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.

Transcription regulation and animal diversity

Abstract

Whole-genome sequence assemblies are now available for seven different animals, including nematode worms, mice and humans. Comparative genome analyses reveal a surprising constancy in genetic content: vertebrate genomes have only about twice the number of genes that invertebrate genomes have, and the increase is primarily due to the duplication of existing genes rather than the invention of new ones. How, then, has evolutionary diversity arisen? Emerging evidence suggests that organismal complexity arises from progressively more elaborate regulation of gene expression.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Comparison of a simple eukaryotic promoter and extensively diversified metazoan regulatory modules.
Figure 2: The multi-subunit general transcription apparatus: identification of tissue-specific and gene-selective subunits.
Figure 3: Diversification of cofactor complexes.

References

  1. Ruvkun, G. & Hobert, O. The taxonomy of developmental control in Caenorhabditis elegans. Science 282, 2033–2041 (1998)

    Article  CAS  Google Scholar 

  2. Adams, M. D. et al. The genome sequence of Drosophila melanogaster. Science 287, 2185–2195 (2000)

    Article  Google Scholar 

  3. Baltimore, D. Our genome unveiled. Nature 409, 814–816 (2001)

    Article  CAS  Google Scholar 

  4. Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001)

    Article  CAS  Google Scholar 

  5. Graveley, B. R. Alternative splicing: increasing diversity in the proteomic world. Trends Genet. 17, 100–107 (2001)

    Article  CAS  Google Scholar 

  6. Agrawal, A., Eastman, Q. M. & Schatz, D. G. Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system. Nature 394, 744–751 (1998)

    Article  CAS  Google Scholar 

  7. Harafuji, N., Keys, D. N. & Levine, M. Genome-wide analysis of tissue-specific enhancers in the Ciona tadpole. Proc. Natl Acad. Sci. 99, 6802–6805 (2002)

    Article  CAS  Google Scholar 

  8. Davidson, E. H. Genomic Regulatory Systems: Development and Evolution (Academic, New York, 2001)

    Google Scholar 

  9. Wyrick, J. J. & Young, R. A. Deciphering gene expression regulatory networks. Curr. Opin. Genet. Dev. 12, 130–136 (2002)

    Article  CAS  Google Scholar 

  10. Aoyagi, N. & Wassarman, D. A. Genes encoding Drosophila melanogaster RNA polymerase II general transcription factors: diversity in TFIIA and TFIID components contributes to gene-specific transcription regulation. J. Cell Biol. 150, F45–F50 (2000)

    Article  CAS  Google Scholar 

  11. Struhl, K., Kadosh, D., Keaveney, M., Kuras, L. & Moqtaderi, Z. Activation and repression mechanisms in yeast. Cold Spring Harb. Symp. Quant Biol 63, 413–421 (1998)

    Article  CAS  Google Scholar 

  12. de Bruin, D., Zaman, Z., Liberatore, R. A. & Ptashne, M. Telomere looping permits gene activation by a downstream UAS in yeast. Nature 409, 109–113 (2001)

    Article  CAS  Google Scholar 

  13. Brand, A. H., Breeden, L., Abraham, J., Sternglanz, R. & Nasmyth, K. Characterization of a “silencer” in yeast: a DNA sequence with properties opposite to those of a transcriptional enhancer. Cell 41, 41–48 (1985)

    Article  CAS  Google Scholar 

  14. Smale, S. T. & Kadonaga, J. T. The RNA polymerase II core promoter. Annu. Rev. Biochem. (in the press)

  15. Su, W., Jackson, S., Tjian, R. & Echols, H. DNA looping between sites for transcriptional activation: self-association of DNA-bound Sp1. Genes Dev. 5, 820–826 (1991)

    Article  CAS  Google Scholar 

  16. Calhoun, V. C., Stathopoulos, A. & Levine, M. Promoter-proximal tethering elements regulate enhancer-promoter specificity in the Drosophila Antennapedia complex. Proc. Natl Acad. Sci. USA 99, 9243–9247 (2002)

    Article  CAS  Google Scholar 

  17. Burgess-Beusse, B. et al. The insulation of genes from external enhancers and silencing chromatin. Proc. Natl Acad. Sci. USA 99, 16433–16437 (2002)

    Article  CAS  Google Scholar 

  18. Banerji, J., Rusconi, S. & Schaffner, W. Expression of a beta-globin gene is enhanced by remote SV40 DNA sequences. Cell 27, 299–308 (1981)

    Article  CAS  Google Scholar 

  19. DiMattia, G. E. et al. The Pit-1 gene is regulated by distinct early and late pituitary-specific enhancers. Dev. Biol. 182, 180–190 (1997)

    Article  CAS  Google Scholar 

  20. Vesque, C. et al. Hoxb-2 transcriptional activation in rhombomeres 3 and 5 requires an evolutionarily conserved cis-acting element in addition to the Krox-20 binding site. EMBO J. 15, 5383–5396 (1996)

    Article  CAS  Google Scholar 

  21. Genetta, T., Ruezinsky, D. & Kadesch, T. Displacement of an E-box-binding repressor by basic helix-loop-helix proteins: implications for B-cell specificity of the immunoglobulin heavy-chain enhancer. Mol. Cell Biol. 14, 6153–6163 (1994)

    Article  CAS  Google Scholar 

  22. Webber, A. L., Ingram, R. S., Levorse, J. M. & Tilghman, S. M. Location of enhancers is essential for the imprinting of H19 and Igf2 genes. Nature 391, 711–715 (1998)

    Article  CAS  Google Scholar 

  23. Leighton, P. A., Saam, J. R., Ingram, R. S., Stewart, C. L. & Tilghman, S. M. An enhancer deletion affects both H19 and Igf2 expression. Genes Dev. 9, 2079–2089 (1995)

    Article  CAS  Google Scholar 

  24. Dorsett, D. Distant liaisons: long-range enhancer-promoter interactions in Drosophila. Curr. Opin. Genet. Dev. 9, 505–514 (1999)

    Article  CAS  Google Scholar 

  25. Merli, C., Bergstrom, D. E., Cygan, J. A. & Blackman, R. K. Promoter specificity mediates the independent regulation of neighboring genes. Genes Dev. 10, 1260–1270 (1996)

    Article  CAS  Google Scholar 

  26. DiLeone, R. J., Russell, L. B. & Kingsley, D. M. An extensive 3′ regulatory region controls expression of Bmp5 in specific anatomical structures of the mouse embryo. Genetics 148, 401–408 (1998)

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Small, S., Arnosti, D. N. & Levine, M. Spacing ensures autonomous expression of different stripe enhancers in the even-skipped promoter. Development 119, 762–772 (1993)

    CAS  PubMed  Google Scholar 

  28. Fujioka, M., Emi-Sarker, Y., Yusibova, G. L., Goto, T. & Jaynes, J. B. Analysis of an even-skipped rescue transgene reveals both composite and discrete neuronal and early blastoderm enhancers, and multi-stripe positioning by gap gene repressor gradients. Development 126, 2527–2538 (1999)

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Mannervik, M., Nibu, Y., Zhang, H. & Levine, M. Transcriptional coregulators in development. Science 284, 606–609 (1999)

    Article  CAS  Google Scholar 

  30. Schroder, C., Tautz, D., Seifert, E. & Jackle, H. Differential regulation of the two transcripts from the Drosophila gap segmentation gene hunchback. EMBO J. 7, 2881–2887 (1988)

    Article  CAS  Google Scholar 

  31. Bell, A. C., West, A. G. & Felsenfeld, G. Insulators and boundaries: versatile regulatory elements in the eukaryotic genome. Science 291, 447–450 (2001)

    Article  CAS  Google Scholar 

  32. Kellum, R. & Schedl, P. A position-effect assay for boundaries of higher order chromosomal domains. Cell 64, 941–950 (1991)

    Article  CAS  Google Scholar 

  33. Choi, O. R. & Engel, J. D. Developmental regulation of beta-globin gene switching. Cell 55, 17–26 (1988)

    Article  CAS  Google Scholar 

  34. Ohtsuki, S., Levine, M. & Cai, H. N. Different core promoters possess distinct regulatory activities in the Drosophila embryo. Genes Dev. 12, 547–556 (1998)

    Article  CAS  Google Scholar 

  35. Butler, J. E. & Kadonaga, J. T. Enhancer-promoter specificity mediated by DPE or TATA core promoter motifs. Genes Dev. 15, 2515–2519 (2001)

    Article  CAS  Google Scholar 

  36. Perkins, A. C., Gaensler, K. M. & Orkin, S. H. Silencing of human fetal globin expression is impaired in the absence of the adult beta-globin gene activator protein EKLF. Proc. Natl Acad. Sci. 93, 12267–12271 (1996)

    Article  CAS  Google Scholar 

  37. Roeder, R. G. Role of general and gene-specific cofactors in the regulation of eukaryotic transcription. Cold Spring Harb. Symp Quant. Biol. 63, 201–218 (1998)

    Article  CAS  Google Scholar 

  38. Freiman, R. N. et al. Requirement of tissue-selective TBP-associated factor TAFII105 in ovarian development. Science 293, 2084–2087 (2001)

    Article  CAS  Google Scholar 

  39. Hiller, M. A., Lin, T. Y., Wood, C. & Fuller, M. T. Developmental regulation of transcription by a tissue-specific TAF homolog. Genes Dev. 15, 1021–1030 (2001)

    Article  CAS  Google Scholar 

  40. Holmes, M. & Tjian, R. Promoter selective properties of the TBP-related factor TRF1. Science 288, 867–870 (2000)

    Article  CAS  Google Scholar 

  41. Rabenstein, M. D., Zhou, S., Lis, J. T. & Tjian, R. TATA box-binding protein (TBP)-related factor 2 (TRF2), a third member of the TBP family. Proc. Natl Acad. Sci. USA 96, 4791–4796 (1999)

    Article  CAS  Google Scholar 

  42. Kaltenbach, L., Horner, M. A., Rothman, J. H. & Mango, S. E. The TBP-like factor CeTLF is required to activate RNA polymerase II transcription during C. elegans embryogenesis. Mol. Cell 6, 705–713 (2000)

    Article  CAS  Google Scholar 

  43. Veenstra, G. J., Weeks, D. L. & Wolffe, A. P. Distinct roles for TBP and TBP-like factor in early embryonic gene transcription in Xenopus. Science 290, 2312–2315 (2000)

    Article  CAS  Google Scholar 

  44. Zhang, D., Penttila, T. L., Morris, P. L., Teichmann, M. & Roeder, R. G. Spermiogenesis deficiency in mice lacking the Trf2 gene. Science 292, 1153–1155 (2001)

    Article  CAS  Google Scholar 

  45. Martianov, I. et al. Late arrest of spermiogenesis and germ cell apoptosis in mice lacking the TBP-like TLF/TRF2 gene. Mol. Cell 7, 509–515 (2001)

    Article  CAS  Google Scholar 

  46. Hochheimer, A., Zhou, S., Zheng, S., Holmes, M. & Tjian, R. Promoter Selectivity and target gene identification of a DREF-containing TRF2 complex. Nature 420, 439–445 (2002)

    Article  CAS  Google Scholar 

  47. Kim, Y.-J., Bjorklund, S., Li, Y., Sayre, M. H. & Kornberg, R. D. A multiprotein mediator of transcriptional activation and its interaction with the C-terminal repeat domain of RNA polymerase II. Cell 77, 599–608 (1994)

    Article  CAS  Google Scholar 

  48. Koleske, A. J. & Young, R. A. An RNA polymerase II holoenzyme responsive to activators. Nature 368, 466–469 (1994)

    Article  CAS  Google Scholar 

  49. Fondell, J. D., Ge, H. & Roeder, R. G. Ligand induction of a transcriptionally active thyroid hormone receptor coactivator complex. Proc. Natl Acad. Sci. USA 93, 8329–8333 (1996)

    Article  CAS  Google Scholar 

  50. Rachez, C. et al. Ligand-dependent transcription activation by nuclear receptors requires the DRIP complex. Nature 398, 824–828 (1999)

    Article  CAS  Google Scholar 

  51. Gu, W. et al. A novel human SRB/MED-containing cofactor complex, SMCC, involved in transcription regulation. Mol. Cell 3, 97–108 (1999)

    Article  CAS  Google Scholar 

  52. Akoulitchev, S., Chuikov, S. & Reinberg, D. TFIIH is negatively regulated by cdk8-containing mediator complexes. Nature 407, 102–106 (2000)

    Article  CAS  Google Scholar 

  53. Taatjes, D. J., Naar, A. M., Andel, F., Nogales, E. & Tjian, R. Structure, function, and activator-induced conformations of the CRSP co-activators. Science 295, 1058–1062 (2002)

    Article  CAS  Google Scholar 

  54. Naar, A. M. et al. Composite co-activator ARC mediates chromatin-directed transcriptional activation. Nature 398, 828–832 (1999)

    Article  CAS  Google Scholar 

  55. Ryu, S., Zhou, S., Ladurner, A. G. & Tjian, R. The transcriptional cofactor complex CRSP is required for activity of the enhancer-binding protein Sp1. Nature 397, 446–450 (1999)

    Article  CAS  Google Scholar 

  56. Ito, M. & Roeder, R. G. The TRAP/SMCC/Mediator complex and thyroid hormone receptor function. Trends Endocrinol. Metab. 12, 127–134 (2001)

    Article  CAS  Google Scholar 

  57. Dotson, M. R. et al. Structural organization of yeast and mammalian mediator complexes. Proc. Natl Acad. Sci. USA 97, 14307–14310 (2000)

    Article  CAS  Google Scholar 

  58. Malik, S. & Roeder, R. G. Transcriptional regulation through Mediator-like coactivators in yeast and metazoan cells. Trends Biochem. Sci. 25, 277–283 (2000)

    Article  CAS  Google Scholar 

  59. Glass, C. K. & Rosenfeld, M. G. The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev. 14, 121–141 (2000)

    CAS  Google Scholar 

  60. Bromberg, J. & Chen, X. STAT proteins: signal transducers and activators of transcription. Methods Enzymol. 333, 138–151 (2001)

    Article  CAS  Google Scholar 

  61. Wang, W. et al. Diversity and specialization of mammalian SWI/SNF complexes. Genes Dev. 10, 2117–2130 (1996)

    Article  CAS  Google Scholar 

  62. Goodman, R. H. & Smolik, S. CBP/p300 in cell growth, transformation, and development. Genes Dev. 14, 1553–1577 (2000)

    CAS  Google Scholar 

  63. Tamkun, J. W. et al. Brahma: a regulator of Drosophila homeotic genes structurally related to the yeast transcriptional activator SNF2/SWI2. Cell 68, 561–572 (1992)

    Article  CAS  Google Scholar 

  64. Khavari, P. A., Peterson, C. L., Tamkun, J. W., Mendel, D. B. & Crabtree, G. R. BRG1 contains a conserved domain of the SWI2/SNF2 family necessary for normal mitotic growth and transcription. Nature 366, 170–174 (1993)

    Article  CAS  Google Scholar 

  65. Feng, Q. & Zhang, Y. The NuRD complex: linking histone modification to nucleosome remodeling. Curr. Top. Microbiol. Immunol. 274, 269–290 (2003)

    CAS  PubMed  Google Scholar 

  66. Tsukiyama, T., Daniel, C., Tamkun, J. & Wu, C. ISWI, a member of the SWI2/SNF2 ATPase family, encodes the 140 kDa subunit of thenucleosome remodeling factor. Cell 83, 1021–1026 (1995)

    Article  CAS  Google Scholar 

  67. LeRoy, G., Loyola, A., Lane, W. S. & Reinberg, D. Purification and characterization of a human factor that assembles and remodels chromatin. J. Biol. Chem. 275, 14787–14790 (2000)

    Article  CAS  Google Scholar 

  68. Olave, I. A., Reck-Peterson, S. L. & Crabtree, G. R. Nuclear actin and actin-related proteins in chromatin remodeling. Annu. Rev. Biochem. 71, 755–781 (2002)

    Article  CAS  Google Scholar 

  69. Kehle, J. et al. dMi-2, a hunchback-interacting protein that functions in polycomb repression. Science 282, 1897–1900 (1998)

    Article  CAS  Google Scholar 

  70. Markstein, M., Markstein, P., Markstein, V. & Levine, M. Genome-wide analysis of clustered Dorsal binding sites identifies putative target genes in the Drosophila embryo. Proc. Natl Acad. Sci. USA 99, 763–768 (2002)

    Article  CAS  Google Scholar 

  71. Berman, B. P. et al. Exploiting transcription factor binding site clustering to identify cis-regulatory modules involved in pattern formation in the Drosophila genome. Proc. Natl Acad. Sci. USA 99, 757–762 (2002)

    Article  CAS  Google Scholar 

  72. Rebeiz, M., Reeves, N. L. & Posakony, J. W. SCORE: A computational approach to the identification of cis-regulatory modules and target genes in whole-genome sequence data. Proc. Natl Acad. Sci. USA (in the press)

  73. Halfon, M. S., Grad, Y., Church, G. M. & Michelson, A. M. Computation-based discovery of related transcriptional regulatory modules and motifs using an experimentally validated combinatorial model. Genome Res. 12, 1019–1028 (2002)

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Rajewsky, N., Vergassola, M., Gaul, U. & Siggia, E. D. Computational detection of genomic cis-regulatory modules applied to body patterning in the early Drosophila embryo. BMC Bioinform. 3, 30 (2002)

    Article  Google Scholar 

Download references

Acknowledgements

We thank Y. Nibu, A. Ladurner and J. Ziegalbauer for preparing the figures. We also thank D. Rio and L. Mirels for critically reviewing the manuscript. M.L is supported by the NIH and R.T. is funded in part by a grant from the NIH.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Michael Levine or Robert Tjian.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Levine, M., Tjian, R. Transcription regulation and animal diversity. Nature 424, 147–151 (2003). https://doi.org/10.1038/nature01763

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature01763

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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