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Epigenetics

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  • 1. Epigenetics• ‘Epi’genetics - ‘On’ or ‘over’ the genetic information encoded in the DNA
  • 2. Epigenetics• The study of reversible heritable changes in gene function that occur without a change in the sequence of nuclear DNA• Gene-regulatory information that is not expressed in DNA sequences is transmitted from one generation (of cells or organisms) to the next
  • 3. Epigenetics and Different Aspects of Life• Development of multicellular organism• Environment-organism interaction For examples: Nutrition supplements and environmental toxins Image: Randy Jirtle• Pathogenesis of diseases
  • 4. Molecular Mechanisms that Mediate Epigenetic Phenomena• DNA methylation (CpG dinucleotides)• Histone modifications Nucleosome
  • 5. Histone ModificationsAdapted from Lund and Lohuizen Genes Dev 2004
  • 6. Epigenetic Regulation of Gene Expression• Epigenetic information modulates gene expression without modifying actual DNA sequence• Histone modifications change the chromatin structure and affect the accessibility of DNA to regulatory proteins
  • 7. Epigenetic Regulation of Gene Expression Methylated DNA Histone
  • 8. Histone Modification Status Correlates with Transcriptional Activity• Gene activation correlated with H3-K9 acetylation• Gene silencing associated with H3-K9 methylation
  • 9. Epigenetic Inheritance• Transmission of non-DNA sequence information through either meiosis or mitosis• When a methylated DNA sequence replicates, only one strand of the next-generation double helix has all its methyl markers intact; the other strand needs to be remethylated• Maintenance methylase theory – DNA methyltransferases (DNMTs): Enzymes that bind methyl groups to cytosine nucleotides – DNMTs bind methyl groups to the naked cytosines based on the methylation template provided by the other strand-
  • 10. Epigenetics and Cancer• Chromosomal infrastructure is essential for gene control, determining both active and repressed states• It is important not only to turn the right genes on but also to turn the right genes off• Histones and chromatin components have key roles in this decision making process• If as few as three inappropriate genes are turned off, a normal cell can be converted into a cancer cell• This epigenetic silencing of genes underlies a new approach to cancer therapy• Mistargeting of these enzymes leads to tumorigenesis, but inhibition of their activity presents a novel approach to therapy