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SOX2 O-GlcNAcylation alters its protein-protein interactions and genomic occupancy to modulate gene expression in pluripotent cells.

  • Author(s): 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
  • et al.
Abstract

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.

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