LAUSR

Bivalent genes are ready for activation upon the arrival of developmental cues. Here, we report that BEND3 is a CpG island (CGI)–binding protein that is enriched at regulatory elements. The cocrystal structure of BEND3 in complex with its target DNA reveals the structural basis for its DNA methylation–sensitive binding property. Mouse embryos ablated of Bend3 died at the pregastrulation stage. Bend3 null embryonic stem cells (ESCs) exhibited severe defects in differentiation, during which hundreds of CGI-containing bivalent genes were prematurely activated. BEND3 is required for the stable association of polycomb repressive complex 2 (PRC2) at bivalent genes that are highly occupied by BEND3, which suggests a reining function of BEND3 in maintaining high levels of H3K27me3 at these bivalent genes in ESCs to prevent their premature activation in the forthcoming developmental stage. Description Safeguarding stem cells Bivalent genes co-occupied by the epigenetic markers histone 3 trimethyllysine 4 (H3K4me3) and 27 (H3K27me3) were first observed in embryonic stem cells (ESCs). Gene bivalency has been widely thought to be a priming mechanism to facilitate gene induction kinetics during differentiation. However, loss of H3K4me3 at bivalent promoters by deleting the methyltransferase Mll2 has little effect on gene induction kinetics. Zhang et al. report that the protein BEND3 is required for optimal H3K27me3 occupancy at hundreds of bivalent promoters, and deletion of the Bend3 gene in ESC causes premature activation of bivalent genes and the failure of differentiation. The authors propose BEND3-mediated Polycomb stabilization as a mechanism to prevent premature activation and to safeguard the differentiation process. —DJ BEND3-mediated reining provides a mechanism to prevent premature activation of bivalent genes during differentiation.