Pioneer transcription factors coordinate active and repressive gene expression states to regulate cell fate [CUT&Run and ChIP-seq]

Pioneer transcription factors (TFs) regulate cell fate by establishing transcriptionally primed and active states. However, cell fate control requires the coordination of both lineage-specific gene activation and repression of alternative lineage programs, a process that is poorly understood. Here, we demonstrate that the pioneer TF Forkhead box A (FOXA), required for endoderm lineage commitment, coordinates with the PR domain zinc finger 1 (PRDM1) TF to recruit Polycomb repressive complexes, which establish bivalent enhancers and repress alternative lineage programs. Similarly, the pioneer TF OCT4 coordinates with PRDM14 to repress cell differentiation programs in pluripotent stem cells, suggesting this is a common feature of pioneer TFs. We propose that pioneer and PRDM TFs coordinate recruitment of Polycomb complexes to safeguard cell fate. Overall design: ChIP-seq or CUT&RUN for transcription factors, PRC components, and histone modifications in human PSCs, definitive endoderm, foregut cells, and their KD derivatives (FOXA-TKD and OCT4-KD) .