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

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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 modification, and provide a novel regulatory mechanism for this crucial pluripotency transcription factor.

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Samuel A Myers

Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States

Competing interests
No competing interests declared.
Sailaja Peddada

Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States

Competing interests
No competing interests declared.
Nilanjana Chatterjee

Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States

Competing interests
No competing interests declared.
Tara Freidreich

Gladstone Institute University of California, San Francisco, San Francisco, United States

Competing interests
No competing interests declared.
Kiichrio Tomoda

Gladstone Institute University of California, San Francisco, San Francisco, United States

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No competing interests declared.
Gregor Krings

Department of Pathology, University of California, San Francisco, San Francisco, United States

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No competing interests declared.
Sean Thomas

Gladstone Institute University of California, San Francisco, San Francisco, United States

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No competing interests declared.
Michael Broeker

Center for Systems and Synthetic Biology, University of California, San Francisco, San Francisco, United States

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No competing interests declared.
Jason Maynard

Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States

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No competing interests declared.
Matthew Thomson

Center for Systems and Synthetic Biology, University of California, San Francisco, San Francisco, United States

Competing interests
No competing interests declared.
Katherine Pollard

Gladstone Institute University of California, San Francisco, San Francisco, United States

Competing interests
No competing interests declared.
Shinya Yamanaka

Gladstone Institute University of California, San Francisco, San Francisco, United States

Competing interests
Shinya Yamanaka, scientific advisor of iPS Academia Japan without salary.
Alma L Burlingame

Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States

Competing interests
No competing interests declared.
Barbara Panning

Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States

For correspondence
barbara.panning@gmail.com

Competing interests
No competing interests declared.

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