YAP-TEAD regulates the super-enhancer network to control early surface ectoderm commitment

Super enhancers (SEs), characterized by clusters of enhancers, are instrumental in shaping cellular identity and function. Given this crucial involvement of SEs in cell lineage commitment, and considering the pivotal position of surface ectoderm in differentiating into a wide array of cell types, the study of these SEs holds immense promise for advancing cell-based therapeutic applications. In this study, we profiled the SE landscape in surface ectoderm cells derived from pluripotent stem cell differentiation. By leveraging 3D genomic data, we discerned active histone modifications and frequent chromatin interactions of SEs with target genes. Notably, perturbing specific SE using a CRISPR-dCas9-mediated approach resulted in decreased expression of the connected gene. Subsequently, we constructed a regulatory network of core transcription factors (TFs) operating on SEs and uncovered their control over the differentiation process by forming regulatory network with key TFs, such as TEAD1. Knocking down TEADs attenuated the differentiation process and target gene activation, whereas YAP-TEAD activation expedited the differentiation process by promoting the early establishment of SEs. Collectively, our findings shed light on the crucial role of SEs and identify YAP-TEAD as vital regulators controlling surface ectoderm commitment, thereby providing a novel insight into lineage commitment and stem cell-based epithelial regeneration.