Myers Samuel A, Peddada Sailaja, Chatterjee Nilanjana, Friedrich Tara, Tomoda Kiichrio, Krings Gregor, Thomas Sean, Maynard Jason, Broeker Michael, Thomson Matthew, Pollard Katherine, Yamanaka Shinya, Burlingame Alma L, Panning Barbara
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States.
Chemistry and Chemical Biology Graduate Program, University of California, San Francisco, San Francisco, United States.
Elife. 2016 Mar 7;5:e10647. doi: 10.7554/eLife.10647.
The transcription factor SOX2 is central in establishing and maintaining pluripotency. The processes that modulate SOX2 activity to promote pluripotency are not well understood. Here, we show SOX2 is O-GlcNAc modified in its transactivation domain during reprogramming and in mouse embryonic stem cells (mESCs). Upon induction of differentiation SOX2 O-GlcNAcylation at serine 248 is decreased. Replacing wild type with an O-GlcNAc-deficient SOX2 (S248A) increases reprogramming efficiency. ESCs with O-GlcNAc-deficient SOX2 exhibit alterations in gene expression. This change correlates with altered protein-protein interactions and genomic occupancy of the O-GlcNAc-deficient SOX2 compared to wild type. In addition, SOX2 O-GlcNAcylation impairs the SOX2-PARP1 interaction, which has been shown to regulate ESC self-renewal. These findings show that SOX2 activity is modulated by O-GlcNAc, and provide a novel regulatory mechanism for this crucial pluripotency transcription factor.
转录因子SOX2在建立和维持多能性方面起着核心作用。调节SOX2活性以促进多能性的过程尚未得到充分了解。在此，我们表明在重编程过程中以及在小鼠胚胎干细胞（mESC）中，SOX2在其反式激活结构域中发生了O-GlcNAc修饰。在诱导分化时，丝氨酸248处的SOX2 O-GlcNAcylation减少。用缺乏O-GlcNAc的SOX2（S248A）取代野生型可提高重编程效率。具有缺乏O-GlcNAc的SOX2的ESC在基因表达上表现出改变。与野生型相比，这种变化与缺乏O-GlcNAc的SOX2的蛋白质-蛋白质相互作用和基因组占据的改变相关。此外，SOX2 O-GlcNAcylation损害了SOX2-PARP1相互作用，而该相互作用已被证明可调节ESC的自我更新。这些发现表明SOX2活性受O-GlcNAc调节，并为这种关键的多能性转录因子提供了一种新的调节机制。
