Abstract
SOX2 is a key regulator of multiple types of stem cells, especially embryonic stem cells (ESCs) and neural progenitor cells (NPCs). Understanding the mechanism underlying the function of SOX2 is of great importance for realizing the full potential of ESCs and NPCs. Here, through genome-wide comparative studies, we show that SOX2 executes its distinct functions in human ESCs (hESCs) and hESC-derived NPCs (hNPCs) through cell type- and stage-dependent transcription programs. Importantly, SOX2 suppresses non-neural lineages in hESCs and regulates neurogenesis from hNPCs by inhibiting canonical Wnt signaling. In hESCs, SOX2 achieves such inhibition by direct transcriptional regulation of important Wnt signaling modulators, WLS and SFRP2. Moreover, SOX2 ensures pluripotent epigenetic landscapes via interacting with histone variant H2A.Z and recruiting polycomb repressor complex 2 to poise developmental genes in hESCs. Together, our results advance our understanding of the mechanism by which cell type-specific transcription factors control lineage-specific gene expression programs and specify cell fate.
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Acknowledgements
This study was supported by grants from the Chinese Academy of Science (XDA01010102), Ministry of Science and Technology of China (2011CB965101, 2013CB967101) and the National Natural Science Foundation (31471393, 91419309, 31322031, 31371288 and 31571365).
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Supplementary information
Supplementary information, Figure S1
SOX2 binds to genes involved in diverse aspects of hESCs and hNPCs maintenance. Related to Figure 1. (PDF 512 kb)
Supplementary information, Figure S2
SOX2 regulates self-renewal and protects survival, proliferation and cell cycle in hESCs and hESC-derived hNPCs. Related to Figure 3. (PDF 733 kb)
Supplementary information, Figure S3
Knock down of SOX2 leads to enhanced non-neural lineage differentiation by activating the Wnt pathway. Related to Figure 4. (PDF 575 kb)
Supplementary information, Figure S4
SFRP2 and WLS are two major SOX2 targets in hESCs, functioning as WNT antagonist and agonist, respectively, in mediating Wnt pathway induced non-neural lineage differentiation. Related to Figure 6. (PDF 661 kb)
Supplementary information, Figure S5
SOX2 and H2A.Z co-localize to development genes for the establishment of H3K27me3 modification. Related to Figure 7. (PDF 546 kb)
Supplementary information, Figure S6
Species retained SOX2 peaks contain a higher percentage of promoter peaks than turnover or unique peaks. Related to Figure 8. (PDF 411 kb)
Supplementary information, Data S1
Detailed Materials and Methods (PDF 143 kb)
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Zhou, C., Yang, X., Sun, Y. et al. Comprehensive profiling reveals mechanisms of SOX2-mediated cell fate specification in human ESCs and NPCs. Cell Res 26, 171–189 (2016). https://doi.org/10.1038/cr.2016.15
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DOI: https://doi.org/10.1038/cr.2016.15
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