Bivalent domains, containing both the activating H3K4me3 and silencing H3K27me3 histone modifications, are considered essential in Embryonic Stem Cells (ESCs) to rapidly respond to differentiation cues by either up- or downregulation, thereby providing an epigenetic blueprint for lineage determination.
Together with the group of Francis Stewart, the team of Henk Stunnenberg (photo left) now shows in the current issue of Development that Mll2, one of the six Set1/Trithorax-type H3K4 methyltransferases in mammals, is required for trimethylation of bivalent promoters in mouse ESCs. Also, Mll2 is bound to bivalent promoters. Intriguingly, loss of H3K4me3 on bivalent promoters by KO of MLL2 did not affect differentiation of ES cells, thereby arguing against a priming model for bivalency.
In contrast, we propose that Mll2 is the pioneer trimethyltransferase for promoter definition in the naïve epigenome and that Polycomb group action on bivalent promoters blocks the premature establishment of active, Set1 complex-bound, promoters.
Mll2 is required for H3K4 trimethylation on bivalent promoters in embryonic stem cells, whereas Mll1 is redundant. Denissov S*, Hofemeister H*, Marks H*, Kranz A*, Ciotta G, Singh S, Anastassiadis K, Stunnenberg HG^, Stewart AF^. Development. 2014 Feb;141(3):526-37. doi: 10.1242/dev.102681. Epub 2014 Jan 14. *shared; ^Corresponding authors
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