Coassembly of REST and its cofactors at sites of gene repression in embryonic stem cells

  1. Lawrence W. Stanton1,2,5
  1. 1Stem Cell and Developmental Biology, Genome Institute of Singapore, 138672 Singapore;
  2. 2Department of Biological Sciences, National University of Singapore, 117543 Singapore
    1. 3 These authors contributed equally to this work.

    • 4 Present address: Bioinformatics and Genomics Group, Centre for Genomic Regulation, Barcelona, Catalonia, Spain.

    Abstract

    The differentiation of pluripotent embryonic stem cells is regulated by networks of activating and repressing transcription factors that orchestrate determinate patterns of gene expression. With the recent mapping of target sites for many transcription factors, it has been a conundrum that so few of the genes directly targeted by these factors are transcriptionally responsive to the binding of that factor. To address this, we generated genome-wide maps of the transcriptional repressor REST and five of its corepressors in mouse embryonic stem cells. Combining these binding-site maps with comprehensive gene-expression profiling, we show that REST is functionally heterogeneous. Approximately half of its binding sites apparently are nonfunctional, having weaker binding of REST and low recruitment of corepressors. In contrast, the other sites strongly recruit REST and corepressor complexes with varying numbers of components. Strikingly, the latter sites account for almost all observed gene regulation. These data support a model where productive gene repression by REST requires assembly of a multimeric “repressosome” complex, whereas weak recruitment of REST and its cofactors is insufficient to repress gene expression.

    Footnotes

    • 5 Corresponding author.

      E-mail stantonl{at}gis.a-star.edu.sg.

    • [Supplemental material is available for this article.]

    • Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.114488.110.

    • Received August 30, 2010.
    • Accepted May 24, 2011.
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