Histone modification
- Created by: natasha8sherry
- Created on: 10-11-13 16:18
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- Histone modification
- Acetylation
- Always positive regulation
- N-terminal tails acetylated by co-activators:
- CBP/p300
- SAGA
- VP16 recruits SAGA experiment
- Viral protein 16 activator used alongside Gcn4 activator in studies - activation domain from VP16, DNA binding domain from Gcn4
- On naked DNA templates in absence of SAGA there is SOME activation by VP16 as GTFs and TFIIB are recruited
- When SAGA added it is recruied by VP16 + higher levels of transcription are observed
- VP16 recruits SAGA experiment
- Gcn5
- Recruited by Gcn4
- PCAF
- Acetylation of lysine residues (DNA acidic -ve , lysine basic +ve)
- Acetylation reduces +ve charge so weakens attraction
- Activators can then compete with histones
- Chromatin remodellers can move nucleosomes
- Transfer of acetyl groups from Acetyl Co-A
- Acetylation reduces +ve charge so weakens attraction
- Ubiquitylation
- Most commonly ubiquitinated:
- H2A
- Lys-119
- Enriched in the satellite regions of genome
- Lys-119
- H2B
- Lys-120
- Binds to the gene body of transcriptionally active genes
- By E2 - Rad6
- By E3 - Bre1
- Lys-120
- Mainly mono
- H2A
- Ubiquitination enzymes
- Addition
- E1
- E2
- E3
- Ubiquitin ligase - combines with ubiquitin-containing E2 ubiquitin-conjugating enzyme, reocgnises target protein and causes attachment of ubiquitin to a lysine on target via isopeptide bond
- Removal
- Isopeptidases
- Addition
- Regulates transcription via proteasome-dependent destruction of transcription factors
- Activator or repressor?
- REPRESSOR
- Rad-6 mediated H2B ubiqu linked with silencing genes in budding yeast
- Deletion of rad6 gene = defects in telomeric silencing
- ACTIVATOR
- Transcriptionally stalled hsp70 genes contain 50% ubiquitylated-H2A whereas regions of non-transcribed satellite DNA contian only 4% uH2A
- In fission yeast the level of uH2B increases when gal1 gene is activated - but isopeptidases deubiquitylate H2B as gal1 mRNA product accumulates (drop in level of uH2B acts as a repressor)
- REPRESSOR
- How does it work?
- May affect chromatin higher order structure, allowing machinery access
- May act as signalling molecule to recruit other regulatory molecules
- May impact other histone modifications which in turn regulate transcription
- Evidence of ubiquitylation affection histone acetylation and methylation
- Most commonly ubiquitinated:
- The different histones
- H1
- Positioned between nucleosomes - bringing them closer together - even further condensation of chromatin
- H2A
- H2B
- H3
- H4
- H1
- Phosphorylation
- All 4 histone tails contain acceptor sites
- Phosphorylated by kinases
- Dephosphorylated by phosphatases
- Can occur at:
- Serine
- Tyrosine
- Threonine
- H2B
- Ser-32
- H3
- Ser-10
- Promotes acetylation of H3K14 by Gcn5 + promotes Gcn5-mediated expression of genes in vivo
- Ser-28
- Thre-11
- Phosphorylation of these residues associated with histone acetylation
- Tyr-37
- Phosphorylated by Wee1 enzyme - key component of cell cycle regulation
- Mark important for suppression of replication-dependent core histone protein gene transcription
- Phosphorylation directly blocks binding of transcriptional activator
- Ser-10
- H1
- Can be phosphorylated at multiple residues
- Involved in stabilisation of nucleosome and contributes to 30nm chromatin fibre
- Role in chromatin relaxing --> gene transcription
- Active rRNA promoters on H1 often phosphorylated
- All 4 histone tails contain acceptor sites
- Methylation
- Mainly at lysine residues
- Can be mono/di/tri
- Can alter affinity of histones for DNA
- Can direct binding of additional TFs
- H3k4me3
- Associated with active genes and recognised by co-activators
- Recruits TFIID by binding to TAF3 subunit where TAF1 binds acetylated histones
- H3k79me3
- Associated with repression and silencing genes
- H3k27
- Di
- Activation
- Tri
- Repression
- Di
- H3k4me3
- Acetylation
- Untitled
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