- Chromatin remodelling: any change or modification to the chromatin
- In the paper, authors used term to describe ATP-dependent remodelling factors
- Epigenetic modification of histones makes different transcription patterns possible with the same genome
- Includes acetylation, methylation, ubiquitinylation, phosphorylation, sumoylation, ADP ribosylation, and many other modifications
- Histone modifications can assist with activation and repression of transcription
- H3K4me3: trimethylated lysine-4 of histone 3, activating histone mark
- H3K27me3: trimethylated lysine-27 on histone 3, repressive histone mark
- These two can be found in combination on certain promoters, called bivalent modifications
Bivalent modifications
- HCNE: highly conserved non-coding elements, tend to be enrichev d with these bivalent marks
- Upon depletion of PRC2 subunit, there was a loss of H3K27me3, which led to an upregulation of the genes
- Under wild-type conditions, bivalent genes showed little to no activation, suggesting genes are poised for activation in mouse ESCs
- In human ESCs and iPSCs, bivalent domains were often identified, on developmentally regulated genes
- H3K4me3 and H3K27me3 were found together on regulators of development that were expressed at low levels
- Also seen in other stem cell types, e.g. hematopoietic stem cells
- Some promoters still had bivalent promoters, even when they were terminally differentiated, suggesting that maybe bivalent marks are present at a low level in all cell types
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- Trithorax group (TrxG) deposits the H3K4me3 mark
- Polycomb group (PcG) proteins deposit the H3K27me3 (repressive) mark on histones
- Bivalent domains are mainly associated with CpG islands in ESCs
- H3K4me3 is deposited by the SETD1A, SETD1B, and MLL complexes
- Globally, the mark is deposited by the SETE1A and SET1B complexes
- MLL1 through MLL4 appear to carry out more specific functions
- MLL2: main methyltransferase at bivalent promoters
- MLL1/2: contain CXXC or zinc-finger CXXC (ZF-CXXC) domains, which specifically recognize unmethylated CpGs
- H3K27me3 is deposited by the PRC2 complex at bivalent promoters
- The core PRC2 complex is made up of EZH2 or EZH1, EED, SUZ12
- EZH2: enhancer of zeste homologue 2, catalytic subunit of the PRC2, methyltransferase
- H3K27 is recognized by chromodomain-containing proteins such as CBX
- many developmentally regulated genes are marked by bivalent domains bound by PRC and PRC2, though some exclusively by PRC2
- PRC2-specific bivalent domains are usually found on the promoters of genes that are not true developmentally active genes
- key pluripotent genes are shown to interact with MLL and PRC proteins
- Depletion of Oct4 in ESCs leads to selective depletion of H2K4me3 levels
- When ESCs are undifferentiated, those deficient of PRC2 show aberrant differentiated potential
- PcG proteins are therefore vital for embryonic stem cell differentiation
Chromatin remodelling and bivalency