Histone H3 lysine 4 trimethylation (H3K4me3) is a universal epigenetic mark that is deposited by histone methyltransferases. This mark can be found in the context of bivalent promoters, which harbour both repressive H3K4me3 and active H3K27me3 marks and hence are thought to be poised for lineage-specific activation or repression. Here, Francis Stewart, Henk Stunnenberg and co-workers challenge this model of poising (). They first show that the H3K4 methyltransferase Mll2 is responsible for H3K4me3 on bivalent promoters in embryonic stem cells (ESCs). Accordingly, the researchers find that Mll2 is bound to bivalent promoters but also to active promoters. By contrast, another H3K4 methyltransferase, Set1C, is bound to active but not bivalent promoters. Importantly, they observe that Mll2-deficent ESCs, which lack H3K4me3 on bivalent promoters, exhibit normal transcription responsiveness, thus arguing against a model of poising. Based on these and other findings, the authors propose that Mll2 acts as a pioneer methyltransferase and that Polygroup group action on bivalent promoters blocks the establishment of active Set1C-bound promoters.
