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Variegated gene expression caused by cell-specific long-range DNA interactions

Nature Cell Biology volume 13, pages 944951 (2011) | Download Citation

Abstract

Mammalian genomes contain numerous regulatory DNA sites with unknown target genes. We used mice with an extra β-globin locus control region (LCR) to investigate how a regulator searches the genome for target genes. We find that the LCR samples a restricted nuclear subvolume, wherein it preferentially contacts genes controlled by shared transcription factors. No contacted gene is detectably upregulated except for endogenous β-globin genes located on another chromosome. This demonstrates genetically that mammalian trans activation is possible, but suggests that it will be rare. Trans activation occurs not pan-cellularly, but in ‘jackpot’ cells enriched for the interchromosomal interaction. Therefore, cell-specific long-range DNA contacts can cause variegated expression.

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Acknowledgements

We thank J. Marteijn and W. Vermeulen for providing Rad23a knockout material, Y. Oz for counting FISH slides, V. Buckle for providing BAC probes, J. van Rheenen and the Hubrecht Imaging Center for help with image analysis and E. Splinter and other members of the group for assistance. This work was financially supported by grants from the Dutch Scientific Organization (NWO) (91204082 and 935170621) and a European Research Council Starting Grant (209700, ‘4C’) to W.d.L.

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Author notes

    • Daan Noordermeer

    Present address: Laboratory of Developmental Genomics, School of Life Sciences, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland

    • Daan Noordermeer
    • , Elzo de Wit
    •  & Petra Klous

    These authors contributed equally to this work

Affiliations

  1. Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands

    • Daan Noordermeer
    • , Elzo de Wit
    • , Petra Klous
    • , Harmen van de Werken
    • , Marieke Simonis
    •  & Wouter de Laat
  2. Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA

    • Melissa Lopez-Jones
    •  & Robert H. Singer
  3. Department of Clinical Genetics, Erasmus Medical Centre, PO Box 2040, 3000 CA Rotterdam, The Netherlands

    • Bert Eussen
    •  & Annelies de Klein

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Contributions

D.N. and W.d.L. designed the experiments, analysed the data and, with help from E.d.W., wrote the manuscript. D.N. and P.K. carried out experiments. E.d.W. analysed 4C data and developed the automated FISH image analysis. H.v.d.W. analysed 4C and microarray expression data. M.S. carried out 4C experiments. M.L-J. and R.H.S. designed and synthesized RNA-FISH probes. B.E. and A.d.K. helped with the FISH experiments.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Wouter de Laat.

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DOI

https://doi.org/10.1038/ncb2278

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