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

Promoters of many developmentally regulated genes have a bivalent mark of H3K27me3 and H3K4me3 in embryonic stem cells state, which is proposed to confer precise temporal activation upon differentiation. Although Polycomb repressive complex 2 (PRC2) is known to implement H3K27me3, the COMPASS family member responsible for H3K4me3 at bivalently-marked promoters was previously unknown. Here, we identify Mll2 (KMT2b) as the enzyme responsible for H3K4me3 on bivalently-marked promoters in embryonic stem cells. Although H3K4me3 at bivalent genes is proposed to prime future activation, we did not detect a 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 implementing H3K4me3 at 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.