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

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.

Article and author information

Author details

  1. Samuel A Myers

    Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  2. Sailaja Peddada

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  3. Nilanjana Chatterjee

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  4. Tara Freidreich

    Gladstone Institute University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  5. Kiichrio Tomoda

    Gladstone Institute University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  6. Gregor Krings

    Department of Pathology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  7. Sean Thomas

    Gladstone Institute University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  8. Michael Broeker

    Center for Systems and Synthetic Biology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  9. Jason Maynard

    Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  10. Matthew Thomson

    Center for Systems and Synthetic Biology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  11. Katherine Pollard

    Gladstone Institute University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  12. 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.
  13. Alma L Burlingame

    Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  14. 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.

Reviewing Editor

  1. Kathrin Plath, University of California, Los Angeles, United States

Version history

  1. Received: August 8, 2015
  2. Accepted: March 5, 2016
  3. Accepted Manuscript published: March 7, 2016 (version 1)
  4. Accepted Manuscript updated: March 22, 2016 (version 2)
  5. Version of Record published: April 19, 2016 (version 3)

Copyright

© 2016, Myers et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Samuel A Myers
  2. Sailaja Peddada
  3. Nilanjana Chatterjee
  4. Tara Freidreich
  5. Kiichrio Tomoda
  6. Gregor Krings
  7. Sean Thomas
  8. Michael Broeker
  9. Jason Maynard
  10. Matthew Thomson
  11. Katherine Pollard
  12. Shinya Yamanaka
  13. Alma L Burlingame
  14. Barbara Panning
(2016)
SOX2 O-GlcNAcylation alters its protein-protein interactions and genomic occupancy to modulate gene expression in pluripotent cells
eLife 5:e10647.
https://doi.org/10.7554/eLife.10647

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https://doi.org/10.7554/eLife.10647

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