accident – found significant differences in methylation glucocorticoid (stress) receptors

• Disruptive behaviors – Tremblay (2010) J Child Psy and Psych 51(4), 341

Epigenetics and Autism • Multiple links to epigenetics and a role in

autism

• Fragile X, Rett Syndrome

• Maternally deprived duplications imprinted on chromosomes 15q11-13 and 7q

• Mitochondrial disorders

• Epigenetics from imprinting do not show on genomic sequencing

• Shanen, C. (2006). Human Molecular Genetics, 15(2), R138.

Autism & Epigenetic con’t • Monozygotic twins discordant for Dx of autism

• Microarray analysis lymphoblastoid cell lines

• Methylations profiling – differences between the discordant twins, and between siblings

• Methlation status difference in gene transcription, nervous system development, cell death/ survival all implicated in autism – Nguyen AT, Rauch TA, Pfeifer GP, Hu VW. The FASEB Journal, April 2010

Epigenetic Autism and ADHD A few examples

• Impaired methylation and mutations of mecp2- autism (RETT & Angelman Syndrome) – Currenti (2010). Cell Mol Neurobiolo,30,161.

– DNA hypomethylation of folate maternal carrier gene • James et al. (2010). Am J Med Gen B Neuropsy Genet, May

• Epigenetic and Cognition – Miller (2010). Science, July, 329,27.

• Abstract thinking – Horner (2009). J Am Acad Child Adol Psy,48,1047.

Epigenetics, Nutrigenomics and Environment

From:HealthMatterstoMe.com

Epigenetics, Nutrigenomics and Environment

• BPA and the The Twins

• Good news –

– Maternal Diet and the “The Agouti Twins”

– Maternal nutrition matters BUT don’t count Dad out

http://learn.genetics.utah.edu/

Pharmcogenomics

• Food Drug Administration (FDA) – consider clinical implications of genomics

• Racial and ethic differences

• About 10% drug labels now consider genes

• Warfarin

• Atomoxetine (ADHD medication – simulate) – Variability in metabolism to CYP2D6

– Variant alleles effect metabolism – over or under metabolize (Michelson et al. 2007)

FDA (2007)Table of valid biomarkers/genomics/

Epigenetics, You and Your Family

Surgeon General Family Health

What about you?

What about popular myths?

• Genes inherited from parents do not set your life course in stone

• Adverse fetal and childhood experiences can lead to chemical changes and epigenetic changes

• Despite some marketing – there is no evidence that “enrichment” programs can change the epigenome or enhance brain function From: Nat Scientific Council of Developing Child Harvard University Early Experiences can alter gene expression

and affect long-term development working paper #10

What might be recommended? • High quality health services and nutritional

support for families

• Avoiding exposure to known environmental toxins and toxic substances

• Epigenetic changes happen across generations – reduce stress, economic insecurity

• Education for teachers, healthcare providers, caregivers, families, and the general public about epigenetics

From: Nat Scientific Council of Developing Child Harvard University Early Experiences can alter gene expression

and affect long-term development working paper #10

IN the future

Researchers at UCD, Jorge Dubcovsky and colleagues, improving wheat through epigenetics

Avoiding the controversy regarding “genetic engineering”

Important Ethical Questions for our Future

The Ghost in Your Genes

http://www.pbs.org

/wgbh/nova/genes/

mice.html

QUESTIONS

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