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Epigenetics 101 Why Grandmothers are Important
Photo from: welcomebooks.com
Dian Baker PhD, APRN, PNP
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 [email protected]
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
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
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 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
Repair of DNA
Imagine from: publications.nigms.nih.gov/.../RepairingDNA.htm
• 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/
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.
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
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
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
• 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/
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”
The Ghost in Your Genes
http://www.pbs.org
/wgbh/nova/genes/
mice.html