Histone Modifications and Cancer

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Histone Modifications and CancerHistone Modifications and Cancer

Histone Modifications and CancerHistone Modifications and Cancer

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

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• 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

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Definition of EpigeneticsDefinition of Epigenetics

Heritable and/or acquired changes in gene expression that occur without changes in DNA sequence.

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Histone code hypothesis

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

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Crystal diffraction of histone structure

8Chromatin organization and the tail of histone H3.

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The N-termini of core histones are active domains The N-termini of core histones are active domains

critical to DNA-protein interaction. Many specific amino critical to DNA-protein interaction. Many specific amino

acid residues in N-termini are subject to various covalent acid residues in N-termini are subject to various covalent

chemical modifications, such as chemical modifications, such as acetylationacetylation, , methylationmethylation, ,

phosphorylationphosphorylation, , ubiquitinationubiquitination, etc.etc.

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

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Histone acetylation and deacetylation

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CHEST 129 1 JAUNARY 2006

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TypeA HATs type B HATs

localized in nucleiacetylate nucleosomal histones

cytoplasmic fractionsacetylating 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

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Reversed acetylation modification

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Class I Rpd3p

HDAC1 482 1996

HDAC2 488 1996

HDAC3 428 1998

HDAC8 377 2000

Class II Hda1p

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 Acids Year

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Histone acetylation/deacetylationHistone acetylation/deacetylation

• Acetylation/deacetylation of defined lysine residues of H3, Acetylation/deacetylation of defined lysine residues of H3, H4, H2A and H2B histones;H4, H2A and H2B histones;

• Catalyzed by histone acetyltransferase/deacetylase Catalyzed by histone acetyltransferase/deacetylase complexes (HAT/HDAC);complexes (HAT/HDAC);

• Hyperacetylation (high) Hyperacetylation (high) →→ open nucleosome and chromatin open nucleosome and chromatin structure → transcription activation;structure → transcription activation;

• Hypoacetylation (low) → tight nucleosome and chromatin Hypoacetylation (low) → tight nucleosome and chromatin structure → transcription repression. structure → transcription repression.

• A balanced acetylation level of the genome is critical to the A balanced acetylation level of the genome is critical to the normal function of the cell and organism.normal function of the cell and organism.

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Histone lysine methylation

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Lysine methylation

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H3K4 K9 K27 K36 K79 H4K20

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EZH2

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Thanks for your attention!