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Lecture outline

Lecture outline. Class organization Introduction to Epigenetics. Lecture outline. Class organization Target audience b. Organization: lecture, research lecture, student presentations. Lecture outline. Class organization Target audience

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Lecture outline

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  1. Lecture outline • Class organization • Introduction to Epigenetics

  2. Lecture outline • Class organization • Target audience • b. Organization: lecture, research lecture, student • presentations

  3. Lecture outline • Class organization • Target audience • b. Organization: lecture, research lecture, student • presentations • c. What is expected: • attendance, participation, questions for the student papers • 2 exams (recitations before them) • student presentations • (grad and CAMB enrolled: final proposal)

  4. Student presentations 1. TWO volunteers for next week (September 13th): chromatin assembly 2. For all other slots: everyone needs to present, choose a date or topic and e-mail me as soon as possible IMPORTANT: if you decide to drop the class and have chosen a presentation date already please let me know 3. If >19 students then we double up on papers one students presents the background of the field plus the first half of the paper the second student does the second half of the paper and future directions

  5. Lecture outline • Class organization • Introduction to Epigenetics • what are epigenetic phenomena • where does epigenetic regulation occur

  6. Epigenetic phenomena: heritable alternative states of gene activity that do not result from altered nucleotide sequence

  7. Examples of Epigenetic Phenomena Monozygotic: Genomes are identical

  8. Examples of Epigenetic Phenomena Monozygotic: Genomes are identical Arturas Petronis 2006 Monozygotic (identical) twins and disease etiology

  9. Examples of Epigenetic Phenomena Monozygotic: Genomes are identical

  10. Rainbow and Copycat Cloned cat: Genome is identical Yet looks different from mother

  11. Rainbow and Copycat Calico cat coat color cannot be cloned!!! Not based on genetics Based on Epigenetics: Color gene is X-linked Random X-inactivation of cells in blastula all daughter cells will inherit that pattern

  12. Genetics vs. Epigenetics +germline invariable

  13. * transient (not heritable) * mitotically heritable * meiotically heritable

  14. Plants: many examples of meiotically heritable or transgenerational epigenetic phenomena http://learn.genetics.utah.edu/content/epigenetics/inheritance/

  15. Animals: fewer examples known http://learn.genetics.utah.edu/content/epigenetics/inheritance/

  16. Animals: fewer examples known Kaati, G., Bygren, L.O., Pembrey, M., and Sjostrom, J. (2007). Transgenerational response to nutrition, early life circumstances and longevity. European Journal of Human Genetics 15: 784-790. http://learn.genetics.utah.edu/content/epigenetics/inheritance/

  17. Human transgenerational epigenetic phenomena? Time magazine 2010 Utah Epigenetics website View NOVA special “A ghost in your genes” http://en.sevenload.com/videos/tX02lnf-Nova-The-Ghost-In-Your-Genes-1-6

  18. The material for Epigenetics Nucleus; chromatin

  19. Starting at the beginning The conundrum Human DNA: 2 m Human nucleus r = 10 µm 10,000 x compaction

  20. The solution DNA is compacted via interaction with proteins THIS IS THE TEMPLATE FOR EPIGENTIC PHENOMENA

  21. ac ac ac ac DNA methylation ac Chromatin organizes and compacts DNA Nucleosome from Horn and Peterson Science, 2002

  22. Chromatin structures Woodcock and Dimitrov, COGD, 2001 Caterino and Hayes, Nature Structural and Molecular Biology, 2007

  23. Primary structure the NUCLEOSOMAL DNA

  24. Beads on a string

  25. Twenty-Five Years of the Nucleosome, Fundamental Particle of the Eukaryote Chromosome Roger D. Kornberg and Yahli Lorch; Cell, 1999.

  26. Nucleosome: 147 bp of DNA Histone octamer = 1.7 turns

  27. The nucleosome: histones plus DNA

  28. HISTONES

  29. Two classes of histones (canonical) Core Histones H2A conserved H2B conserved H3 highly conserved H4 very highly conserved Linker Histones H1 not conserved Small proteins, ca. 10 kD, very basic Three domains A. Histone fold B. Histone fold extension C. Extended N (and C)-termini

  30. Histone fold: 3 conserved alpha helices Histone fold extension and N-termini C-termini Linker histone Tails are K (lysine) and R (argenine) rich

  31. HISTONE/ DNA INTERACTIONS • 1. Charge neutralization: basic residues lysine, • argenine • 2. Hydrophobic side chains; threonine, proline, valine, • isoleucine with deoxyribose • 3. Main chain amide with phosphate oxygen

  32. Canonical histones and histone variants

  33. Secondary structure linker histone 30 nm fiber

  34. ac ac ac ac DNA methylation ac Chromatin organizes and compacts DNA Nucleosome from Horn and Peterson Science, 2002

  35. ac ac ac ac DNA methylation ac Chromatin restricts accessibility of the genome Nucleosome from Horn and Peterson Science, 2002

  36. Types of Chromatin

  37. Euchromatin Transcriptionally active, less compacted Heterochromatin Less transcriptionally active, very compacted a) constitutive heterochromatin centromeres, telomeres b) facultative heterochromatin rDNA, transposons, inactive X chromosome

  38. www.nenno.it/publications/mnphdthesis/diss08.jpg Heterochromatin (stained) http://www.biology.wustl.edu/faculty/elgin/hp2chrom.jpg

  39. Barr Body Region * Immunofluorescent straining of the human interphase nucleus. * The white box indicates the Barr body region where the inactive X chromosome resides during interphase. Chadwick and Willard (2004) PNAS

  40. Nucleosomes are obstacles to transcription Hodges et al. Science 2009

  41. Transcription happens outside of condensed chromatin 2003

  42. Transcription happens outside of condensed chromatin 2003

  43. DNA that contacts histones is not readily accessible

  44. Nucleosome: 147 bp of DNA Histone octamer = 1.7 turns

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