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Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute

Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011. Definitions of Epigenetic and Epigenetics.

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Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute

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  1. Epigenetics: from Inheritance to Cancer Maxwell Lee National Cancer Institute Center for Cancer Research Laboratory of Population Genetics April 21, 2011

  2. Definitions of Epigenetic and Epigenetics • Epigenetic is related to epigenesis---The theory that an individual is developed by successive differentiation of an egg rather than by a simple enlarging of a preformed entity. • Epigenetics = epigenesis + genetics---developmental processes that initiated by genotype but don’t involve changes in genetic materials. By Conrad Waddington

  3. Dualism of Genetic and Epigenetic Inheritance systems • Genetics---Genetic inheritance vs. mutation, which operate on individuals to change DNA sequences in the spaces of evolution, population, and pedigree. • Epigenetics---Cellular memory vs. plasticity, which operate on cells to change epigenetic states in the spaces of development, differentiation, and physiology.

  4. Definitions of Epigenetic and Epigenetics • Epigenetic is related to epigenesis---the theory that an individual is developed by successive differentiation of an egg rather than by a simple enlarging of a preformed entity. • Epigenetics = epigenesis + genetics---developmental processes that initiated by genotype but don’t involve changes in genetic materials. By Conrad Waddington Modern Definition of Epigenetics • Epigenetics---the study of mitotically and/or meiotically heritable changes in gene function that can not be explained by changes in DNA sequences. • Biochemical basis of epigenetics---DNA methylation and chromatin structure/modifications. • Function of epigenetics---gene expression regulation.

  5. Chromatin and DNA Methylation

  6. 5-methylcytosine

  7. DNA Methylation and Methyl Transferase

  8. Effects of DNA Methylation on Chromatin and Transcription

  9. Interaction between DNA Methylation and Chromatin

  10. Examples of Epigenetic Phenomena

  11. Multiple Layers of Epigenetic Information • Epigenetic information at the organism level • Epigenetic information at the cellular level • Epigenetic information at the allelic level

  12. Genomic Imprinting Gynogenetic lethal Androgenetic lethal normal

  13. Igf2 Phenotype is Paternally Transmitted

  14. Beckwith-Wiedemann syndrome (BWS) • The cardinal features of this disorder are exomphalos, macroglossia, and gigantism in the neonate. • Patients have enlarged tongue, together with omphalocele or other umbilical abnormalities. Visceromegaly, adrenocortical cytomegaly, and dysplasia of the renal medulla are conspicuous features. • Adrenal carcinoma, nephroblastoma, hepatoblastoma, and rhabdomyosarcoma occur with increased frequency. • BWS is caused by mutation in P57KIP2 and LOI of LIT1 and IGF2.

  15. Beckwith-Wiedemann Syndrome (BWS) Adrenal carcinoma, nephroblastoma, hepatoblastoma, and rhabdomyosarcoma.

  16. P57KIP2 Mutation in Beckwith-Wiedemann Syndrome (BWS)

  17. Loss of Imprinting (LOI) of A Regulatory RNA in BWS mat B N* B 6 kb pat 4.2 kb epigenotype mat pat

  18. Beckwith-Wiedemann syndrome (BWS) mat pat pat pat mat pat mat pat

  19. Loss of Imprinting (LOI) in Cancer

  20. X inactivation and genomic imprinting Inter-individual and intra-individual variation Epigenetics and Allelic Variation in Chromatin TF H3-Ac Pol II RNA Active Repressor H3K9-Me 5mC Inactive

  21. Allelic-specific Chromatin State Determined By ChIP-on-chip Method

  22. Inheritance Analysis Of Allelic Histone H3 Acetylation State

  23. Allelic-specific DNA Methylation Kerkel et al, 2008

  24. Heritable Germline Epimutation of MSH2 in a HNPCC Family Chan et al., 2006

  25. Heritable Epimutation of MSH2 in HNPCC due to Deletion of the 3’ Exons of TACSTD1 Ligtenberg et al., 2009

  26. Part 2 Extension to Knudson’s Two-hits Hypothesis Epigenetic silencing

  27. Part 2 Epigenetic Silencing of Tumor Suppressor Genes in Human Cancer

  28. Part 2 How Epigenetics Affects Genetics?

  29. Multistage Cancer Progression Model

  30. Distribution of CpG Sites in Human Genome

  31. Distribution of Methylation at CpG Sites in Human Genome

  32. Methylation of Human Chromosomes

  33. Common Methods Used in DNA Methylome Studies Sequencing Bisulfite-treated DNA MSO microarry Illumina MeDIP genomic DNA Hpa II enrichment McrBC

  34. High-throughput DNA Methylation Profiling Using Universal Bead Arrays

  35. High-throughput DNA Methylation Profiling Using Universal Bead Arrays

  36. Distribution, Silencing Potential and Evolutionary Impact of Promoter DNA Methylation in the Human Genome

  37. Distribution, Silencing Potential and Evolutionary Impact of Promoter DNA Methylation in the Human Genome

  38. MethylScope Array (McrBC)

  39. HpaII Enrichment by Ligation-mediated PCR (HELP)

  40. DNA Methylation Profiling of Human Chromosomes 6, 20 and 22

  41. DNA Methylation Profiling of Human Chromosomes 6, 20 and 22

  42. Comparison of Sequencing-based Methods to Profile DNA Methylation

  43. Comparison of Sequencing-based Methods to Profile DNA Methylation

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