1. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA
2. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
3. Swammerdam Institute for Life Sciences, University of Amsterdam, 1098 SM Amsterdam, The Netherlands
4. Developmental and Cell Biology Centro de Investigaciones Biológicas (CSIC), 28040 Madrid, Spain
5. Computer Science and Artificial Intelligence Laboratories, 32 Vassar Street, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
6. †Present address: Biological Chemistry Department, David Geffen School of Medicine at UCLA, 36-133 CHS, PO Box 951737, Los Angeles, California 90095-1737, USA
7. *These authors contributed equally to this work

Correspondence to: Rudolf Jaenisch^1,2 Correspondence and requests for materials should be addressed to R.J. (Email: jaenisch@wi.mit.edu). All microarray data from this study are available from ArrayExpress at the EBI (http://www.ebi.ac.uk/arrayexpress) under accession code E-WMIT-12.

Abstract

The mechanisms by which embryonic stem (ES) cells self-renew while maintaining the ability to differentiate into virtually all adult cell types are not well understood. Polycomb group (PcG) proteins are transcriptional repressors that help to maintain cellular identity during metazoan development by epigenetic modification of chromatin structure¹. PcG proteins have essential roles in early embryonic development^{2, 3, 4, 5, 6} and have been implicated in ES cell pluripotency², but few of their target genes are known in mammals. Here we show that PcG proteins directly repress a large cohort of developmental regulators in murine ES cells, the expression of which would otherwise promote differentiation. Using genome-wide location analysis in murine ES cells, we found that the Polycomb repressive complexes PRC1 and PRC2 co-occupied 512 genes, many of which encode transcription factors with important roles in development. All of the co-occupied genes contained modified nucleosomes (trimethylated Lys 27 on histone H3). Consistent with a causal role in gene silencing in ES cells, PcG target genes were de-repressed in cells deficient for the PRC2 component Eed, and were preferentially activated on induction of differentiation. Our results indicate that dynamic repression of developmental pathways by Polycomb complexes may be required for maintaining ES cell pluripotency and plasticity during embryonic development.

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