Download Epigenetics: Histone Modification I

Epigenetics:
Histone Modification I
Nucleosome
• A packaging unit for DNA
(=H3/H4 tetramer + two
sets of H2A/H2B dimer)
• DNA (- charge) and
histones (+ charge)
• histones = tails and
globular domains
Higher-Order Packaging of Chromatins
• An efficient packaging
strategy (10,000-fold
compaction)
• A barrier for gene
transcription
Three strategies to change
nucleosome arrangement
• used for regulating gene
transcription
• cis-effects: acetylationdriven activation
• trans-effects: readerdriven transcriptional
control
• Nucleosome
repositioning and
displacement – ATPdriven reaction
Various histone modifications
• H3 and H4 are most
modified
• Lys and Arg are most
frequent targets
• Acetylation on Lys:
activation
• Methylation on Lys:
activation or repression
• Methylation on Arg:
repression
• Ubiquitylation:
repression
• Phosphorylation on Ser
Thr: cell cycle signal
Major enzymes for histone
modifications
- Modifications are reversible
(HAT vs HDAC, Kinase vs PPase)
- Methylation on Lys has
different states (mono, di, tri)
- Methylations are very stable
Consequences of histone
modifications
- Modification on each amino acid has
a different meaning
- Two different modifications on one
amino acid are exclusive and have
opposite signals (K27me3 vs K27ace)
- Readers
(Acetylation- Bromo proteins,
Methylation- Chromo proteins)
- Main epigenetic regulators
Polycomb (repression memory)
 H3K27me and H2AK119ub
Trithorax (activation memory)
H3K4me
Position Effect Variegation(repression)
 H3K9me
Polycomb mutant
Sex com in the front legs of male flies
Pc mutants have sex comb in other legs
-> homeotic transformation
mis-expression of Hox genes
Polycomb-Group (PcG) genes control
Hox genes and other developmental genes
Main repression mechanism -> provides
“cellular memory or transcriptional memory”
Cellular memory
- Mammals 200 cell types vs
plants 30 cell type
- Different cell types have their own
identity in terms of transcriptional
programs
- Epigenetic modifications serve as a
molecular basis for cellular memory
Cellular memory
- Early genetic studies identified two
types of fly mutants
- Polycomb mutants – defects with
repression memory (H3K27me3
and H2AK119ub)
- Trithorax mutants – defects with
activation memory (H3K4me3)
PcG mutants
- a & b – imaginal disc
- c & d – suz12 mutant
- e & f – Ring1A mutant
Core PcG genes
PRC2 well conserved
PRC1 only in metazoans
Many duplications of PRC2
members in plants
Core PcG genes of PRC2
- three main components
Ezh1/2, Suz12, Eed
Ezh1/2- HMT enzyme
Eed – glue protein
Suz12 – no function yet
- several other proteins
RbAp48/49, Jarid2, Aebp2
RbAp48/49 – histone binding
Jarid2 – DNA binding
Aebp2 – DNA binding
PcG-dependent repression
PRC2 -> H3K27
H3K27 -> PRC1
PRC1 -> H2AK119ub
Targeting of PRC2 & PRC1 is
mediated either by ncRNA or
DNA-bindig protein
Maintenance of H3K27me3
during DNA replication is mediated
through Eed
Genome-wide PRE sites
- more than Hox cluster
- many genes with tissue-specific
genes are controlled through
PRC-mediated mechanisms
- PRC2 serves as temporary
repression mechanism
(poised state) in early stage embryo
- modify CpG islands