OCT4 and PAX6 determine the dual function of SOX2 in human ESCs as a key pluripotent or neural factor.
BACKGROUND
Sox2 is a well-established pluripotent transcription factor that plays an essential role in establishing and maintaining pluripotent stem cells (PSCs). It is also thought to be a linage specifier that governs PSC neural lineage specification upon their exiting the pluripotent state. However, the exact role of SOX2 in human PSCs was still not fully understood. In this study, we studied the role of SOX2 in human embryonic stem cells (hESCs) by gain- and loss-of-function approaches and explored the possible underlying mechanisms.


RESULTS
We demonstrate that knockdown of SOX2 induced hESC differentiation to endoderm-like cells, whereas overexpression of SOX2 in hESCs enhanced their pluripotency under self-renewing culture conditions but promoted their neural differentiation upon replacing the culture to non-self-renewal conditions. We show that this culture-dependent dual function of SOX2 was probably attributed to its interaction with different transcription factors predisposed by the culture environments. Whilst SOX2 interacts with OCT4 under self-renewal conditions, we found that, upon neural differentiation, PAX6, a key neural transcription factor, is upregulated and shows interaction with SOX2. The SOX2-PAX6 complex has different gene regulation pattern from that of SOX2-OCT4 complex.


CONCLUSIONS
Our work provides direct evidence that SOX2 is necessarily required for hESC pluripotency; however, it can also function as a neural factor, depending on the environmental input. OCT4 and PAX6 might function as key SOX2-interacting partners that determine the function of SOX2 in hESCs.
['Zhang|Shuchen|S|', 'Bell|Emma|E|', 'Zhi|Huihan|H|', 'Brown|Sarah|S|', 'Imran|Siti A M|SAM|', 'Azuara|Véronique|V|', 'Cui|Wei|W|0000-0003-2019-380X']
D002454:Cell Differentiation D002460:Cell Line D000066449:Human Embryonic Stem Cells D006801:Humans D058953:Neural Stem Cells D050814:Octamer Transcription Factor-3 D000071841:PAX6 Transcription Factor D055748:SOXB1 Transcription Factors
OCT4 PAX6 SOX2 Human embryonic stem cells Neural differentiation