Article | Published:

Mediator and cohesin connect gene expression and chromatin architecture

Nature volume 467, pages 430435 (23 September 2010) | Download Citation

  • A Corrigendum to this article was published on 13 April 2011

Abstract

Transcription factors control cell-specific gene expression programs through interactions with diverse coactivators and the transcription apparatus. Gene activation may involve DNA loop formation between enhancer-bound transcription factors and the transcription apparatus at the core promoter, but this process is not well understood. Here we report that mediator and cohesin physically and functionally connect the enhancers and core promoters of active genes in murine embryonic stem cells. Mediator, a transcriptional coactivator, forms a complex with cohesin, which can form rings that connect two DNA segments. The cohesin-loading factor Nipbl is associated with mediator–cohesin complexes, providing a means to load cohesin at promoters. DNA looping is observed between the enhancers and promoters occupied by mediator and cohesin. Mediator and cohesin co-occupy different promoters in different cells, thus generating cell-type-specific DNA loops linked to the gene expression program of each cell.

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Accessions

Primary accessions

Gene Expression Omnibus

Data deposits

ChIP-Seq and microarray data have been deposited in the Gene Expression Omnibus under accession code GSE22557.

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Acknowledgements

We thank T. Lee for discussions; D. Root, S. Silver, T. Neiland and H. Le at the RNAi Screening Platform at the Broad Institute for screening advice and technical support; and J.-A. Kwon, J. Love, S. Gupta and T. Volkert for assistance with ChIP-Seq. Immunofluorescence images were collected using the W.M. Keck Foundation Biological Imagining Facility at the Whitehead Institute and Whitehead-MIT Bioimaging Center. This work was supported by Susan Whitehead and Landon and Lavinia Clay, an NIH Fellowship (M.H.K.), a Canadian Institutes of Health Research Fellowship (S.B.), the American Cancer Society (D.J.T.), a Keck Distinguished young scholar award (J.D.) and by NIH grants HG003143 (J.D.) and HG002668 (R.A.Y.).

Author information

Author notes

    • Michael H. Kagey
    • , Jamie J. Newman
    •  & Steve Bilodeau

    These authors contributed equally to this work.

Affiliations

  1. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA

    • Michael H. Kagey
    • , Jamie J. Newman
    • , Steve Bilodeau
    • , David A. Orlando
    • , Peter B. Rahl
    •  & Richard A. Young
  2. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • Jamie J. Newman
    • , Stuart S. Levine
    •  & Richard A. Young
  3. Program in Gene Function and Expression and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, Massachusetts 01605, USA

    • Ye Zhan
    • , Nynke L. van Berkum
    •  & Job Dekker
  4. Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309, USA

    • Christopher C. Ebmeier
    • , Jesse Goossens
    •  & Dylan J. Taatjes

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Contributions

The genetic screen, ChIP-Seq, expression and immunoprecipitation experiments were conducted by M.H.K., J.J.N., S.B., P.B.R., D.A.O. and S.S.L. Mediator purification experiments were done by C.C.E., J.G and D.J.T. 3C experiments were conducted by Y.Z., N.L.v.B., M.H.K. and J.D. The manuscript was written by M.H.K., J.J.N., S.B., J.D., D.J.T. and R.A.Y.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Dylan J. Taatjes or Job Dekker or Richard A. Young.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains a list of Supplementary Tables 1-7 (see separate files 1-7), Supplementary Figures 1-8 with legends, details for Supplementary Data (see separate files - parts 1, 2 and 3), Supplementary Experimental Procedures and References.

Excel files

  1. 1.

    Supplementary Table 1

    This table contains Z-scores of shRNAs Used in the Screen.

  2. 2.

    Supplementary Table 2

    This table contains classification of Screen Hits.

  3. 3.

    Supplementary Table 3

    This table contains Med12, Smc1a and Nipbl Knockdown Expression Data.

  4. 4.

    Supplementary Table 4

    This table contains Bound Genomic Regions.

  5. 5.

    Supplementary Table 5

    This table contains a summary of Occupied Genes.

  6. 6.

    Supplementary Table 6

    This table contains a summary of ChIP-Seq Data Used.

  7. 7.

    Supplementary Table 7

    This table contains Chromosome Conformation Capture (3C) Primers.

Zip files

  1. 1.

    Supplementary Data 1 - part 1

    This file contains zipped data files, formatted (WIG.GZ) for upload into the UCSC genome browser.

  2. 2.

    Supplementary Data 1 - part 2

    This file contains zipped data files, formatted (WIG.GZ) for upload into the UCSC genome browser.

  3. 3.

    Supplementary Data 1 - part 3

    This file contains zipped data files, formatted (WIG.GZ) for upload into the UCSC genome browser. Due to a formatting change on the genome browser, data file mES_Smc3_min0.5.WIG.gz was replaced on 25 October 2010.

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DOI

https://doi.org/10.1038/nature09380

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