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

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

7 Crystal diffraction of histone structure

8 Chromatin organization and the tail of histone H3.

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10 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, ubiquitinationetc. 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.

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

12 Histone acetylation and deacetylation

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15 CHEST JAUNARY 2006

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17 TypeA HATstype B HATs localized in nuclei acetylate nucleosomal histones cytoplasmic fractions acetylating newly synthesized histones before chromatin assembly during DNA replication. Gcn5p and homologs PCAF, p300/CBP, TAFII250 and homologs, and SRC-1 and ACTR yeast Hat1p p300/CBP

18 Reversed acetylation modification

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21 Class I Rpd3p HDAC HDAC HDAC HDAC Class IIClass II Hda1p HDAC HDAC HDAC HDAC HDAC Class III Sir2-like deacetylases (NAD-dependent activity) HDAC Schematic Structure Amino Acids Year

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

23 Histone lysine methylation

24 Lysine methylation

25 H3K4 K9 K27 K36 K79 H4K20

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28 EZH2

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37 Thanks for your attention!