Article | Published:

Global changes in the nuclear positioning of genes and intra- and interdomain genomic interactions that orchestrate B cell fate

Nature Immunology volume 13, pages 11961204 (2012) | Download Citation

Abstract

The genome is folded into domains located in compartments that are either transcriptionally inert or transcriptionally permissive. Here we used genome-wide strategies to characterize domains during B cell development. Structured interaction matrix analysis showed that occupancy by the architectural protein CTCF was associated mainly with intradomain interactions, whereas sites bound by the histone acetyltransferase p300 or the transcription factors E2A or PU.1 were associated with intra- and interdomain interactions that are developmentally regulated. We identified a spectrum of genes that switched nuclear location during early B cell development. In progenitor cells, the transcriptionally inactive locus encoding early B cell factor (Ebf1) was sequestered at the nuclear lamina, which thereby preserved their multipotency. After development into the pro-B cell stage, Ebf1 and other genes switched compartments to establish new intra- and interdomain interactions associated with a B lineage–specific transcription signature.

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Acknowledgements

We thank G. Hardiman, C. Ludka, L. Edsall, S. Kuan, C. Espinoza, U. Wagner, J. Sprague and Z. Ye for help with Solexa DNA sequencing; J. Dixon for help during the initial phase of Hi-C analysis; B. Wold for suggesting fixation with ethylene glycol bis(succinimidylsuccinate); B. Ren for access to the Illumina Hi-Seq; and members of the Murre laboratory for comments on the manuscript. Supported by the American Recovery and Reinvestment Act (ARRA PHS 3RO1AI082850 to Y.C.L.), the European Molecular Biology Organization (C.Bo.), the Swiss National Science Foundation (C.Bo.), the University of California San Diego, Cancer Center (P30 CA23100) and the US National Institutes of Health (AI082850A and AI00880 to C.K.G. and C.M.).

Author information

Author notes

    • Yin C Lin
    •  & Christopher Benner

    These authors contributed equally to this work.

Affiliations

  1. Department of Molecular Biology, University of California San Diego, La Jolla, California, USA.

    • Yin C Lin
    • , Robert Mansson
    • , Kazuko Miyazaki
    • , Masaki Miyazaki
    • , Vivek Chandra
    • , Claudia Bossen
    •  & Cornelis Murre
  2. Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, USA.

    • Christopher Benner
    • , Sven Heinz
    •  & Christopher K Glass
  3. Integrative Genomics and Bioinformatics Core, Salk Institute for Biological Studies, La Jolla, California, USA.

    • Christopher Benner

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Contributions

R.M. and S.H. contributed equally to this work. Y.C.L., R.M. and S.H. designed and did most of the experiments; S.H. did Gro-Seq analysis; C.Be. did the bioinformatics analysis, analyzed data, suggested new approaches and developed SIMA; M.M., K.M. and V.C. did chromatin immunoprecipitation followed by deep sequencing; C.Bo. provided insight into the topology of the Igk locus; Y.C.L., C.Be. and C.M. wrote the manuscript with contributions from C.K.G., R.M. and S.H.; and C.K.G. and C.M. supervised the study.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Christopher Benner or Christopher K Glass or Cornelis Murre.

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    Supplementary Figures 1–7 and Tables 1–3 and Supplementary Methods

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DOI

https://doi.org/10.1038/ni.2432

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