Disruption of Imprinted Regions in a Mouse Model of Fetal Alcohol Spectrum Disorders (FASD)
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Disruption of Imprinted Regions in a Mouse Model of Fetal Alcohol Spectrum Disorders (FASD)
Laufer, B., Diehl, E., Kleiber, M., Janus, K., Wright, E., and Singh, S.
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Nature Vs. Nurture
http://www.askdro.com/wp-content/uploads/2011/02/Nature_versus_Nurture.jpg
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http://www.cosmosmagazine.com/files/imagecache/feature/files/20071004_naturenurture.jpg
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Environmental Insults
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What is Epigenetics?
“A mitotically (or meiotically) inheritable change in gene expression, independent of an alteration in DNA sequence”
– Berger et al. (2009) Genes Dev.
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Epigenetic Mechanisms
• Histone Modifications
• DNA Cytosine Methylation
• MicroRNA6
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DNA Cytosine Methylation
5’------CpG------3’3’ -----GpC------5’
CH3
CH3
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DNA Cytosine Methylation
. Metivier, R. et al. Cyclical DNA methylation of a transcriptionally active promoter. Nature 452, 45–50 (2008).
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Non Coding RNA• 95% of the human genome is transcribed and
produces a vast number of noncoding RNAs (ncRNAs).
• Two types of Interest:– MicroRNAs• Degrade target mRNA or prevent translation
– SnoRNAs• Typically involved in mRNA editing
– However, there are exceptions
Carnicini et al. 2008, Curr Opin Cell Biol
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Environmental Epigenetics
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Alcohol as Environmental Insult
• Fetal Alcohol Exposure (FAE) affects gene expression, behaviour and learning.
• Changes maintained for a lifetime– Even after exposure has ceased for months
• Mechanism unknown
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Fetal Alcohol Exposure • Leading cause of preventable birth defects and
mental deficits
• FASD– Fetal Alcohol Spectrum Disorder – 1 out of 100 pregnancies– Physical abnormalities, behavioural and intellectual
problems
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Continuous Preference Model
• Free choice
• Quantity monitored daily
• 70% preference for 10% EtOH– 120 - 180 mg/dl per day– DBA/2J mice has only 10%
• No Stress13
Young C, Olney JW. Neuroapoptosis in the infant mouse brain triggered by a transient small increase in blood alcohol concentration. Neurobiol Dis 2006;22:548-54.
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Hypothesis
Fetal alcohol exposure induces alterations in brain gene expression that last into adulthood and are correlated with epigenetic modifications.
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Methods: Array Analysis
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Gene Expression MicroRNA DNA Methylation
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Results
3 Large Clusters of Brain Specific Imprinted noncoding RNA (ncRNA)
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Genomic Imprinting
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• Genes are expressed in a parent of origin specific manner.
• Achieved by DNA Methylation.
Maternal Paternal
Normal Bialleic Gene Expression
Maternally Expressed, Paternally Imprinted
Paternally Expressed, Maternally Imprinted
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Imprinted ncRNA
• 30% of parentally imprinted transcripts are ncRNA.
• Key role in neurodevelopment and memory.– Some appear to be fully imprinted in the adult brain
only.
• Imprinted ncRNAs are not only important for early life processes, but are also functionally important for ‘online’ adult brain functions.
Morison et al. 2005, Trends Genet
Wang et al 2004, Mol Cell Biol
Davies et al. 2008, Adv Exp Med Biol
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14q32.21 (Murine 12qF1)
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Pten
AKT-mTOR pathway
Tempo of newborn neuron integration during adult neurogenesis
Implicated in the developmental basis of major psychiatric disorders
Maternally Expressed, Paternally Imprinted
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15q11-q13 (Murine 7qC)
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III5htr2cPre-mRNA
I II III IV Va Vb VI
Receptor with a stronger serotonin response
Inclusion of exon Vb without mRNA editing during alternative splicing
snoRNA binds to mRNA
H/MBII-52(SNORD115)
Paternally Expressed, Maternally Imprinted
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Murine 2qA1
Intron 10
Sfmbt2
Sfmbt2-AS
• Over 130 miRNAs• Mouse Specific• No Imprinting Center
Paternally Expressed, Maternally Imprinted
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Future Directions1. Confirmation of Results
2. Brain Region Specificity– Hippocampus
3. Trans-generational Effects
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What are Trans-generational effects?
http://learn.genetics.utah.edu/content/epigenetics/inheritance/images/DirectExposure.jpg
F0
F1
F2
Direct Exposure Indirect Exposure
Great Grandchildren F3
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Conclusions• The genome is environmentally
responsive.
• The epigenome serves as the bridge between environment and genome.
• Thus, the environment shapes an individual significantly for a lifetime and beyond.
• The nature vs. nurture debate has been solved by epigeneticists.
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Acknowledgements
SupervisorShiva Singh Funding:
Advisory Committee NSERCKathleen Hill CIHRAnthony Percival-Smith OMHF
Singh Lab:Raihan UddinMorgan KleiberHaroon SheikhChristina Castellani
Katarzyna JanusEric DiehlPat McDonaldKiran KumarSujit Maiti
Rachel Danielson Randa Stringer Elizabeth Yan
Aniruddho C. Hoque