SOX2 O-GlcNAcylation alters its protein-protein interactions and genomic occupancy to modulate gene expression in pluripotent cells
Samuel A Myers,
Sailaja Peddada,
Nilanjana Chatterjee,
Tara Friedrich,
Kiichrio Tomoda,
Gregor Krings,
Sean Thomas,
Jason Maynard,
Michael Broeker,
Matthew Thomson,
Katherine Pollard,
Shinya Yamanaka,
Alma L Burlingame,
Barbara Panning
Affiliations
Samuel A Myers
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
Sailaja Peddada
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
Nilanjana Chatterjee
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
Tara Friedrich
Gladstone Institute University of California, San Francisco, San Francisco, United States
Kiichrio Tomoda
Gladstone Institute University of California, San Francisco, San Francisco, United States
Gregor Krings
Department of Pathology, University of California, San Francisco, San Francisco, United States
Sean Thomas
Gladstone Institute University of California, San Francisco, San Francisco, United States
Jason Maynard
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
Michael Broeker
Center for Systems and Synthetic Biology, University of California, San Francisco, San Francisco, United States
Matthew Thomson
Center for Systems and Synthetic Biology, University of California, San Francisco, San Francisco, United States
Katherine Pollard
Gladstone Institute University of California, San Francisco, San Francisco, United States; Institute for Human Genetics, Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, United States
Shinya Yamanaka
Gladstone Institute University of California, San Francisco, San Francisco, United States; Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
Alma L Burlingame
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
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.
