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

Nature Immunology volume 13, pages 1196–1204 (2012)Cite this article

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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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Figure 1: The folding pattern of the pro-B cell genome.
Figure 2: The transcriptionally permissive compartment is spatially segregated into islands of H3K27me3 and H3K4me2.
Figure 3: Two distinct classes of anchors establish the pro-B cell interactome.
Figure 4: Switching between transcriptionally repressive and permissive nuclear compartments during B lineage specification.
Figure 5: The Ebf1 locus is closely associated with the nuclear lamina in pre-pro-B cells.
Figure 6: Repositioning of loci during the developmental progression from a transcriptionally repressive to a permissive compartment is accompanied with activation of gene expression or silencing by deposition of H3K27me3.
Figure 7: Switching nuclear compartments is closely associated with remodeling of chromatin architecture.

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References

  1. Sedat, J. & Manuelidis, L. A direct approach to the structure of eukaryotic chromosomes. Cold Spring Harb. Symp. Quant. Biol. 42, 331–350 (1977).

    Article  Google Scholar 

  2. Rattner, J.B. & Lin, C.C. Radial loops and helixcal coils coexist in metaphase chromosomes. Cell 42, 291–296 (1985).

    Article  CAS  PubMed  Google Scholar 

  3. Paulson, J.R. & Laemmli, U.K. The structure of histone depleted metaphase chromosomes. Cell 12, 817–828 (1977).

    Article  CAS  PubMed  Google Scholar 

  4. Pienta, K.J. & Coffey, D.S. A structural analysis of the nuclear matrix and DNA loops in the organization of the nucleus and chromosome. J. Cell Sci. (suppl. 1), 123–135 (1984).

  5. Munkel, C. & Langowski, J. Chromosome structure described by a polymer model. Phys. Rev. E Stat. Phys. Plasmas Fluids Relat. Interdiscip. Topics 575B, 5888–5896 (1998).

    Google Scholar 

  6. Jhunjhunwala, S. et al. The 3D-structure of the immunoglobulin heavy chain locus: Implications for long-range genomic interactions. Cell 133, 265–279 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bau., D. et al. The three-dimensional folding of the α-globin gene domain reveals formation of chromatin globules. Nat. Struct. Mol. Biol. 18, 107–114 (2011).

    Article  CAS  PubMed  Google Scholar 

  8. Guo, C. et al. Two forms of loops generate the chromatin conformation of the immunoglobulin heavy chain locus. Cell 147, 332–343 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Peric-Hupkes, D. et al. Molecular maps of the reorganization of genome-nuclear lamina interactions during differentiation. Mol. Cell 38, 603–613 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Schneider, R. & Grosschedl, R. Dynamics and interplay of nuclear architecture, genome organization and gene expression. Genes Dev. 21, 3027–3043 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Brown, K.E., Baxtger, J., Graf, D., Merkenschlager, M. & Fisher, A.G. Dynamic repositioning of genes in the nucleus of lymphocytes preparing for cell division. Mol. Cell 3, 207–217 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. Kosak, S.T. et al. Subnuclear compartmentalization of immunoglobulin loci during lymphocyte development. Science 296, 158–162 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. Fuxa, M. et al. Pax5 induces V-DJ rearrangements and locus contraction of the immunoglobulin heavy-chain gene. Genes Dev. 18, 411–422 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Roldán, E. et al. Locus 'decontraction' and centromeric recruitment contribute to allelic exclusion of the immunoglobulin heavy-chain gene. Nat. Immunol. 6, 31–41 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Hewitt, S.L., Chaumeil, J. & Skok, J.A. Chromosome dynamics and the regulation of V(D)J recombination. Immunol. Rev. 237, 43–54 (2010).

    Article  CAS  PubMed  Google Scholar 

  16. Goldmit, M. et al. Epigenetic ontogeny of the IgK locus during B cell development. Nat. Immunol. 6, 198–203 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Lieberman-Aiden, E. et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326, 289–293 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Fullwood, M.J. et al. An oestrogen-receptor-α-bound human chromatin interactome. Nature 462, 58–64 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kalhor, R., Tjong, H., Jayathilaka, N., Alber, F. & Chen, L. Genome architectures revealed by tethered chromosome conformation capture and population-based modeling. Nat. Biotechnol. 30, 90–98 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sexton, T. et al. Three-dimensional folding and functional organization principles of the Drosophila genome. Cell 148, 458–472 (2012).

    Article  CAS  PubMed  Google Scholar 

  21. Li, G. et al. Extensive promoter-centered chromatin interactions provide a topological basis for transcription regulation. Cell 148, 84–98 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhang, Y. et al. Spatial organization of the mouse genome and its role in recurrent chromosomal translocations. Cell 148, 908–921 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Dixon, J.R. et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485, 376–380 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Siepel, A. et al. Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res. 15, 1034–1050 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Dawson, M.A. & Kouzarides, T. Cancer epigenetics: from mechanism to therapy. Cell 150, 12–27 (2012).

    Article  CAS  PubMed  Google Scholar 

  26. Schmidt, D. et al. Waves of retrotransposon expansion remodel genome organization and CTCF binding in multiple mammalian lineages. Cell 148, 335–348 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ochiai, K. et al. A self-reinforcing regulatory network triggered by limiting IL-7 activates pre-BCR signaling and differentiation. Nat. Immunol. 13, 300–307 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Chen, X. et al. Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell 133, 1106–1117 (2008).

    Article  CAS  PubMed  Google Scholar 

  29. Heinz, S. et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell 38, 576–589 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lin, Y.C. et al. A global network of transcription factors, involving E2A, EBF1 and Foxo1, that orchestrates B cell fate. Nat. Immunol. 11, 635–643 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Iborra, F.J., Pombo, A., Jackson, D.A. & Cook, P.R. Active RNA polymerase are localized within discrete transcription factories in human nuclei. J. Cell Sci. 109, 142–2436 (1996).

    Google Scholar 

  32. Edelman, L.B. & Fraser, F. Transcription factories: genetic programming in three dimensions. Curr. Opin. Gen. Dev. 22, 110–114 (2012).

    Article  CAS  Google Scholar 

  33. Corcoran, A.E. The epigenetic role of non-coding RNA transcription and nuclear organization in immunoglobulin repertoire generation. Semin. Immunol. 6, 353–361 (2010).

    Article  CAS  Google Scholar 

  34. Simonis, M. et al. Nuclear organization of active and inactive chromatin domains uncovered by chromosome capture-on-chip (4C). Nat. Genet. 38, 1348–1354 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Jhunjhunwala, S., van Zelm, M.C., Peak, M. & Murre, C. Chromatin architecture and the generation of antigen receptor diversity. Cell 138, 435–448 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Inlay, M.A., Tina, H., Lin, T. & Xu, Y. Important roles for E protein binding sites within the immunoglobulin kappa chain intronic enhancer in activating Vκ to Jκ rearrangement. J. Exp. Med. 200, 1205–1211 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Romanow, W.J. et al. E2A and EBF act in synergy with the V(D)J recombinase to generate a diverse immunoglobulin repertoire in non-lymphoid cells. Mol. Cell 5, 343–353 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Sakamoto, S. et al. E2A and CBP/p300 act in synergy to promote chromatin accessibility of the immunoglobulin κ locus. J. Immunol. 188, 5547–5560 (2012).

    Article  CAS  PubMed  Google Scholar 

  39. Bossen, C., Mansson, R. & Murre, C. Chromatin topology and the regulation of antigen receptor assembly. Annu. Rev. Immunol. 30, 337–356 (2012).

    Article  CAS  PubMed  Google Scholar 

  40. Li, L., Leid, M. & Rothenberg, E.V. An early T cell lineage commitment checkpoint dependent on the transcription factor Bcl11b. Science 329, 89–93 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ikawa, T. et al. An essential developmental checkpoint for production of the T cell lineage. Science 329, 93–96 (2010).

    Article  CAS  PubMed  Google Scholar 

  42. Li, P. et al. Reprogamming of T cells to natural killer-like cells upon Bcl11b deletion. Science 329, 85–89 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Welinder, E. et al. E2A and HEB act in concert to induce the expression of FOXO1 in the common lymphoid progenitor. Proc. Natl. Acad. Sci. USA 108, 17402–17407 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Seet, C.S., Brumbaugh, R.L. & Kee, B.L. Early B cell factor promotes B lymphopoiesis with reduced interleukin 7 responsiveness in the absence of E2A. J. Exp. Med. 199, 1689–1700 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Semerad, C.L., Mercer, E.M., Inlay, M.A., Weissman, I.L. & Murre, C. E2A proteins maintain the hematopoietic stem cell pool and promote the maturation of myelolymphoid and myeloerythroid progenitors. Proc. Natl. Acad. Sci. USA 106, 1930–1935 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Zullo, J.M. et al. DNA sequence-dependent compartmentalization and silencing of chromatin at the nuclear lamina. Cell 149, 1474–1487 (2012).

    Article  CAS  PubMed  Google Scholar 

  47. Ikawa, T., Kawamoto, H., Wright, L.Y. & Murre, C. Long-term cultured E2A-deficient hematopoietic progenitor cells are pluripotent. Immunity 20, 349–360 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Sayegh, C.E., Jhunjhunwala, S., Riblet, R. & Murre, C. Visualization of looping involving the immunoglobulin heavy-chain locus in developing B cells. Genes Dev. 22, 322–327 (2005).

    Article  CAS  Google Scholar 

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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.).

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  1. Yin C Lin and Christopher Benner: These authors contributed equally to this work.

Authors and 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.

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

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Lin, Y., Benner, C., Mansson, R. et al. Global changes in the nuclear positioning of genes and intra- and interdomain genomic interactions that orchestrate B cell fate. Nat Immunol 13, 1196–1204 (2012). https://doi.org/10.1038/ni.2432

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