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SOX2O-GlcNAcylation alters its protein-protein interactions and genomic occupancy to modulate gene expression in pluripotent cells

Myers, Samuel A. and Peddada, Sailaja and Chatterjee, Nilanjana and Friedrich, Tara and Tomoda, Kiichrio and Krings, Gregor and Thomas, Sean and Maynard, Jason and Broeker, Michael and Thomson, Matthew and Pollard, Katherine and Yamanaka, Shinya and Burlingame, Alma L. and Panning, Barbara (2016) SOX2O-GlcNAcylation alters its protein-protein interactions and genomic occupancy to modulate gene expression in pluripotent cells. eLife, 5 . Art. No. e10647. ISSN 2050-084X. PMCID PMC4841768. https://resolver.caltech.edu/CaltechAUTHORS:20170217-152208931

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


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.7554/eLife.10647DOIArticle
https://elifesciences.org/content/5/e10647PublisherArticle
https://elifesciences.org/content/5/e10647/supp-material1PublisherSupplementary Information
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4841768/PubMed CentralArticle
ORCID:
AuthorORCID
Panning, Barbara0000-0002-8301-1172
Additional Information:Copyright Myers et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Received: 08 August 2015. Accepted: 05 March 2016. Published: 07 March 2016. We greatly appreciate the generous gifts from Tom Fazzio for the fMBD3 mESCs, Tim Townes for the KI SOX2 mESCs, Suzanne Walker for the His-OGT plasmid, Sy Redding, and David Bauer for Avi-tagged human Bio-SOX2. We thank Anne Claude Gingras, Joe Kleigman, Michael Lopez, Katie Worringer, and Anthony Shiver for technical assistance. Thank you to Kathyrn Lovero and Jonathan Fistorino for useful discussion, and Emily Myers and Lucas Sullivan for critical assessment of this manuscript. We also thank the Arraystar and the Gladstone Bioinformatics core for assistance analyzing the microarray and ChIP-seq data, respectively. This work was supported by the Biomedical Technology Research Centers program of the NIH National Institute of General Medical Sciences, NIH NIGMS P41GM103481, 1S10RR019934, Howard Hughes Medical Institute (purchase of ETD mass spectrometer) and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (ALB), NIH R01GM085186, CIRM RB4-05990, and University of California San Francisco Program for Breakthrough Biomedical Research (BP). SAM is supported by a National Institutes of Health National Institute of General Medical Sciences T32 training grant, the Genentech Predoctoral Fellowship Program and the QBC Fellowship for Interdisciplinary Research. The Cornell Stem Cell Core is supported by the Empire State Stem Cell fund through NYSDOH Contract # C024174, and opinions expressed here are solely those of the author and do not necessarily reflect those of the Empire State Stem Cell Fund, the NYSDOH, or the State of NY.
Funders:
Funding AgencyGrant Number
NIHP41GM103481
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
California Institute for Regenerative Medicine (CIRM)RB4-05990
Dr. Miriam and Sheldon G. Adelson Medical Research FoundationUNSPECIFIED
University of California, San Francisco (UCSF)UNSPECIFIED
NIH1S10RR019934
NIHR01GM085186
Genentech Predoctoral Fellowship ProgramUNSPECIFIED
QBC Fellowship for Interdisciplinary ResearchUNSPECIFIED
Empire State Stem Cell fundC024174
PubMed Central ID:PMC4841768
Record Number:CaltechAUTHORS:20170217-152208931
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170217-152208931
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:74409
Collection:CaltechAUTHORS
Deposited By: Donna Wrublewski
Deposited On:18 Feb 2017 03:52
Last Modified:03 Oct 2019 16:38

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