The Mll2 branch of the COMPASS family regulates bivalent promoters in mouse embryonic stem cells

Embryonic stem cells (ESCs) possess a unique chromatin landscape in which 'bivalent' domains of trimethylated histone H3 Lys4 (H3K4me3) and Lys27 (H3K27me3) mark key lineage-specific genes. A new study now reports the identification of Mll2 (KMT2b) as the enzyme responsible for implementing H3K4me3 on bivalently marked promoters in ESCs. Promoters of many developmentally regulated genes, in the embryonic stem cell state, have a bivalent mark of H3K27me3 and H3K4me3, proposed to confer precise temporal activation upon differentiation. Although Polycomb repressive complex 2 is known to implement H3K27 trimethylation, the COMPASS family member responsible for H3K4me3 at bivalently marked promoters was previously unknown. Here, we identify Mll2 (KMT2b) as the enzyme catalyzing H3K4 trimethylation at bivalentlymarked promoters in embryonic stem cells. Although H3K4me3 at bivalent genes is proposed to prime future activation, we detected no substantial defect in rapid transcriptional induction after retinoic acid treatment in Mll2-depleted cells. Our identification of the Mll2 complex as the COMPASS family member responsible for H3K4me3 marking bivalent promoters provides an opportunity to reevaluate and experimentally test models for the function of bivalency in the embryonic stem cell state and in differentiation.