1 / 48

Epigenetics: ”From Phenomenon to Field” and Impact on Plastic Surgery Research

Epigenetics: ”From Phenomenon to Field” and Impact on Plastic Surgery Research. Basic Science Seminar Series University of Michigan Department of Surgery Section of Plastic Surgery Brent M. Egeland, MD October 13, 2007. Outline. Importance History Definitions Chemistry

tate
Download Presentation

Epigenetics: ”From Phenomenon to Field” and Impact on Plastic Surgery Research

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Epigenetics: ”From Phenomenon to Field” and Impact on Plastic Surgery Research Basic Science Seminar Series University of Michigan Department of Surgery Section of Plastic Surgery Brent M. Egeland, MD October 13, 2007

  2. Outline • Importance • History • Definitions • Chemistry • Laboratory Techniques • Implications in Plastic Surgery

  3. Why?

  4. Definition: Epigenetics • Waddington 1942 • Originally a combination of the words "genetics" and "epigenesis" • Epigenesis: differentiation of cells from a totipotent state in embryonic development (used in contrast to "preformationism").

  5. Definition: Epigenetics • 69th CSH Symposia (2004): • Conference Dedicated to Epigenetics • No definition could be agreed upon • ”An epigenetic phenomenon is a switch-like change in phenotype that is heritable, but does not involve DNA mutation.” C. David Allis

  6. Why Epigenetics? • Post-Genomic Era • ENCODE • Genomics and proteomics is not enough • Contol of above beyond promoters and regulators is of utmost importance in: • Oncogenesis • Stem Cell Biology • Genetic therapy • Aging

  7. History • Coalesced into field of study that affects all areas of biology • Collection of apparently disparate phenomena • Over 1000 manuscripts on topic • First observations dates to 1941 • HJ Mueller ”eversporting displacement” • McClintock noted that these positional effects were the basis of ”mutible loci”

  8. History • X-Chromosome Inactivation • Pre-32 cell stage • mosaic cell population

  9. History • 1980's: Molecular Biology and Genetics • 1990's: Genomics • 2003: Human Genome Complete • 2004: ENCODE • 2005: NCI announce: • Human Epigenome Project

  10. Definition: Epigenome ”Sum of genome-wide epigenetic patterns, distinguishes and defines one tissue from another, stem cells from somatic cells, and aged from young cells.” National Cancer Institute (NCI), Division of Cancer Biology (DCB)‏ Workshop on Defining the Epigenome: Addressing the Value and Scope of a Human Epigenome Project November 28–29, 2005 Andrew P. Feinberg and Peter A. Jones

  11. Chromatin • Euchromatin: • Uncompacted • Active • Heterochromatin: • Compacted • Untranscribed • Changes with cell cycle

  12. 30nm Fiber

  13. Beads on a String • H1: Linker histone: contacts the exit/entry of the DNA strand on the nucleosome. • Linker DNA between Histones

  14. Nucleosome

  15. Histone

  16. DNA Packaging • Varys greatly with Cell Cycle • DNA never completely ”naked”

  17. Scaffold or Dynamic? • Is chromatin simply a scaffold for packaging DNA?

  18. Dynamic • Histones are Modified • DNA is Modified • Heritable transcription states

  19. Histone Modifications K K Acetylation = Transcriptional Competence Methylation= Transcriptionally Silenced

  20. DNA Cellular Differentiation • All cells inherit the same DNA sequences • Cellular differentiation processes rely strongly on epigenetic rather than genetic inheritance.

  21. DNA Modification • Chemical modification of DNA • Can be inherited without sequence change • Part of the epigenetic code • Methylation is most characterized epigenetic mechanism • Commonly occurs at ”junk” DNA

  22. DNA Methylation

  23. DNA Methylation

  24. CpG Islands

  25. Laboratory Techniques • Chromatin Immunoprecipitation • Inhibition of Deacetylases (HDAC-I)‏ • Site-specific analysis of histone methylation • Multigenerational assesment of above • Methylation-specific PCR in-situ Hybridization • Q-PCR in Combination with ChIP

  26. Consequences • Genome is static • Genotype • Germ Cell Inheritance • Epigenome is dynamic • Phenotype • Somatic epigenetic inheritance • Cellular "memory" • Most terminally (irreversibly) differentiate • Morphogens activate/silence genes – DNA is not altered

  27. Consequences • Mammals cannot respond to loss of some tissues • Inability to regenerate limbs • Plant cells do not terminally differentiate

  28. Evolution • Short-term adaptation • allowing for reversible phenotype • Allows multigenerational revisible phenotypic switch to express and repress that particular gene • DNA message is unchanged • Differential mutation rates associated with epigenetic features to control the mutation rates of particular genes

  29. Teratogens • Exert effects on fetus by epigenetic means • Epigenetic effects may preserve effect of teratogen throughout life of child • Can a teratogen exert influence offspring? • Diethylstilbestrol: Second and possibly Third generation effects

  30. Research

  31. Why Do I Care? ?

  32. Plastic Surgery • Fundamentally involved in clinical epigenetics • Aging • Oncology • Wound Healing • Basic Science in Plastic Surgery • Regenerative medicine • Stem Cell biology • Organogenesis • Neural plasticity

  33. Oncology Clin Cancer Res 2007;13(13) July 1, 2007

  34. Aging • Chronological or Epigenetically Defined? • Free-Radicals • Oxidants • Telomeres • methylation

  35. Aging Change in phenotype with methylation of DNA.

  36. Werner Syndrome

  37. Breast Cancer

  38. Stem Cells

  39. Organogenesis

  40. Neuroal Plasticity • Why does the CNS lack plasticity? • What are the possibilitys of increasing this plasticity towards regenerative capacity?

  41. Hernia

  42. Male Pattern Baldness

  43. The list goes on.... • Are there differing methylation signatures of fibroblasts in normal, hypertrophic, keloid scarring. • Can fibrotic tissue (fibroblasts) be reversed to form skin, bone, muscle? • Is cleft lip epigenetically inhereited?

  44. Can we Modify Epigenetics? • Can methylation be reversed? • Rate decreased? • Environment? • Diet? • Pharmacologically?

  45. Diet Agouti Gene: Yellow fur, obesity, diabetes, tumorogenesis Methyl Donor Diet: (onions, garlic, beets, folic acid, B12, genestein)‏ No Supplements .

  46. HCC: Histone deacetylase inhibitors (HDAC-I) & Demethylating agents Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 10066

  47. Decitabine & Azacitidine 5-aza-2'-deoxycytidine • Mechanism of action: • Phosphorylation and direct insertion into DNA • Blocks effects of DNA methyltransferase • Causing hypomethylation fo DNA. • May reverse inactivation of supressor genes • Can lead to cytotoxicity, bone marrow suppression • aza- Azacitidine

  48. References Age-related DNA methylation changes in normal huma...[Clin Cancer Res. 2007] - PubMed Result A method to study the expression of DNA methyltran...[Methods Mol Biol. 2007] - PubMed Result Clinical Trial: Epigenetics in the Aging Process Decreased androgen receptor gene methylation in pr...[J Clin Endocrinol Metab. 2006] - PubMed Result EMF Award: Epigenetic Control of Senescence and Aging Entirely new approach to the treatment of aging Epidermal stem cells are defined by global histone...[PLoS ONE. 2007] - PubMed Result Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer -- Agrelo et al. 103 (23): 8822 -- Proceedings of the National Academy of Sciences From The Cover: Epigenetic differences arise during the lifetime of monozygotic twins -- Fraga et al. 102 (30): 10604 -- Proceedings of the National Academy of Sciences Google Image Result for http://edoc.hu-berlin.de/dissertationen/seitz-stefanie-2004-10-20/HTML/seitz_html_21996ee1.png Google Image Result for http://www.biophysik.uni-bremen.de/radmacher/gallery/osteoblast_b.gif Google Image Result for http://www.med.ufl.edu/biochem/keithr/fig2pt2_flowchart-sm.gif Google Image Result for http://www.mun.ca/biology/desmid/brian/BIOL2250/Week_Two/bead2sol.jpg Human hair genealogies and stem cell latency. [BMC Biol. 2006] - PubMed Result IngentaConnect Techniques Used in Studies of Age-Related DNA Methylation Changes It Is Time for a Human Epigenome Project -- Rauscher 65 (24): 11229 -- Cancer Research Leukemia - Abstract of article: Age-related differences in leukemia biology and prognosis: the paradigm of MLL-AF4-positive acute lymphoblastic leukemia Mitochondria, oxidants, and aging. [Cell. 2005] - PubMed Result Modern Pathology - Abstract of article: DNA methylation in breast and colorectal cancers NOVA | Ghost in Your Genes | Epigenetic Therapy | PBS NOVA: Epigenetic Therapy http://www.bio.sci.osaka-u.ac.jp/bio_web/lab_page/ogura/photo-neuron.jpg PLoS Biology - DNA Methylation Profiling of the Human Major Histocompatibility Complex: A Pilot Study for the Human Epigenome Project Program | The First Annual Iberian Congress on Anti-Aging Medicine and Biomedical Technologies Proteome analysis of human hair shaft: from protei...[Mol Cell Proteomics. 2006] - PubMed Result Reversal of Maternal Programming of Stress Responses ... Altering Epigenetic Marking Later in Life -- Weaver et al. 25 (47): 11045 -- Journal of Neuroscience Title: Epigenetics and aging: the targets and the marks. Source: Trends in genetics [0168-9525] Fraga yr:2007 vol:23 iss:8 pg:413 -8 The DNA methyltransferases of mammals. [Hum Mol Genet. 2000] - PubMed Result The emerging role of epigenetics in cellular and o...[Exp Gerontol. 2003 Nov-Dec] - PubMed Result Transposable Elements: Targets for Early Nutritional Effects on Epigenetic Gene Regulation -- Waterland and Jirtle 23 (15): 5293 -- Molecular and Cellular Biology Transposable Elements: Targets for Early Nutritional Effects on Epigenetic Gene Regulation -- Waterland and Jirtle 23 (15): 5293 -- Molecular and Cellular Biology NCI Epigenome Project

More Related