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

Elife. 2016 Mar 7;5:e10647. doi: 10.7554/eLife.10647.

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.

Keywords: O-GlcNAc; SOX2; biochemistry; developmental biology; electron transfer dissociation; embryonic stem cells; mouse; pluripotency; stem cells; transcription factors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylglucosamine / metabolism*
  • Animals
  • Cell Differentiation
  • Gene Expression Regulation*
  • Mice
  • Pluripotent Stem Cells / physiology*
  • Protein Binding
  • Protein Processing, Post-Translational*
  • SOXB1 Transcription Factors / metabolism*

Substances

  • SOXB1 Transcription Factors
  • Sox2 protein, mouse
  • Acetylglucosamine