Oct1 recruits the histone lysine demethylase Utx to canalize lineage specification

The pathways used to transition from an undifferentiated, pluripotent state into cell type-specific states are incompletely understood. Here we show that the transcription factor Oct1/Pou2f1 allows for correct induction of silent, developmental lineage-specific genes to "canalize" developmental progression. Using inducible-conditional Oct1 knockout embryonic stem cells and single-cell gene expression profiling, we show that mesodermal differentiation is impaired in the Oct1 deficient condition. Oct1 deficient cells fail to form late paraxial mesoderm and early somite stage populations, and show "leaky" developmental trajectories with inappropriate lineage branching and accumulation of poorly differentiated cells that retain gene expression and metabolic hallmarks of pluripotency. Oct1 directly binds and regulates genes critical for developmental regulation, including genes encoding mesoderm-specific master regulators and components of chromatin regulatory complexes. Oct1 positively resolves gene bivalency by recruiting Utx to mesoderm-specific, bivalent/poised targets, thereby removing inhibitory H3K27me3 chromatin marks to activate their expression. Oct1 deficient cells fail to remove H3K27me3 and positively resolve bivalency. Ectopic Oct1 expression improves the ability of cells to differentiate accurately under mesoderm lineage-inducing conditions.