Transcript 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
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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 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 a
few micrometers. Nucleosomes as basic units.
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Crystal diffraction of histone structure
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Chromatin organization
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and the tail of histone H3.
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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.
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Various modifications at defined sites of the core histone N-termini
constitute the “histone 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 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
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Reversed acetylation modification
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HDAC
Class I
Schematic Structure
Rpd3p
Amino Acids
Year
HDAC1
482
1996
HDAC2
488
1996
HDAC3
428
1998
HDAC8
377
2000
HDAC4
1084
1999
HDAC5
1122
1999
HDAC7
912
2000
HDAC6
1215
1999
HDAC9
673
2001
Class II
Hda1p
Class III
Sir2-like deacetylases (NAD-dependent activity)
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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.
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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!
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