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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 FOXA coordinates with PRDM1 TF to recruit nucleosome remodeling and deacetylation (NuRD) complexes and Polycomb repressive complexes (PRCs), which establish highly occupied, accessible nucleosome conformation with bivalent epigenetic states, thereby preventing precocious and alternative-lineage gene expression during human endoderm differentiation. Similarly, the pioneer TF OCT4 coordinates with PRDM14 to form bivalent enhancers and repress cell differentiation programs in human pluripotent stem cells, suggesting that this may be a common and critical function of pioneer TFs. We propose that pioneer and PRDM TFs coordinate to safeguard cell fate through epigenetic repression mechanisms.
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•FOXA recruits PRDM1 to prevent alternative-lineage and precocious gene expression•FOXA and PRDM1 interact with NuRD, establishing accessible nucleosome conformation•FOXA and PRDM1 promote the recruitment of PRC1 to establish bivalent enhancers•OCT4 and PRDM14 promote the recruitment of PRC1 for poising developmental genes
Matsui et al. reveal pioneer transcription factor FOXA and OCT4’s unexpected role in repressing precocious gene expression and alternative-lineage programs, thereby safeguarding cell fate. The mechanism involves cooperation between pioneer transcription factors and PRDM transcription factors to recruit repressive epigenetic complexes and establish bivalent chromatin domains.