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Molecular and Cellular Biology, May 2007, p. 3769-3779, Vol. 27, No. 10
0270-7306/07/$08.00+0     doi:10.1128/MCB.01432-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Polycomb Group Protein Suz12 Is Required for Embryonic Stem Cell Differentiation{triangledown} ,{dagger}

Diego Pasini,1 Adrian P. Bracken,1 Jacob B. Hansen,2 Manuela Capillo,3,4 and Kristian Helin1*

Centre for Epigenetics and BRIC, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark,1 Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark,2 Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy,3 Institute of Molecular Oncology of the Italian Foundation for Cancer Research, Via Adamello 16, 20139 Milan, Italy4

Received 3 August 2006/ Returned for modification 10 October 2006/ Accepted 22 February 2007

Polycomb group (PcG) proteins form multiprotein complexes, called Polycomb repressive complexes (PRCs). PRC2 contains the PcG proteins EZH2, SUZ12, and EED and represses transcription through methylation of lysine (K) 27 of histone H3 (H3). Suz12 is essential for PRC2 activity and its inactivation results in early lethality of mouse embryos. Here, we demonstrate that Suz12–/– mouse embryonic stem (ES) cells can be established and expanded in tissue culture. The Suz12–/– ES cells are characterized by global loss of H3K27 trimethylation (H3K27me3) and higher expression levels of differentiation-specific genes. Moreover, Suz12–/– ES cells are impaired in proper differentiation, resulting in a lack of repression of ES cell markers as well as activation of differentiation-specific genes. Finally, we demonstrate that the PcGs are actively recruited to several genes during ES cell differentiation, which despite an increase in H3K27me3 levels is not always sufficient to prevent transcriptional activation. In summary, we demonstrate that Suz12 is required for the establishment of specific expression programs required for ES cell differentiation. Furthermore, we provide evidence that PcGs have different mechanisms to regulate transcription during cellular differentiation.

* Corresponding author. Mailing address: Centre for Epigenetics and BRIC, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark. E-mail: kristian.helin{at}bric.dk. Phone: 45 3532 5666. Fax: 45 3532 5669. E-mail: kristian.helin{at}bric.dk

{triangledown} Published ahead of print on 5 March 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, May 2007, p. 3769-3779, Vol. 27, No. 10
0270-7306/07/$08.00+0     doi:10.1128/MCB.01432-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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