p53 Integrates Temporal WDR5 Inputs during Neuroectoderm and Mesoderm Differentiation of Mouse Embryonic Stem Cells

How ubiquitous transcription factors (TFs) coordinate temporal inputs from broadly expressed epigenetic factors to control cell fate remains poorly understood. Here, we uncover a molecular relationship between p53, an abundant embryonic TF, and WDR5, an essential member of the MLL chromatin modifying complex, that regulates mouse embryonic stem cell fate. Wild-type Wdr5 or transient Wdr5 knockout promotes a distinct pattern of global chromatin accessibility and spurs neuroectodermal differentiation through an RbBP5-dependent process in which WDR5 binds to, and activates transcription of, neural genes. Wdr5 rescue after its prolonged inhibition targets WDR5 to mesoderm lineage-specifying genes, stimulating differentiation toward mesoderm fates in a p53-dependent fashion. Finally, we identify a direct interaction between WDR5 and p53 that enables their co-recruitment to, and regulation of, genes known to control cell proliferation and fate. Our results unmask p53-dependent mechanisms that temporally integrate epigenetic WDR5 inputs to drive neuroectoderm and mesoderm differentiation from pluripotent cells. [Display omitted] •WDR5-RbBP5 interaction surface controls ESC-to-neuroectoderm organoid differentiation•Wdr5 inhibition stabilizes p53 and activates p53 signaling•Transient Wdr5 inhibition stimulates ESC differentiation toward mesoderm fates via p53 How ubiquitous chromatin-associated proteins and transcription factors (TFs) regulate cell fate determination is poorly understood. Li et al. show that regulation of the broadly expressed TF p53 by the chromatin-associated protein WDR5 is required for neuroectoderm versus mesoderm lineage determination in mouse embryonic stem cells (ESCs).