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Embryonic Stem Cells/Induced Pluripotent Stem Cells
Article first published online: 22 MAY 2013
Copyright © 2013 AlphaMed Press
Volume 31, Issue 6, pages 1107–1120, June 2013
How to Cite
Campbell, P. A. and Rudnicki, M. A. (2013), Oct4 Interaction with Hmgb2 Regulates Akt Signaling and Pluripotency. STEM CELLS, 31: 1107–1120. doi: 10.1002/stem.1365
Author contributions: P.C.: conception and design, collection and/or assembly of data, data analysis and interpretation, and manuscript writing; M.R.: financial support and final approval of manuscript.
Disclosure of potential conflicts of interest is found at the end of this article.
first published online in STEM CELLS EXPRESS February 4, 2013.
- Issue published online: 22 MAY 2013
- Article first published online: 22 MAY 2013
- Accepted manuscript online: 14 MAR 2013 12:00AM EST
- Manuscript Accepted: 31 JAN 2013
- Manuscript Revised: 26 JAN 2013
- Manuscript Received: 15 OCT 2012
- Ontario Genomics Institute, the Stem Cell Network
- Canadian Institutes of Health Research
- SET complex;
- Bivalent domains
In pluripotent stem cells, bivalent domains mark the promoters of developmentally regulated loci. Histones in these chromatin regions contain coincident epigenetic modifications of gene activation and repression. How these marks are transmitted to maintain the pluripotent state in daughter progeny remains poorly understood. Our study demonstrates that Oct4 post-translational modifications (PTMs) form a positive feedback loop, which promotes Akt activation and interaction with Hmgb2 and the SET complex. This preserves H3K27me3 modifications in daughter progeny and maintains the pluripotent gene expression signature in murine embryonic stem cells. However, if Oct4 is not phosphorylated, a negative feedback loop is formed that inactivates Akt and initiates the DNA damage response. Oct4 sumoylation then is required for G1/S progression and transmission of the repressive H3K27me3 mark. Therefore, PTMs regulate the ability of Oct4 to direct the spatio-temporal formation of activating and repressing complexes to orchestrate chromatin plasticity and pluripotency. Our work highlights a previously unappreciated role for Oct4 PTM-dependent interactions in maintaining restrained Akt signaling and promoting a primitive epigenetic state. STEM Cells 2013;31:1107–1120