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Molecular and Cellular Biology, October 2008, p. 5986-5995, Vol. 28, No. 19
0270-7306/08/$08.00+0     doi:10.1128/MCB.00301-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Estrogen-Related Receptor Beta Interacts with Oct4 To Positively Regulate Nanog Gene Expression{triangledown}

Debbie L. C. van den Berg,1 Wensheng Zhang,2 Adam Yates,2 Erik Engelen,1 Katalin Takacs,3 Karel Bezstarosti,4 Jeroen Demmers,4 Ian Chambers,2 and Raymond A. Poot1*

Department of Cell Biology, Erasmus MC, Dr. Molewaterplein 50, 3015GE Rotterdam, The Netherlands,1 MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, King's Buildings, West Mains Road, Edinburgh EH9 3JQ, Scotland,2 MRC Clinical Sciences Centre, Du Cane Road, London W12 0NN, United Kingdom,3 Proteomics Center, Erasmus MC, Rotterdam, The Netherlands4

Received 22 February 2008/ Returned for modification 15 April 2008/ Accepted 14 July 2008

Embryonic stem (ES) cell self-renewal is regulated by transcription factors, including Oct4, Sox2, and Nanog. A number of additional transcriptional regulators of ES cell self-renewal have recently been identified, including the orphan nuclear receptor estrogen-related receptor beta (Esrrb). However, the mode of action of Esrrb in ES cells is unknown. Here, using an Oct4 affinity screen, we identify Esrrb as an Oct4 partner protein. Esrrb can interact with Oct4 independently of DNA. Esrrb is recruited near the Oct-Sox element in the Nanog proximal promoter, where it positively regulates Nanog expression. Esrrb recruitment to the Nanog promoter requires both the presence of Oct4 and a degenerate estrogen-related receptor DNA element. Consistent with its role in Nanog regulation, expression of the Esrrb protein within the Oct4-positive ES cell population is mosaic and correlates with the mosaic expression of the Nanog protein. Together with previous reports that Nanog may regulate Esrrb gene expression, our results suggest that Esrrb and Nanog act as part of a feedback regulatory circuit that modulates the fluctuating self-renewal capacity of ES cell populations.

* Corresponding author. Mailing address: Department of Cell Biology, Erasmus MC, Dr. Molewaterplein 50, 3015GE Rotterdam, The Netherlands. Phone: 31-10-7043352. Fax: 31-10-7044743. E-mail: r.poot{at}erasmusmc.nl

{triangledown} Published ahead of print on 28 July 2008.

Molecular and Cellular Biology, October 2008, p. 5986-5995, Vol. 28, No. 19
0270-7306/08/$08.00+0     doi:10.1128/MCB.00301-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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