Chromatin remodelling and bivalent histone modifications in ESCs. EMBO Reports.
- Nucleosome formed by pair of each of the core histones – H2A, H2B, H3, H4
- Linked histones (H1) between the nucleosomes forms higher-order chromatin structure
- Histone modification can assist with transcriptional activation and repression
- Combination of H3K4me3 (activating) and H3K27me3 (repressive) found in some promoters, called bivalent modifications
- HCNEs (highly conserved noncoding elements) tend to be enriched with bivalent modifications
- WT conditions there was little activation of these bivalent promoters
- Depletion of PRC2 subunit leads to loss of H3K27me3, upregulation of genes
- Concluded that the promoters are “poised” for gene expression
- Bivalent domains tend to be developmentally regulated, although some have been found in terminally differentiated cells
- In ESCs, bivalent domains tend to be associated with CpG islands
- Challenge: have yet to develop single nucleosome resolution technique, hard to determine function of these domains conclusively
- Trithorax group (TrxG) proteins deposit H3K4me3 – SETD1A, SETD1B, MLL complexes
- SET1A/B – responsible for global deposition of H3K4me3
- MLL2 is the main methyltransferase at bivalent domains
- Contains CXXC and ZF-CXXC domains, which recognize unmethylated CpGs
- MLL2 KO is embryonic lethal, shows developmentally important
- PcG proteins (PRC2) mainly deposit H3K27me3 at bivalent promoters
- Core PRC2 made up of EZH2 or EZH1, EED, SUZ12
- EZH2: enhancer of Zeste, catalytic subunit of the complex, methyltransferase for H3K27me3
- PRC2-specific bivalent domains are usually on promoters of not “bona fide” developmentally active genes
- PcG proteins are vital for ESC differentiation, depletion of PRC2 in ESCs shows aberrant differentiation potential
Key takeaways:
Glossary:
HCNE: highly conserved noncoding elements, tend to be enriched with bivalent modifications
Bivalent modifications: combination of both repressive and activating histone modifications
Chromatin remodelling: any change or modification to chromatin
H2K27me3: trimethylated lysine 27 on histone 3, repressive mark
H3K4me3: trimethylated lysine 4 on histone 3, activating mark