Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The role of chromatin structure in regulating the expression of clustered genes

Nature Reviews Genetics volume 6, pages 775–781 (2005)Cite this article

Key Points

  • It is not only functionally related genes that cluster in the mammalian genome: there also seems to be general clustering of apparently unrelated genes.

  • Specialized genomic regions, such as the homeobox, globin and major histocompatibility complex regions, can give useful insights into how 'ordinary' regions of the genome are regulated. However, they also use specialized means of coordinate regulation that might not be generally applicable.

  • Histone modifications seem to operate at a local level in the mammalian genome — they do not generally spread over large domains.

  • Locus-control regions do not seem to operate over clusters of unrelated genes.

  • Regions of open chromatin-fibre structure are clustered in the human genome. It is suggested that this creates an environment that is permissive for gene activation by transcription factors.

  • Open chromatin regions contain clusters of broadly expressed unrelated genes. This might be a selective force for maintaining these gene clusters during evolution.

  • Gene regulation cannot be understood by considering individual genes. Whole-genome approaches, such as the use of genomic microarrays, can begin to tell us about large-scale mechanisms of gene regulation.

Abstract

Much of what we know about the chromatin-based mechanisms that regulate gene expression in mammals has come from the study of what are, paradoxically, atypical genes. These are clusters of structurally and/or functionally related genes that are coordinately regulated during development, or between different cell types. Can unravelling the mechanisms of gene regulation at these gene clusters help us to understand how other genes are controlled? Moreover, can it explain why there is clustering of apparently unrelated genes in mammalian genomes?

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Chromatin structure at the MHC and EDC superclusters.
Figure 2: Relationship of chromatin-fibre structure to gene density and gene expression.
Figure 3: Correlation between chromatin-fibre structure and the transcriptional misregulation of genes in cancer.

Similar content being viewed by others

References

  1. Hurst, L. D., Pal, C. & Lercher, M. J. The evolutionary dynamics of eukaryotic gene order. Nature Rev. Genet. 5, 299–310 (2004).

    Article  CAS  Google Scholar 

  2. De Leo, A. A. et al. Sequencing and mapping hemoglobin gene clusters in the Australian model dasyurid marsupial Sminthopsis macroura. Cytogenet. Genome Res. 108, 333–341 (2005).

    Article  CAS  Google Scholar 

  3. Gillemans, N. et al. Functional and comparative analysis of globin loci in pufferfish and humans. Blood 101, 2842–2849 (2003).

    Article  CAS  Google Scholar 

  4. Mason, M. M., Lee, E., Westphal, H. & Reitman, M. Expression of the chicken β-globin gene cluster in mice: correct developmental expression and distributed control. Mol. Cell. Biol. 15, 407–414 (1995).

    Article  CAS  Google Scholar 

  5. Kmita, M. & Duboule, D. Organizing axes in time and space; 25 years of colinear tinkering. Science 301, 331–333 (2003).

    Article  CAS  Google Scholar 

  6. Ikuta, T., Yoshida, N., Satoh, N. & Saiga, H. Ciona intestinalis Hox gene cluster: its dispersed structure and residual colinear expression in development. Proc. Natl Acad. Sci. USA 101, 15118–15123 (2004).

    Article  CAS  Google Scholar 

  7. Seo, H. C. et al. Hox cluster disintegration with persistent anteroposterior order of expression in Oikopleura dioica. Nature 431, 67–71 (2004).

    Article  CAS  Google Scholar 

  8. Patel, N. H. Evolutionary biology: time, space and genomes. Nature 431, 28–29 (2004).

    Article  CAS  Google Scholar 

  9. 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 

  10. Plant, K. E., Routledge, S. J. & Proudfoot, N. J. Intergenic transcription in the human β-globin gene cluster. Mol. Cell. Biol. 21, 6507–6514 (2001).

    Article  CAS  Google Scholar 

  11. Trowsdale, J. The gentle art of gene arrangement: the meaning of gene clusters. Genome Biol. 3, COMMENT2002 (2002).

  12. Danchin, E. G. & Pontarotti, P. Towards the reconstruction of the bilaterian ancestral pre-MHC region. Trends Genet. 20, 587–591 (2004).

    Article  CAS  Google Scholar 

  13. Kumanovics, A., Takada, T. & Lindahl, K. F. Genomic organization of the mammalian MHC. Annu. Rev. Immunol. 21, 629–657 (2003).

    Article  CAS  Google Scholar 

  14. Horton, R. et al. Gene map of the extended human MHC. Nature Rev. Genet. 5, 889–899 (2004).

    Article  CAS  Google Scholar 

  15. Wang, J. et al. Promyelocytic leukemia nuclear bodies associate with transcriptionally active genomic regions. J. Cell Biol. 164, 515–526 (2004).

    Article  CAS  Google Scholar 

  16. Shykind, B. M. Regulation of odorant receptors: one allele at a time. Hum. Mol. Genet. 14 (Suppl. 1), R33–R39 (2005).

    Article  CAS  Google Scholar 

  17. Amadou, C. et al. Co-duplication of olfactory receptor and MHC class I genes in the mouse major histocompatibility complex. Hum. Mol. Genet. 12, 3025–3040 (2003).

    Article  CAS  Google Scholar 

  18. Shiina, T. et al. Genomic anatomy of a premier major histocompatibility complex paralogous region on chromosome 1q21–q22. Genome Res. 11, 789–802 (2001).

    Article  CAS  Google Scholar 

  19. Alibardi, L. & Toni, M. Localization and characterization of specific cornification proteins in avian epidermis. Cells Tissues Organs 178, 204–215 (2004).

    Article  CAS  Google Scholar 

  20. Williams, R. R., 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 

  21. Craig, J. M. & Bickmore, W. A. The distribution of CpG islands in mammalian chromosomes. Nature Genet. 7, 376–382 (1994).

    Article  CAS  Google Scholar 

  22. Caron, H. et al. The human transcriptome map: clustering of highly expressed genes in chromosomal domains. Science 291, 1289–1292 (2001).

    Article  CAS  Google Scholar 

  23. Versteeg, R. et al. The human transcriptome map reveals extremes in gene density, intron length, GC content, and repeat pattern for domains of highly and weakly expressed genes. Genome Res. 13, 1998–2004 (2003).

    Article  CAS  Google Scholar 

  24. Lercher, M. J., Urrutia, A. O. & Hurst, L. D. Clustering of housekeeping genes provides a unified model of gene order in the human genome. Nature Genet. 31, 180–183 (2002). This paper proposes that genes that are broadly expressed, rather than those that are highly expressed, cluster in the human genome.

    Article  CAS  Google Scholar 

  25. Cajiao, I., Zhang, A., Yoo, E. J., Cooke, N. E. & Liebhaber, S. A. Bystander gene activation by a locus control region. EMBO J. 23, 3854–3863 (2004).

    Article  CAS  Google Scholar 

  26. Singer, G. A., Lloyd, A. T., Huminiecki, L. B. & Wolfe, K. H. Clusters of co-expressed genes in mammalian genomes are conserved by natural selection. Mol. Biol. Evol. 22, 767–775 (2005).

    Article  CAS  Google Scholar 

  27. Carter, D., Chakalova, L., Osborne, C. S., Dai, Y. F. & Fraser, P. Long-range chromatin regulatory interactions in vivo. Nature Genet. 32, 1–4 (2002).

    Article  Google Scholar 

  28. 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). This study used the 3C (chromosome conformation capture) technique to show that regulatory and coding regions of the β-globin locus are brought into close proximity with each other.

    Article  CAS  Google Scholar 

  29. Drissen, R. et al. The active spatial organization of the β-globin locus requires the transcription factor EKLF. Genes Dev. 18, 2485–2490 (2004).

    Article  CAS  Google Scholar 

  30. Vakoc, C. R. et al. Proximity among distant regulatory elements at the β-globin locus requires GATA-1 and FOG-1. Mol. Cell 17, 453–462 (2005).

    Article  CAS  Google Scholar 

  31. Palstra, R. J. et al. The β-globin nuclear compartment in development and erythroid differentiation. Nature Genet. 35, 190–194 (2003).

    Article  CAS  Google Scholar 

  32. Spitz, F., Gonzalez, F. & Duboule, D. A global control region defines a chromosomal regulatory landscape containing the HoxD cluster. Cell 113, 405–417 (2003).

    Article  CAS  Google Scholar 

  33. Zakany, J., Kmita, M. & Duboule, D. A dual role for Hox genes in limb anterior–posterior asymmetry. Science 304, 1669–1672 (2004).

    Article  CAS  Google Scholar 

  34. Carson, S. & Wiles, M. V. Far upstream regions of class II MHC Ea are necessary for position-independent, copy-dependent expression of Ea transgene. Nucleic Acids Res. 21, 2065–2072 (1993).

    Article  CAS  Google Scholar 

  35. Krawczyk, M. et al. Long distance control of MHC class II expression by multiple distal enhancers regulated by regulatory factor X complex and CIITA. J. Immunol. 173, 6200–6210 (2004).

    Article  CAS  Google Scholar 

  36. Forsberg, E. C. et al. Developmentally dynamic histone acetylation pattern of a tissue-specific chromatin domain. Proc. Natl Acad. Sci. USA 97, 14494–14499 (2000).

    Article  CAS  Google Scholar 

  37. Chambeyron, S. & Bickmore, W. A. Chromatin decondensation and nuclear reorganization of the HoxB locus upon induction of transcription. Genes Dev. 18, 1119–1130 (2004).

    Article  CAS  Google Scholar 

  38. Rastegar, M., Kobrossy, L., Kovacs, E. N., Rambaldi, I. & Featherstone, M. Sequential histone modifications at Hoxd4 regulatory regions distinguish anterior from posterior embryonic compartments. Mol. Cell. Biol. 24, 8090–8103 (2004).

    Article  CAS  Google Scholar 

  39. Bernstein, B. E. et al. Genomic maps and comparative analysis of histone modifications in human and mouse. Cell 120, 169–181 (2005). This large-scale analysis of histone modifications in mammalian cells reveals punctate domains of modification for most genomic regions, but broad domains of active histone modifications at Hox gene loci.

    Article  CAS  Google Scholar 

  40. Raval, A. et al. Transcriptional coactivator, CIITA, is an acetyltransferase that bypasses a promoter requirement for TAFII250. Mol. Cell 7, 105–115 (2001).

    Article  CAS  Google Scholar 

  41. Zika, E. & Ting, J. P. Epigenetic control of MHC-II: interplay between CIITA and histone-modifying enzymes. Curr. Opin. Immunol. 17, 58–64 (2005).

    Article  CAS  Google Scholar 

  42. Masternak, K., Peyraud, N., Krawczyk, M., Barras, E. & Reith, W. Chromatin remodeling and extragenic transcription at the MHC class II locus control region. Nature Immunol. 4, 132–137 (2003).

    Article  CAS  Google Scholar 

  43. Kimura, A. P., Liebhaber, S. A. & Cooke, N. E. Epigenetic modifications at the human growth hormone locus predict distinct roles for histone acetylation and methylation in placental gene activation. Mol. Endocrinol. 18, 1018–1032 (2004).

    Article  CAS  Google Scholar 

  44. Roh, T. Y., Cuddapah, S. & Zhao, K. Active chromatin domains are defined by acetylation islands revealed by genome-wide mapping. Genes Dev. 19, 542–552 (2005). This study used a novel combination of immunoprecipitation and serial analysis of gene expression (SAGE) for mapping histone modifications across the genome.

    Article  CAS  Google Scholar 

  45. Chambeyron, S., Da Silva, N. R., Lawson, K. A. & Bickmore, W. A. Nuclear re-organisation of the Hoxb complex during mouse embryonic development. Development 132, 2215–2223 (2005).

    Article  CAS  Google Scholar 

  46. Ragoczy, T., Telling, A., Sawado, T., Groudine, M. & Kosak, S. T. A genetic analysis of chromosome territory looping: diverse roles for distal regulatory elements. Chromosome. Res. 11, 513–525 (2003).

    Article  CAS  Google Scholar 

  47. 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). This was the first study to show that a region of the genome can be extruded from a chromosome territory in a regulated fashion.

    CAS  PubMed  Google Scholar 

  48. Gilbert, N. et al. Chromatin architecture of the human genome: gene-rich domains are enriched in open chromatin fibres. Cell 118, 555–566 (2004). This paper highlights the first global survey of the biophysical properties of chromatin fibres across the human genome. It also proposes that an open chromatin structure is present in regions of high gene density.

    Article  CAS  Google Scholar 

  49. Lercher, M. J., Urrutia, A. O., Pavlicek, A. & Hurst, L. D. A unification of mosaic structures in the human genome. Hum. Mol. Genet. 12, 2411–2415 (2003).

    Article  CAS  Google Scholar 

  50. Mahy, N. L., Perry, P. E. & Bickmore, W. A. Gene density and transcription influence the localization of chromatin outside of chromosome territories detectable by FISH. J. Cell Biol. 159, 753–763 (2002).

    Article  CAS  Google Scholar 

  51. Zhou, Y. et al. Genome-wide identification of chromosomal regions of increased tumor expression by transcriptome analysis. Cancer Res. 63, 5781–5784 (2003).

    CAS  PubMed  Google Scholar 

  52. Murrell, A., Rakyan, V. K. & Beck, S. From genome to epigenome. Hum. Mol. Genet. 14 (Suppl. 1), R3–R10 (2005).

    Article  CAS  Google Scholar 

  53. Crawford, G. E. et al. Identifying gene regulatory elements by genome-wide recovery of DNase hypersensitive sites. Proc. Natl Acad. Sci. USA 101, 992–997 (2004).

    Article  CAS  Google Scholar 

  54. Sabo, P. J. et al. Genome-wide identification of DNaseI hypersensitive sites using active chromatin sequence libraries. Proc. Natl Acad. Sci. USA 101, 4537–4542 (2004).

    Article  CAS  Google Scholar 

  55. Weil, M. R., Widlak, P., Minna, J. D. & Garner, H. R. Global survey of chromatin accessibility using DNA microarrays. Genome Res. 14, 1374–1381 (2004).

    Article  CAS  Google Scholar 

  56. Marenholz, I., Heizmann, C. W. & Fritz, G. S100 proteins in mouse and man: from evolution to function and pathology (including an update of the nomenclature). Biochem. Biophys. Res. Commun. 322, 1111–1122 (2004).

    Article  CAS  Google Scholar 

  57. Marenholz, I. et al. Identification of human epidermal differentiation complex (EDC)-encoded genes by subtractive hybridization of entire YACs to a gridded keratinocyte cDNA library. Genome Res. 11, 341–355 (2001).

    Article  CAS  Google Scholar 

  58. Marshall, D., Hardman, M. J., Nield, K. M. & Byrne, C. Differentially expressed late constituents of the epidermal cornified envelope. Proc. Natl Acad. Sci. USA 98, 13031–13036 (2001).

    Article  CAS  Google Scholar 

  59. Huber, M. et al. Isolation and characterization of human repetin, a member of the fused gene family of the epidermal differentiation complex. J. Invest. Dermatol. 124, 998–1007 (2005).

    Article  CAS  Google Scholar 

  60. Contzler, R., Favre, B., Huber, M. & Hohl, D. Cornulin, a new member of the 'fused gene' family, is expressed during epidermal differentiation. J. Invest. Dermatol. 124, 990–997 (2005).

    Article  CAS  Google Scholar 

  61. Jang, S. I. & Steinert, P. M. Loricrin expression in cultured human keratinocytes is controlled by a complex interplay between transcription factors of the Sp1, CREB, AP1, and AP2 families. J. Biol. Chem. 277, 42268–42279 (2002).

    Article  CAS  Google Scholar 

  62. Martin, N., Patel, S. & Segre, J. A. Long-range comparison of human and mouse Sprr loci to identify conserved noncoding sequences involved in coordinate regulation. Genome Res. 14, 2430–2438 (2004).

    Article  CAS  Google Scholar 

  63. Johnnidis, J. B. et al. Chromosomal clustering of genes controlled by the aire transcription factor. Proc. Natl Acad. Sci. USA 102, 7233–7238 (2005).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

D.S. is a Medical Research Council (MRC) pre-doctoral training fellow and W.A.B. is a Centennial fellow of the James S. McDonnell foundation. This work was funded by the MRC UK, and in part by the EU FP6 Network of Excellence Epigenome.

Author information

Authors and Affiliations

  1. Chromosomes and Gene Expression Section, Medical Research Council Human Genetics Unit, Crewe Road, Edinburgh, EH4 2XU, United Kingdom

    Duncan Sproul, Nick Gilbert & Wendy A. Bickmore

Authors
  1. Duncan Sproul
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nick Gilbert
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wendy A. Bickmore
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wendy A. Bickmore.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Entrez Gene

CD74

CD79B

Evx2

GH1

HLA-DRA

Hoxb1

Hoxb9

Hoxd

Hoxd4

IFNG

Lnp

MHC2TA

Nuclear Protein Database

PML bodies

Glossary

IMMUNO-PROTEASOME

A proteasome complex that degrades proteins into peptides for presentation with MHC class I molecules.

COLLINEARITY

The correspondence between the linear order of genes on the chromosome and the sequential order of their expression.

UROCHORDATES

A subphylum of Chordata that are also known as tunicates. They have a notochord during their early stages of development.

LINKAGE DISEQUILIBRIUM

The non-random association of alleles at adjacent loci along a chromosome.

TELEOSTS

A taxonomic group that comprises most extant bony fishes.

PML NUCLEAR BODIES

Sub-nuclear compartments that are defined by the presence of the PML (promyelocytic leukaemia) protein. They have been associated with diverse nuclear functions including transcription, DNA repair, viral defence, stress, cell-cycle regulation, proteolysis and apoptosis.

LORICRIN

The predominant protein of the cornified envelope in keratinocytes, which is encoded by a gene in the EDC.

FILAGGRIN

A protein that is involved in aggregating keratin during the terminal differentiation of epidermal keratinocytes, and is encoded by a gene in the EDC.

SUPRABASAL LAYERS

Layers of progressively differentiating keratinocytes that are found above the basal layer of stem cells.

CORNIFIED ENVELOPE

A tough protein–lipid structure that is formed under the plasma membrane of keratinocytes during their terminal differentiation.

INVOLUCRIN

A component of the cornified envelope.

SYNTENY

The preserved order of genes along a chromosome in related organisms.

YOLK SAC

The first site of blood formation in the mammalian embryo.

FLUORESCENCE IN SITU HYBRIDIZATION

This is a cytological technique that is used to detect and localize DNA sequences on chromosomes, or in nuclei, using fluorescent probes.

B-LYMPHOBLASTOID CELLS

Peripheral blood mononuclear cells that are transformed with the Epstein–Barr virus.

ANTIGEN-PRESENTING CELLS

Dendritic cells, macrophages and B cells. These cells express MHC class II genes, display foreign antigens that form complexes with MHC on their surfaces, and can activate T cells.

SUCROSE GRADIENT SEDIMENTATION

An ultracentrifugation technique that separates macromolecules on the basis of their mass and their size or shape (frictional coefficient).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sproul, D., Gilbert, N. & Bickmore, W. The role of chromatin structure in regulating the expression of clustered genes. Nat Rev Genet 6, 775–781 (2005). https://doi.org/10.1038/nrg1688

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg1688

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing