Research seminars Pioneer factor-mediated repressive epigenetic mechanisms in cell fate control

Pioneer transcription factors (TFs) possess a unique ability to open target sites on chromatin, facilitating access for multiple epigenetic and transcriptional regulators to initiate new gene regulatory programs. Current dogma is that pioneer TFs play activating roles in epigenetic and gene regulation, by opening local chromatin to activate enhancers and target genes. 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. Our recent studies revealed unexpected roles of FOXA pioneer TF in repressing alternative-lineage gene expression programs, while simultaneously activating endodermal genes during human endoderm differentiation. Through proteomics and genomics analyses, we gained insight into the repressive mechanisms by which FOXA cooperates with PRDM1 TF to recruit epigenetic repressors, including the PRC and NuRD complexes. Similarly, OCT4 pioneer TF coordinates with PRDM14 to repress cell differentiation programs in human pluripotent stem cells, suggesting this may be a common mechanism. We propose that pioneer and PRDM TFs cooperate to safeguard cell fate through epigenetic repression mechanisms.