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Disclosure Bart Rutten
• Speaker fees received from: Lundbeck
• Positions held on Advisory Boards: No
• Grants and sponsoring: No
Disclosure Marco Boks
• Speaker fees received from: - Astra Zenica
- Lundbeck
• Positions held on Advisory Boards: - Geen
• Grants and sponsoring: - Geen
Stellingen
• 1. Alleen de DNA sequentie (i.e. genetische factoren) is overerfbaar
• 2. Het epigenetisch profiel van een individu is stabiel over de tijd
• 3. Epigenetische mechanismen medieren de persistentie van de invloeden van omgevingsinvloeden op phenotypes
Development of the number of citations including the term epigenetic.
Gräff J et al. Physiol Rev 2011;91:603-649
©2011 by American Physiological Society
DNA mutation
X
Genotype changed Phenotype changed
no DNA mutation
X
Genotype unchanged Phenotype changed
X
Genotype unchanged Phenotype unchanged
EPIGENETICS
Epigenetic
Mechanisms
• DNA methylation
• histone tail
alterations
• microRNA, etc…
2 meters DNA per cell
millions of neurons
Epigenetics & the environment = changes in phenotype and/or gene expression by
mechanisms other than changes in the DNA sequence itself
ENV
IRO
NM
ENT`
I. blocks transcription factors
II. attracts gene repressing molecules
Pishva et al. Translational Neuroscience. 2012
DNA Methylation ↓Gene Transcription
promoter exon 1 exon 2
quantity
gene methyl
e.g. MeCP2, mutations in MeCP2 -> Rett syndrome *
MTHFR, DNMT1, DNMT3a, DNMT3b
Jirtle et al. NRG 2007
Agouti
ACATATACGCGCGCGCGCGCGCGATATATCTGTCAA
promoter exon 1 exon 2 Agouti-gen
methyl administration
Postnatal environment
RNA of
glucocorticoid receptor
in hippocampus
promoter exon 1 exon 2
glucocorticoid receptor gene
methyl
Low maternal care
High maternal care
Glucocorticoid receptor mRNA expression Glucocorticoid receptor methylation
McGowan et al. Nature Neuroscience 2009
Epigenetics and childhood trauma in human brain
Tsankova et al. NRN 2007
no stress
chronic stress
chronic stress chronic TCA
Social Stress
BDNF
BDNF
BDNF
bdnf bdnf
bdnf bdnf bdnf
bdnf bdnf bdnf
bdnf
gene protein
Hippocampus
Genes regulating chromatin & bipolar disorder?
Genetic variations in genes involved in H3K4 methylation show associations with bipolar disorder
Identical environment
Anyway et al. Science 2005 Jirtle et al. NRG 2007
F4
pregnant female
Transgenerational Epigenetics
Altered DNA methylation Several generations: Identical genetic sequence
Altered DNA methylation Altered phenotype
Theory: Heritability of acquired traits
Lamarckism
1920s, William McDougall: training rats in a maze
Offspring of trained rats >> offspring of non-trained rats
Jean-Baptiste Lamarck 1744 -1829
History repeating?
DNA
RNA
Protein
promoter exon 1 exon 2
SNP/mutation
quantity quality
Cell functions
gene
Environment
EPIGENETIC
Inheritable
Working model
Paternal age
Nutrition
Maternal stress
Hypoxia
Rearing environment
Childhood trauma
Urban environment
Maternal infection Cannabis
Migration
Subclinical experiences
Prodromal state
Perinatal events
Rutten & Mill. Schiz Bull. 2009
Stress
Disorder
Wat is interessant aan epigenetica?
• Erfelijk
• Omgeving
• Trans generationele leer effecten
• Belangrijk in ontwikkeling
• Beïnvloedbaar door medicatie en dieet
Uitdagingen
• Invloed leeftijd en geslacht
• Invloed van DNA sequence variatie
• Invloed van medicatie
• Weefsel type
Correlatie tussen bloed en brein voor methylation levels onder invloed van
leeftijd
Horvath et al. Genome Biology 2012 13:R97
Sample plot of methylation levels by genotype groups
Boks MP et al. The relationship of DNA methylation with age, gender and genotype in twins and
healthy controls. PLoS One. 2009.
Cis and Trans correlations between DNA methylation and gene expression
van Eijk KR, de Jong S, Boks MP, et alBMC Genomics. 2012 Nov 17;13(1):636.
Boks MP, de Jong NM, Kas MJ, Vinkers CH, Fernandes C, Kahn RS, Mill J, Ophoff RA. Current status and future prospects for epigenetic psychopharmacology.
Epigenetics. 2012 Jan 1;7(1)
Omgevingsinvloed
• Prenatal nutrition
• Prenatal exposure to alcohol
• Other drugs of abuse
• Prenatal stress
• Maternal care
• Traumatic early life experiences
• Environmental enrichment
Psychiatrische aandoeningen
• Depressie
• Autisme
• Schizofrenie
• Bipolaire stoornis
• Cocaïne afhankelijkheid
• Alcoholisme
• Alzheimer
Bunnik Angry Bird Epigenetics Award
• 12 stellingen
• Rechterhand omhoog is JUIST
• Bij fout antwoord gaan zitten
Vragen
• Er zijn meer dan 25 epigenetische mechanismen
• Honger voor de geboorte heeft effect op de epigenetische status van het kind
• Met de leeftijd neemt DNA methylatie af (alles wordt minder).
• Er zijn geen medicijnen die direct op DNA methylatie werken