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The β-globin nuclear compartment in development and erythroid differentiation

Nature Genetics volume 35, pages 190–194 (2003)Cite this article

Abstract

Efficient transcription of genes requires a high local concentration of the relevant trans-acting factors. Nuclear compartmentalization can provide an effective means to locally increase the concentration of rapidly moving trans-acting factors; this may be achieved by spatial clustering of chromatin-associated binding sites for such factors1,2,3,4,5. Here we analyze the structure of an erythroid-specific spatial cluster of cis-regulatory elements and active β-globin genes, the active chromatin hub (ACH; ref. 6), at different stages of development and in erythroid progenitors. We show, in mice and humans, that a core ACH is developmentally conserved and consists of the hypersensitive sites (HS1–HS6) of the locus control region (LCR), the upstream 5′ HS–60/–62 and downstream 3′ HS1. Globin genes switch their interaction with this cluster during development, correlating with the switch in their transcriptional activity7. In mouse erythroid progenitors that are committed to but do not yet express β-globin, only the interactions between 5′ HS–60/–62, 3′ HS1 and hypersensitive sites at the 5′ side of the LCR are stably present. After induction of differentiation, these sites cluster with the rest of the LCR and the gene that is activated. We conclude that during erythroid differentiation, cis-regulatory DNA elements create a developmentally conserved nuclear compartment dedicated to RNA polymerase II transcription of β-globin genes.

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Figure 1: Spatial organization of the mouse β-globin locus.
Figure 2: A developmental switch occurs in contacts between individual β-globin genes and the core ACH of the mouse β-globin locus.
Figure 3: Spatial organization of the human β-globin locus.
Figure 4: Spatial organization of the mouse β-globin locus in erythroid progenitors.
Figure 5: Cis-regulatory elements of the β-globin locus create a nuclear compartment dedicated to RNA polymerase II transcription: the active chromatin hub.

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References

  1. Isogai, Y. & Tjian, R. Targeting genes and transcription factors to segregated nuclear compartments. Curr. Opin. Cell Biol. 15, 296–303 (2003).

    Article  CAS  Google Scholar 

  2. Misteli, T. The concept of self-organization in cellular architecture. J. Cell Biol. 155, 181–185 (2001).

    Article  CAS  Google Scholar 

  3. Carmo-Fonseca, M. The contribution of nuclear compartmentalization to gene regulation. Cell 108, 513–521 (2002).

    Article  CAS  Google Scholar 

  4. Droge, P. & Muller-Hill, B. High local protein concentrations at promoters: strategies in prokaryotic and eukaryotic cells. Bioessays 23, 179–183 (2001).

    Article  CAS  Google Scholar 

  5. Chubb, J.R. & Bickmore, W.A. Considering nuclear compartmentalization in the light of nuclear dynamics. Cell 112, 403–406 (2003).

    Article  CAS  Google Scholar 

  6. Tolhuis, B., Palstra, R.J., Splinter, E., Grosveld, F. & de Laat, W. Looping and interaction between hypersensitive sites in the active β-globin locus. Mol. Cell 10, 1453–1465 (2002).

    Article  CAS  Google Scholar 

  7. Stamatoyannopoulos, G. & Grosveld, F. Hemoglobin switching. in The molecular basis of blood diseases (eds. Stamatoyannopoulos, G., Majerus, P., Perlmutter, R. & Varmus, H.) 135–182 (W.B. Saunders, Philadelphia, 2001).

  8. Farrell, C.M. et al. A large upstream region is not necessary for gene expression or hypersensitive site formation at the mouse β-globin locus. Proc. Natl. Acad. Sci. USA 97, 14554–14559 (2000).

    Article  CAS  Google Scholar 

  9. Bulger, M. et al. Comparative structural and functional analysis of the olfactory receptor genes flanking the human and mouse β-globin gene clusters. Proc. Natl. Acad. Sci. USA 97, 14560–14565 (2000).

    Article  CAS  Google Scholar 

  10. Dekker, J., Rippe, K., Dekker, M. & Kleckner, N. Capturing chromosome conformation. Science 295, 1306–1311 (2002).

    Article  CAS  Google Scholar 

  11. Trimborn, T., Gribnau, J., Grosveld, F. & Fraser, P. Mechanisms of developmental control of transcription in the murine α- and β-globin loci. Genes Dev. 13, 112–124 (1999).

    Article  CAS  Google Scholar 

  12. Ellis, J., Talbot, D., Dillon, N. & Grosveld, F. Synthetic human β-globin 5′ HS2 constructs function as locus control regions only in multicopy transgene concatamers. EMBO J. 12, 127–134 (1993).

    Article  CAS  Google Scholar 

  13. Ellis, J. et al. A dominant chromatin-opening activity in 5′ hypersensitive site 3 of the human β-globin locus control region. EMBO J. 15, 562–568 (1996).

    Article  CAS  Google Scholar 

  14. Fraser, P., Pruzina, S., Antoniou, M. & Grosveld, F. Each hypersensitive site of the human β-globin locus control region confers a different developmental pattern of expression on the globin genes. Genes Dev. 7, 106–113 (1993).

    Article  CAS  Google Scholar 

  15. Fiering, S. et al. Targeted deletion of 5′ HS2 of the murine β-globin LCR reveals that it is not essential for proper regulation of the β-globin locus. Genes Dev. 9, 2203–2213 (1995).

    Article  CAS  Google Scholar 

  16. Hug, B.A. et al. Analysis of mice containing a targeted deletion of β-globin locus control region 5′ hypersensitive site 3. Mol. Cell Biol. 16, 2906–2912 (1996).

    Article  CAS  Google Scholar 

  17. Carter, D., Chakalova, L., Osborne, C.S., Dai, Y.F. & Fraser, P. Long-range chromatin regulatory interactions in vivo. Nat. Genet. 32, 623–626 (2002).

    Article  CAS  Google Scholar 

  18. Hardison, R. & Miller, W. Use of long sequence alignments to study the evolution and regulation of mammalian globin gene clusters. Mol. Biol. Evol. 10, 73–102 (1993).

    CAS  PubMed  Google Scholar 

  19. Strouboulis, J., Dillon, N. & Grosveld, F. Developmental regulation of a complete 70-kb human β-globin locus in transgenic mice. Genes Dev. 6, 1857–1864 (1992).

    Article  CAS  Google Scholar 

  20. Imam, A.M. et al. Modification of human β-globin locus PAC clones by homologous recombination in Escherichia coli. Nucleic Acids Res. 28, E65 (2000).

  21. Wai, A.W.K. et al. HS5 of the human β-globin locus control region: a developmental stage-specific border in erythroid cells. EMBO J. 22, 4489–4500 (2003).

    Article  CAS  Google Scholar 

  22. Dolznig, H. et al. Establishment of normal, terminally differentiating mouse erythroid progenitors: molecular characterization by cDNA arrays. FASEB J. 15, 1442–1444 (2001).

    Article  CAS  Google Scholar 

  23. von Lindern, M. et al. Leukemic transformation of normal murine erythroid progenitors: v- and c-ErbB act through signaling pathways activated by the EpoR and c-Kit in stress erythropoiesis. Oncogene 20, 3651–3664 (2001).

    Article  CAS  Google Scholar 

  24. Bulger, M. et al. A complex chromatin landscape revealed by patterns of nuclease sensitivity and histone modification within the mouse β-globin locus. Mol. Cell Biol. 23, 5234–5244 (2003).

    Article  CAS  Google Scholar 

  25. Jackson, D.A., Hassan, A.B., Errington, R.J. & Cook, P.R. Visualization of focal sites of transcription within human nuclei. EMBO J. 12, 1059–1065 (1993).

    Article  CAS  Google Scholar 

  26. Pombo, A. et al. Regional specialization in human nuclei: visualization of discrete sites of transcription by RNA polymerase III. EMBO J. 18, 2241–2253 (1999).

    Article  CAS  Google Scholar 

  27. Cook, P.R. The organization of replication and transcription. Science 284, 1790–1795 (1999).

    Article  CAS  Google Scholar 

  28. Wijgerde, M., Grosveld, F. & Fraser, P. Transcription complex stability and chromatin dynamics in vivo. Nature 377, 209–213 (1995).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank K. Hussain and R. Hendriks for technical assistance and M. von Lindern for I/11 cells. This work is supported by The Netherlands Organisation for Scientific Research to W.d.L. as part of the Innovational Research Incentives Scheme and by grants from The Netherlands Organisation for Scientific Research and European Community to F.G.

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  1. Robert-Jan Palstra and Bas Tolhuis: These authors contributed equally to this work.

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  1. Department of Cell Biology and Genetics, ErasmusMC, PO Box 1738, Rotterdam, 3000 DR, The Netherlands

    Robert-Jan Palstra, Bas Tolhuis, Erik Splinter, Rian Nijmeijer, Frank Grosveld & Wouter de Laat

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  1. Robert-Jan Palstra
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Correspondence to Wouter de Laat.

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Palstra, RJ., Tolhuis, B., Splinter, E. et al. The β-globin nuclear compartment in development and erythroid differentiation. Nat Genet 35, 190–194 (2003). https://doi.org/10.1038/ng1244

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