| Summary: | Neural differentiation from human embryonic stem cells (hESCs) provides a promising source for cell replacement therapies. However, the mechanisms underlying the control of neural specification remains unclear, which largely hinders their use. Sox2, one of the core transcription factors, has been well documented to be vital in the maintenance of pluripotency. However, recent studies on mESCs reveal that overexpression of Sox2 promotes neural differentiation, indicating a dual role of Sox2 in mESCs, which is still unknown in hESCs. Thus, the function of Sox2 in neural specification was investigated. Downregulation of Sox2 in hESCs dramatically leads to non-neural differentiation, while in NPCs, the depletion results in the loss of NPC identity, supporting its important role in both cells. Interestingly, overexpression of Sox2 regulates hESCs depending on their culture conditions. When culture condition is optimized for hESC self-renewal, Sox2 functions to suppress differentiation and enhance pluripotency. However, when culture condition does not support hESCs, upon exit of pluripotency, Sox2 appears to promote neural differentiation and inhibit the differentiation to other lineages. Furthermore, Pax6 is identified to be a binding partner of Sox2 during neural induction and Sox2 binds to Oct4 and Pax6 via a same interface. Sox2 and Pax6 co-bind to several regulatory elements within Sox2, Pax6 and Oct4 genes during neural differentiation, implying that Sox2 and Pax6 function as a complex to regulate these genes. Functionally, an overexpression of Pax6 inhibits the transcription activity of Oct4 PE and DE enhancers, possibly with Sox2. Collectively, these results demonstrate dual roles of Sox2 in hESCs: maintaining pluripotency and specifying neural differentiation upon losing pluripotency, which is likely to be implemented by switching its binding partner from Oct4 to Pax6. This study provides a better understanding in the neural differentiation of hESCs. In the long term, it will be beneficial for stem cell therapies.
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