Promoter bivalency favors an open architecture of the stem cell genome

In embryonic stem cells (ESCs), bivalency characterizes the chromatin state of developmental gene promoters, simultaneously modified by Mll2 and Polycomb complexes. Despite its essential role in embryogenesis, the function of bivalency is currently unclear. Here we show that Mll2 plays a central role in stem cell genome organization. We generate a catalog of bona-fide bivalent genes in mESCs and demonstrate that loss of Mll2 leads to increased Polycomb occupancy. Consequently, promoters lose accessibility and long-range interactions become redistributed, affecting ESC differentiation. We propose that bivalency balances accessibility and long-range connectivity of promoters to modulate developmental gene expression. List of ChIPseq samples (Mll2 wt and mutant), ATACseq samples (Mll2 wt and mutant) and RNAseq samples (differentiation in embryoid bodies, day0, day3, day6 and day9). List of new ChIPseq samples and PROseq samples (Mll2 wt and mutant). List of HiC samples. Conditional MLL2 KO samples: OH means WT and TAM means KO. Catalytic inactive MLL2 samples: WT means WT and CD means Catalytic Dead.