Abstract

Polycomb group (PcG) proteins are known to repress developmental genes during embryonic development and tissue homeostasis. Here, we report that PCGF6 controls neuroectoderm specification of human pluripotent stem cells (PSCs) by activating SOX2 gene. Human PSCs with PCGF6 depletion display impaired neuroectoderm differentiation coupled with increased mesendoderm outcomes. Transcriptome analysis reveals that de-repression of the WNT/β-catenin signaling pathway is responsible for the differentiation of PSC toward the mesendodermal lineage. Interestingly, PCGF6 and MYC directly interact and co-occupy a distal regulatory element of SOX2 to activate SOX2 expression, which likely accounts for the regulation in neuroectoderm differentiation. Supporting this notion, genomic deletion of the SOX2-regulatory element phenocopies the impaired neuroectoderm differentiation, while overexpressing SOX2 rescues the neuroectoderm phenotype caused by PCGF6-depletion. Together, our study reveals that PCGF6 can function as lineage switcher between mesendoderm and neuroectoderm in human PSCs by both suppression and activation mechanisms.