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Mediator and cohesin connect gene expression and chromatin architecture

Nature volume 467, pages 430–435 (2010)Cite this article

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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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Figure 1: Mediator and cohesin contribute to the ES cell state.
Figure 2: Genome-wide occupancy of mediator and cohesin in ES cells.
Figure 3: Mediator and cohesin interact.
Figure 4: Mediator and cohesin binding profiles predict enhancer–promoter looping events.
Figure 5: Cell-type-specific occupancy of mediator and cohesin.

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Accession codes

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

  1. Michael H. Kagey, Jamie J. Newman and Steve Bilodeau: These authors contributed equally to this work.

Authors and Affiliations

  1. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, 02142, Massachusetts, 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, 02139, Massachusetts, 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, 80309, Colorado, 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.

Corresponding authors

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

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The authors declare no competing financial interests.

Supplementary information

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. (PDF 2037 kb)

Supplementary Table 1

This table contains Z-scores of shRNAs Used in the Screen. (XLS 1238 kb)

Supplementary Table 2

This table contains classification of Screen Hits. (XLS 12 kb)

Supplementary Table 3

This table contains Med12, Smc1a and Nipbl Knockdown Expression Data. (XLS 3830 kb)

Supplementary Table 4

This table contains Bound Genomic Regions. (XLS 34265 kb)

Supplementary Table 5

This table contains a summary of Occupied Genes. (XLS 9408 kb)

Supplementary Table 6

This table contains a summary of ChIP-Seq Data Used. (XLS 13 kb)

Supplementary Table 7

This table contains Chromosome Conformation Capture (3C) Primers. (XLS 28 kb)

Supplementary Data 1 - part 1

This file contains zipped data files, formatted (WIG.GZ) for upload into the UCSC genome browser. (ZIP 15975 kb)

Supplementary Data 1 - part 2

This file contains zipped data files, formatted (WIG.GZ) for upload into the UCSC genome browser. (ZIP 21843 kb)

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. (ZIP 25059 kb)

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Kagey, M., Newman, J., Bilodeau, S. et al. Mediator and cohesin connect gene expression and chromatin architecture. Nature 467, 430–435 (2010). https://doi.org/10.1038/nature09380

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