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Opinion-decision making in the immune system

Cellular identity and lineage choice

Nature Reviews Immunology volume 2, pages 977–982 (2002)Cite this article

Abstract

In multicellular organisms, cells usually respond to signals that they encounter in a manner that depends on their particular lineage 'identity'. In other words, cells that have identical genomes can respond in markedly different ways to the same stimulus, with the outcome being determined largely by the previous developmental history of the cell. This general observation implies that individual somatic cells retain a 'working memory' of their ancestry and that this epigenetic information can be passed through successive rounds of DNA replication and cell division. Here, I discuss whether recent advances in our knowledge of chromatin biology and gene silencing can provide new insights into how cell fate is chosen and maintained during development.

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Figure 1: Contrasting models of haematopoiesis.
Figure 2: A chromatin-based model of gene activation and silencing.
Figure 3: Repositioning of immunoglobulin alleles in developing B cells.

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References

  1. Becket, A. J., MucCulloch, A. E. & Till, J. E. Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells. Nature 197, 452 (1963).

    Article  Google Scholar 

  2. Abramson, S., Miler, R. G. & Phillips, R. A. The identification in adult bone marrow of pluripotent and restricted stem cells of the myeloid and lymphoid systems. J. Exp. Med. 145, 1567 –1579 (1977).

    Article  CAS  Google Scholar 

  3. Akashi, K., Traver, D., Miyamoto, T. & Weissman, I. L. A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 404, 193–197 (2000).

    Article  CAS  Google Scholar 

  4. Kondo, M., Weissman, I. L. & Akashi, K. Clonogenic common lymphoid progenitors in mouse bone marrow. Cell 91, 661–672 (1997).

    Article  CAS  Google Scholar 

  5. Miyamoto, T. et al. Myeloid or lymphoid promiscuity as a critical step in hematopoietic lineage commitment. Dev. Cell 3, 137–147 (2002).

    Article  CAS  Google Scholar 

  6. Hu, M. et al. Multilineage gene expression precedes commitment in the hemopoietic system. Genes Dev. 11, 774–785 (1997).

    Article  CAS  Google Scholar 

  7. Enver, T., Heyworth, C. M. & Dexter, T. M. Do stem cells play dice? Blood 92, 348–351 (1998).

    CAS  PubMed  Google Scholar 

  8. De Krom, M., van de Corput, M., von Lindern, M., Grosveld, F. & Stouboulis, J. Stochastic patterns in globin gene expression are established prior to transcriptional activation and are clonally inheritied Mol. Cell 9, 1319–1326 (2002).

    Article  CAS  Google Scholar 

  9. Festenstein, R. & Kioussis, D. Locus-control regions and epigenetic chromatin modifiers. Curr. Opin. Genet. Dev. 10, 199–203 (2000).

    Article  CAS  Google Scholar 

  10. Brown, G., Bunce, C. M. & Guy, G. R. Sequential determination of lineage potentials during haemopoiesis. Br. J. Cancer 52, 681–686 (1985).

    Article  CAS  Google Scholar 

  11. Novak, J. P. & Stewart, C. C. Stochastic versus deterministic in haemopoiesis: what is what? Br. J. Haematol. 78, 149–154 (1991).

    Article  CAS  Google Scholar 

  12. Singh, H. Gene targeting reveals a hierarchy of transcription factors regulating specification of lymphoid cell fates. Curr. Opin. Immunol. 8, 160–165 (1996).

    Article  CAS  Google Scholar 

  13. Lu, M., Kawamoto, H., Katsube, Y., Ikawa, T. & Katsura, Y. The myelolymphoid progenitor: a key intermediate stage in hemopoiesis generating T and B cells. J. Immunol. 169, 3519–3525 (2002).

    Article  CAS  Google Scholar 

  14. Sieweke, M. H. & Graf, T. A transcription factor party during blood-cell differentiation. Curr. Opin. Genet. Dev. 8, 545–551 (1998).

    Article  CAS  Google Scholar 

  15. Cantor, A. B. & Orkin, S. H. Transcriptional regulation of erythropoiesis: an affair involving multiple partners. Oncogene 21, 3368–3376 (2002).

    Article  CAS  Google Scholar 

  16. Heyworth, C., Pearson, S., May, G. & Enver, T. Transcription factor-mediated lineage switching reveals plasticity in primary committed progenitor cells. EMBO J. 21, 3770–3781 (2002).

    Article  CAS  Google Scholar 

  17. Rekhtman, N., Radparvar, F., Evans, T. & Skoultchi, A. I. Direct interaction of haemopoietic transcription factors PU.1 and GATA-1: functional antagonism in erythroid cells. Genes Dev. 13, 1398–1411 (1999).

    Article  CAS  Google Scholar 

  18. Zhang, P. et al. PU.1 inhibits GATA-1 function and erythroid differentiation by blocking GATA-1 DNA binding. Blood 96, 2641–2648 (2000).

    CAS  PubMed  Google Scholar 

  19. Visvader, J. E., Crossley, M., Hill, J., Orkin, S. H. & Adams, J. M. The C-terminal zinc finger of GATA-1 or GATA-2 is sufficient to induce megakaryocytic differentiation of an early myeloid cell line. Mol. Cell. Biol. 15, 634–641 (1995).

    Article  CAS  Google Scholar 

  20. Kulessa, H., Frampton, J. & Graf, T. GATA-1 reprograms avian myelomonocytic cell lines into eosinophils, thromboblasts and erythrocytes. Genes Dev. 9, 1250–1262 (1995).

    Article  CAS  Google Scholar 

  21. Lassar, A. B., Paterson, B. M. & Weintrub, H. Transfection of a DNA locus that mediates the conversion of 10T1/2 fibroblasts to myoblasts. Cell 47, 649–656 (1986).

    Article  CAS  Google Scholar 

  22. Choi, J. et al. MyoD converts primary dermal fibroblasts, chondroblasts, smooth muscle and retinal pigmented epithelial cells into striated mononucleated myoblasts and multinucleated myotubes. Proc. Natl Acad. Sci. USA 87, 7988–7992 (1990).

    Article  CAS  Google Scholar 

  23. Nutt, S. L., Heavey, B., Rolink, A. G. & Busslinger, M. Commitment to the B-lymphoid lineage depends on the transcription factor Pax5. Nature 401, 556–562 (1999).

    Article  CAS  Google Scholar 

  24. Busslinger, M., Nutt, S. L. & Rolink, A. G. Lineage commitment in lymphopoiesis. Curr. Opin. Immunol. 2, 151–158 (2000).

    Article  Google Scholar 

  25. Mikkola, I., Heavey, B., Horcher, M. & Busslinger, M. Reversion of B-cell commitment upon loss of Pax5 expression. Science 297, 110–113 (2002).

    Article  CAS  Google Scholar 

  26. Horcher, M., Souabni, A. & Busslinger, M. Pax5/BSAP maintains the identity of B cells in late B lymphopoiesis. Immunity 6, 779–790 (2001).

    Article  Google Scholar 

  27. Kozmik, Z., Wang, S., Dorfler, P., Adams, B. & Busslinger, M. The promoter of the CD19 gene is a target for the B-cell-specific transcription factor BSAP. Mol. Cell. Biol. 12, 2662–2672 (1992).

    Article  CAS  Google Scholar 

  28. Eberhard, D., Jimenez, G., Heavey, B. & Busslinger, M. Transcriptional repression by Pax5 (BSAP) through interaction with corepressors of the Groucho family. EMBO J. 10, 2292–2303 (2000).

    Article  Google Scholar 

  29. Fisher, A. G. & Merkenschlager, M. Gene silencing, cell fate and nuclear organisation. Curr. Opin. Genet. Dev. 12, 193–197 (2002).

    Article  CAS  Google Scholar 

  30. Sieweke, M. H., Tekotte, H., Frampton, J. & Graf, T. MafB is an interaction partner and repressor of Ets-1 that inhibits erythroid differentiation. Cell 85, 49–60 (1996).

    Article  CAS  Google Scholar 

  31. Zhang, P. et al. Negative cross-talk between hematopoietic regulators: GATA proteins repress PU.1. Proc. Natl Acad. Sci. USA 96, 8705–8710 (1996).

    Article  Google Scholar 

  32. Nerlov, C., Querfurth, E., Kulessa, H. & Graf, T. GATA-1 interacts with the myeloid PU.1 transcription factor and represses PU.1-dependent transcription. Blood 95, 2543–2551 (2000).

    CAS  PubMed  Google Scholar 

  33. Muhr, J., Anderson, E., Persson, M., Jessel, T. M. & Ericson, J. Groucho-mediated transcriptional repression establishes progenitor-cell pattern and neuronal fate in the ventral neural tube. Cell 104, 861–873 (2001).

    Article  CAS  Google Scholar 

  34. Marquardt, T. & Pfaff, S. L. Cracking the transcriptional code for cell specification in the neural tube. Cell 106, 651–654 (2001).

    Article  CAS  Google Scholar 

  35. Phillips, R. L. et al. The genetic program of hematopoietic stem cells. Science 288, 1635–1640 (2000).

    Article  CAS  Google Scholar 

  36. Muschen, M. et al. Molecular portraits of B-cell lineage commitment. Proc. Natl Acad. Sci. USA 99, 10014–10019 (2002).

    Article  CAS  Google Scholar 

  37. Ivanova, N. B. et al. A stem-cell molecular signature. Science 298, 601–604 (2002).

    Article  CAS  Google Scholar 

  38. Holstege, F. C. & Young, R. A. Transcriptional regulation: contending with complexity. Proc. Natl Acad. Sci. USA 96, 2–4 (1999).

    Article  CAS  Google Scholar 

  39. Ohlsson, R., Tycko, B. & Sapienza, C. Monoallelic expression: 'there can only be one'. Trends Genet. 11, 435–438 (1998).

    Article  Google Scholar 

  40. Bird, A. The essentials of DNA methylation. Cell 70, 5–8 (1992).

    Article  CAS  Google Scholar 

  41. Leonhardt, H., Page, A. W., Weier, H. U. & Bestor, T. H. A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei. Cell 71, 865–873 (1992).

    Article  CAS  Google Scholar 

  42. Bird, A. P. & Wolffe, A. P. Methylation-induced repression — belts, braces and chromatin. Cell 99, 451–454 (1999).

    Article  CAS  Google Scholar 

  43. Allshire, R. & Bickmore, W. Pausing for thought on the boundaries of imprinting. Cell 102, 705–708 (2000).

    Article  CAS  Google Scholar 

  44. Jenuwein, T. & Allis, C. D. Translating the histone code. Science 293, 1074–1080 (2001).

    Article  CAS  Google Scholar 

  45. Gasser, S. M. Positions of potential: nuclear organization and gene expression. Cell 104, 639–642 (2001).

    Article  CAS  Google Scholar 

  46. Zhang, Y. & Reinberg, D. Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails. Genes Dev. 15, 2343–2360 (2002).

    Article  Google Scholar 

  47. Lachner, M., O'Carroll, D., Rea, S., Mechtler, K. & Jenuwein, T. Methylation of histone H3 lysine-9 creates a binding site for HP1 proteins. Nature 410, 116–120 (2001).

    Article  CAS  Google Scholar 

  48. Bannister, A. J. et al. Selective recognition of methylated lysine-9 on histone H3 by the HP1 chromo domain. Nature 410, 120–124 (2001).

    Article  CAS  Google Scholar 

  49. Müller, J. et al. Histone methyltransferase activity of a Drosophila polycomb-group repressor complex. Cell 111, 197–208 (2002)

    Article  Google Scholar 

  50. Czermin, B. et al. Drosophila enhancer of Zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal polycomb sites. Cell 111, 185–196 (2002).

    Article  CAS  Google Scholar 

  51. Tamaru, H. & Selker, E. U. A histone H3 methyltransferase controls DNA methylation in Neurospora crassa. Nature 414, 277–283 (2001).

    Article  CAS  Google Scholar 

  52. Bird, A. Molecular biology. Methylation talk between histones and DNA. Science 294, 2113–2115 (2002).

    Article  Google Scholar 

  53. Gribnau, J., Diderich, K., Pruzina, S., Calzolari, R. & Fraser, P. Intergenic transcription and developmental remodeling of chromatin subdomains in the human β-globin locus. Mol. Cell 5, 377–386 (2000).

    Article  CAS  Google Scholar 

  54. Schubeler, D. et al. Nuclear localization and histone acetylation: a pathway for chromatin opening and transcriptional activation of the human β-globin locus. Genes Dev. 14, 940–950 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Agarwal, S. & Rao, A. Modulation of chromatin structure regulates cytokine gene expression during T-cell differentiation. Immunity 9, 765–775 (1998).

    Article  CAS  Google Scholar 

  56. Lee, D. U., Agarwal, S. & Rao, A. TH2-lineage commitment and efficient IL-4 production involves extended demethylation of the IL-4 gene. Immunity 16, 649–660 (2002).

    Article  CAS  Google Scholar 

  57. Avni, O. et al. T(H)-cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes. Nature Immunol. 3, 643–651 (2002).

    Article  CAS  Google Scholar 

  58. Grogan, J. L. & Locksley, R. M. T-helper cell differentiation: on again, off again. Curr. Opin. Immunol. 3, 366–372 (2002).

    Article  Google Scholar 

  59. Dernburg, A. F. et al. Perturbation of nuclear architecture by long-distance chromosome interactions. Cell 85, 745–759 (1996).

    Article  CAS  Google Scholar 

  60. Francastel, C., Walters, M. C., Groudine, M. & Martin D. I. A functional enhancer suppresses silencing of a transgene and prevents its localization close to centromeric heterochromatin. Cell 99, 259–269 (1999).

    Article  CAS  Google Scholar 

  61. Volpi, E. V. et al. Large-scale chromatin organization of the major histocompatibility complex and other regions of human chromosome 6 and its response to interferon in interphase nuclei. J. Cell Sci. 113, 1565–1576 (2000).

    CAS  PubMed  Google Scholar 

  62. Williams, R. E., Broad, S., Sheer, D. & Ragoussis, J. Subchromosomal positioning of the epidermal differentiation complex (EDC) in keratinocyte and lymphoblast interphase nuclei. Exp. Cell Res. 272, 163–175 (2002).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  64. Skok, J. A. et al. Nonequivalent nuclear location of immunoglobulin alleles in B lymphocytes. Nature Immunol. 2, 848–854 (2002).

    Article  Google Scholar 

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Acknowledgements

I would like to thank my colleagues, in particular members of the Lymphocyte Development Group, for helpful discussions.

Author information

Authors and Affiliations

  1. the Lymphocyte Development Group, Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK

    Amanda G. Fisher

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  1. Amanda G. Fisher
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Related links

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DATABASES

LocusLink

CBP

CD19

DNMT1

EDR1

EFNB2

EKLF

FOG1

GATA1

H3

HES1

IFN-γ

IL-4

MAFB

MECP2

MyoD

NFAT1

p300

PAX5

PRC1

PU.1

SP1

SUV39H

TCF3

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Fisher, A. Cellular identity and lineage choice. Nat Rev Immunol 2, 977–982 (2002). https://doi.org/10.1038/nri958

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