Histone-Fold Domain Protein NF-Y Promotes Chromatin Accessibility for Cell Type-Specific Master Transcription Factors

Cell type-specific master transcription factors (TFs) play vital roles in defining cell identity and function. However, the roles ubiquitous factors play in the specification of cell identity remain underappreciated. Here we show that the ubiquitous CCAAT-binding NF-Y complex is required for the maintenance of embryonic stem cell (ESC) identity and is an essential component of the core pluripotency network. Genome-wide studies in ESCs and neurons reveal that NF-Y regulates not only genes with housekeeping functions through cell type-invariant promoter-proximal binding, but also genes required for cell identity by binding to cell type-specific enhancers with master TFs. Mechanistically, NF-Y’s distinct DNA-binding mode promotes master/pioneer TF binding at enhancers by facilitating a permissive chromatin conformation. Our studies unearth a conceptually unique function for histone-fold domain (HFD) protein NF-Y in promoting chromatin accessibility and suggest that other HFD proteins with analogous structural and DNA-binding properties may function in similar ways. [Display omitted] •NF-Y uses distinct modes to regulate housekeeping and cell-identity programs•NF-Y co-occupies active enhancers with cell type-specific master TFs•NF-Y promotes master TF binding by facilitating a favorable chromatin conformation•NF-Y is required for the maintenance of ESC identity The ubiquitously expressed NF-Y regulates key cell-cycle genes by binding to their proximal promoters. Oldfield et al. demonstrate a cell type-specific role for NF-Y at active enhancers, where it promotes chromatin accessibility for cell type-specific master transcription factors through its distinct DNA-binding mode.