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Disruption of Imprinted Regions in a Mouse Model of Fetal Alcohol Spectrum Disorders (FASD)

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. Nature Vs. Nurture. http:// www.askdro.com / wp-content / uploads /2011/02/ Nature_versus_Nurture.jpg.

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Disruption of Imprinted Regions in a Mouse Model of Fetal Alcohol Spectrum Disorders (FASD)

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  1. 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.

  2. Nature Vs. Nurture http://www.askdro.com/wp-content/uploads/2011/02/Nature_versus_Nurture.jpg

  3. http://www.cosmosmagazine.com/files/imagecache/feature/files/20071004_naturenurture.jpghttp://www.cosmosmagazine.com/files/imagecache/feature/files/20071004_naturenurture.jpg

  4. Environmental Insults

  5. 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.

  6. Epigenetic Mechanisms • Histone Modifications • DNA Cytosine Methylation • MicroRNA

  7. DNA Cytosine Methylation CH3 5’------CpG------3’ 3’ -----GpC------5’ CH3

  8. DNA Cytosine Methylation . Metivier, R. et al. Cyclical DNA methylation of a transcriptionally active promoter. Nature452, 45–50 (2008).

  9. 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,CurrOpin Cell Biol

  10. Environmental Epigenetics

  11. 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

  12. 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

  13. 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 Stress 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.

  14. Hypothesis Fetal alcohol exposure induces alterations in brain gene expression that last into adulthood and are correlated with epigenetic modifications.

  15. Methods: Array Analysis Gene Expression DNA Methylation MicroRNA

  16. Results 3 Large Clusters of Brain Specific Imprinted noncoding RNA (ncRNA)

  17. Genomic Imprinting Maternal Paternal Normal Bialleic Gene Expression • Genes are expressed in a parent of origin specific manner. • Achieved by DNA Methylation. Maternally Expressed, Paternally Imprinted Paternally Expressed, Maternally Imprinted

  18. 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 CellBiol Davies et al. 2008,AdvExp Med Biol

  19. 14q32.21 (Murine 12qF1) Maternally Expressed, Paternally Imprinted Pten AKT-mTORpathway Tempo of newborn neuron integration during adult neurogenesis Implicated in the developmental basis of major psychiatric disorders

  20. 15q11-q13 (Murine 7qC) Paternally Expressed, Maternally Imprinted H/MBII-52 (SNORD115) snoRNA binds to mRNA III I II IV Va Vb VI III 5htr2c Pre-mRNA Inclusion of exon Vb without mRNA editing during alternative splicing Receptor with a stronger serotonin response

  21. Murine 2qA1 Paternally Expressed, Maternally Imprinted Sfmbt2-AS Sfmbt2 Intron 10 • Over 130 miRNAs • Mouse Specific • No Imprinting Center

  22. Future Directions • Confirmation of Results • Brain Region Specificity • Hippocampus • Trans-generational Effects

  23. What are Trans-generational effects? Direct Exposure Indirect Exposure F0 F1 F2 Great Grandchildren F3 http://learn.genetics.utah.edu/content/epigenetics/inheritance/images/DirectExposure.jpg

  24. 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.

  25. Acknowledgements Supervisor Shiva Singh Funding: Advisory Committee NSERC Kathleen Hill CIHR Anthony Percival-Smith OMHF Singh Lab: RaihanUddin Morgan Kleiber Haroon Sheikh Christina Castellani KatarzynaJanus Eric Diehl Pat McDonald Kiran Kumar SujitMaiti Rachel Danielson Randa Stringer Elizabeth Yan Aniruddho C. Hoque

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