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Histone Modifications and Cancer

Histone Modifications and Cancer. - Yu Zhang, Ph.D., ( 张瑜 ) - Institute of Genetics and Cytology, School of Life Sciences, - Northeast Normal University. Histone code hypothesis Histone acetylation and deacetylation Histone lysine methylation

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Histone Modifications and Cancer

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  1. Histone Modifications and Cancer - Yu Zhang, Ph.D., (张瑜) - Institute of Genetics and Cytology, School of Life Sciences, - Northeast Normal University

  2. Histone code hypothesis • Histone acetylation and deacetylation • Histone lysine methylation • Argine methylation and transcriptional regulation • Histone modification in cancer • Epigenetic diagnosis and therapies of cancer

  3. Definition of Epigenetics Heritable and/or acquired changes in gene expression that occur without changes in DNA sequence.

  4. Histone code hypothesis

  5. Package of 2-meter long genomic DNA into nucleus of only a few micrometers. Nucleosomes as basic units.

  6. Crystal diffraction of histone structure

  7. Chromatin organization and the tail of histone H3.

  8. The N-termini of core histones are active domains critical to DNA-protein interaction. Many specific amino acid residues in N-termini are subject to various covalent chemical modifications, such as acetylation, methylation, phosphorylation, ubiquitination, etc.

  9. Various modifications at defined sites of the core histone N-termini constitute the “histone code”.

  10. Histone acetylation and deacetylation

  11. CHEST 129 1 JAUNARY 2006

  12. p300/CBP

  13. Reversed acetylation modification

  14. Class I Rpd3p HDAC1 482 1996 HDAC2 488 1996 HDAC3 428 1998 HDAC8 377 2000 Class IIHda1p HDAC4 1084 1999 HDAC5 1122 1999 HDAC7 912 2000 HDAC6 1215 1999 HDAC9 673 2001 Class III Sir2-like deacetylases (NAD-dependent activity) HDAC Schematic Structure Amino AcidsYear

  15. Histone acetylation/deacetylation • Acetylation/deacetylation of defined lysine residues of H3, H4, H2A and H2B histones; • Catalyzed by histone acetyltransferase/deacetylase complexes (HAT/HDAC); • Hyperacetylation (high) → open nucleosome and chromatin structure →transcription activation; • Hypoacetylation (low) → tight nucleosome and chromatin structure → transcription repression. • A balanced acetylation level of the genome is critical to the normal function of the cell and organism.

  16. Histone lysine methylation

  17. Lysine methylation

  18. H3K4 K9 K27 K36 K79 H4K20

  19. EZH2

  20. Thanks for your attention!

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