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How I became one of the fathers of a superfamily

Nature Medicine volume 10, pages 1027–1031 (2004)Cite this article

Elucidating the mechanisms underlying transcriptional control in vertebrates has been my main research project for almost 45 years. It originated from my M.D. thesis work (1958) on the effects of X-ray irradiation on free ribonucleotides in rat tissues, which suggested that RNA could be synthesized from nucleoside triphosphates. A year later, the field of in vitro transcription opened up with the discovery of a nucleoside triphosphate–dependent RNA polymerase activity in rat liver nuclei1. However, the mechanism of DNA-directed RNA synthesis was established in the 1960s using purified bacterial RNA polymerase, because only little soluble activity could be recovered from vertebrate nuclei; the bulk of RNA polymerase, the 'aggregate' enzyme, was transcriptionally engaged and tightly bound to chromatin2. Nevertheless, two important observations emerged from my studies with such nuclear preparations. First, in 1963, I discovered poly(ADP-ribose) polymerase3, which has recently been shown to belong to a multigene family with highly diverse functions4,5. Second, and more decisively for my future, I found that administration of estradiol to immature chickens elicited an increase of liver 'aggregate' polymerase, which preceded the induction of protein synthesis6. This finding suggested that the bound estrogen receptor (ER), just discovered by Elwood Jensen, could act positively on the initiation of transcription.

As interesting as this hormonal induction was, there was no hope of explaining its molecular mechanism in the foreseeable future. The complexity of vertebrate genomes and the lack of molecular approaches precluded the prerequisite characterization and isolation of promoter regions of the responding genes. Why characterize RNA polymerase in animals if it could not be used to study how the expression of their genetic programs is controlled? Furthermore, the opinion at the time was that the mechanisms involved would be simple variations upon those already established for prokaryotes. Was it therefore wise to pursue such an ill-fated project?

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Figure 1: Ribbon diagrams of the unliganded human RXRα (left) and of the human RARγ bound to all-trans retinoic acid in a ball-and-stick representation (right).

References

  1. Weiss, S.B. & Gladstone, L. A mammalian system for the incorporation of cytidine triphosphate into ribonucleic acid. J. Am. Chem. Soc. 81, 4118–4119 (1959).

    Article  CAS  Google Scholar 

  2. Ramuz, M., Doly, J., Mandel, P. & Chambon, P. A soluble DNA-dependent RNA polymerase in nuclei of non-dividing animal cells. Biochem. Biophys. Res. Commun. 19, 114–120 (1965).

    Article  CAS  Google Scholar 

  3. Chambon, P., Weill, J.D., Doly, J., Strosser, M.T. & Mandel, P. On the formation of a novel adenylic compound by enzymatic extracts of liver nuclei. Biochem. Biophys. Res. Commun. 25, 638–643 (1966).

    Article  CAS  Google Scholar 

  4. Ménissier-de Murcia, J. et al. Functional interaction between PARP-1 and PARP-2 in chromosome stability and embryonic development in mouse. EMBO J. 22, 2255–2263 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Amé J-C., Spenlehauer, C. & de Murcia, G. The PARP superfamily. Bioessays 26, 882–893 (2004).

    Article  PubMed  CAS  Google Scholar 

  6. Weill, J.D., Busch, S., Chambon, P. & Mandel, P. The effect of estradiol injections upon chicken liver nuclei RNA polymerase. Biochem. Biophys. Res. Commun. 10, 122–126 (1963).

    Article  CAS  PubMed  Google Scholar 

  7. Stirpe, F. & Fiume, L. Studies on the pathogenesis of liver necrosis by α-amanitin. Biochem. J. 105, 779–782 (1967).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chambon, P. Eukaryotic nuclear RNA polymerases. Annu. Rev. Biochem. 44, 613–638 (1975).

    Article  CAS  PubMed  Google Scholar 

  9. Roeder, R.G. & Rutter, W.J. Multiple forms of DNA-dependent RNA polymerase in eukaryotic organisms. Nature 224, 234–237 (1969).

    Article  CAS  PubMed  Google Scholar 

  10. Kédinger, C., Gniazdowski, M., Mandel, J.L., Gissinger, F. & Chambon, P. α-Amanitin: a specific inhibitor of one of two DNA dependent RNA polymerase activities from calf thymus. Biochem. Biophys. Res. Comm. 38, 165–171 (1970).

    Article  PubMed  Google Scholar 

  11. Weinmann, R. & Roeder, R.G. Role of DNA-dependent RNA polymerase III in transcription of the tRNA and 5S RNA genes. Proc. Natl Acad. Sci. USA 71, 1790–1794 (1974).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chambon, P. et al. Purification and properties of Calf thymus DNA-dependent RNA polymerases A and B. Cold Spring Harb. Symp. Quant. Biol. 35, 693–707 (1970).

    Article  CAS  Google Scholar 

  13. Sklar, V.E.F., Schwartz, L.B. & Roeder, R.G. Distinct molecular structure of nuclear class I, II and III DNA-dependent RNA polymerases. Proc. Natl Acad. Sci. USA 72, 348–352 (1975).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Roeder, R.G. Eukaryotic nuclear RNA polymerases. in RNA Polymerase (R. Losick & M. Chamberlin, eds.) 285–329 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, USA, 1979).

    Google Scholar 

  15. Oudet, P., Gross-Bellard, M. & Chambon, P. Electron microscopic and biochemical evidence that chromatin structure is a repeating unit. Cell 4, 281–300 (1975).

    Article  CAS  PubMed  Google Scholar 

  16. Oudet, P. & Chambon, P. Seeing is believing. Cell S116, S79–S80 (2004).

    Article  Google Scholar 

  17. Gannon, F. et al. Organisation and sequences at the 5′ end of a cloned complete ovalbumin gene. Nature 278, 423–434 (1979).

    Article  Google Scholar 

  18. Cochet, M. et al. Organisation and sequence studies of the 17-piece conalbumin gene. Nature 282, 567–574 (1979).

    Article  CAS  PubMed  Google Scholar 

  19. Breathnach, R., Mandel, J.L. & Chambon, P. The ovalbumin gene is split in chicken DNA. Nature 270, 314–319 (1977).

    Article  CAS  PubMed  Google Scholar 

  20. Wasylyk, B., Kédinger, C., Corden, J., Brison, O. & Chambon, P. Specific in vitro initiation of transcription on conalbumin and ovalbumin genes and comparison with adenovirus-2 early and late genes. Nature 285, 388–390 (1980).

    Article  Google Scholar 

  21. Corden, J. et al. Promoter sequences of eukaryotic protein-coding genes. Science 209, 1406–1414 (1980).

    Article  CAS  PubMed  Google Scholar 

  22. Wasylyk, B. et al. Specific in vitro transcription of conalbumin gene is drastically decreased by single-point mutation in TATA box homology sequence. Proc. Natl Acad. Sci. USA 77, 7024–7028 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wu, G-J. Adenovirus DNA-directed transcription of 5.5S RNA in vitro. Proc. Natl Acad. Sci. USA 75, 2175–2219 (1978).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Grosschedl, R., Wasylyk, B., Chambon, P. & Birnstiel, M.L. Point mutation in the TATA box curtails expression of sea urchin H2A histone gene in vivo. Nature 294, 179–181 (1981).

    Article  Google Scholar 

  25. Davison, B.L., Egly, J-M., Mulvihill, E.R. & Chambon, P. Formation of stable preinitiation complexes between eukaryotic class B transcription factors and promoter sequences. Nature 301, 680–686 (1983).

    Article  CAS  PubMed  Google Scholar 

  26. Cavallini, B. et al. Cloning of the gene encoding the yeast protein BTF1Y that can substitute for the human TATA box factor. Proc. Natl Acad. Sci. USA 86, 9803–9807 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Buratowski, S., Hahn, S., Sharp, P.A. & Guarente, L. Function of a yeast TATA element-binding protein in a mammalian transcription system. Nature 334, 37–42 (1988).

    Article  CAS  PubMed  Google Scholar 

  28. Cavallini, B. et al. A yeast activity can substitute for the HeLa cell TATA box factor in vitro. Nature 334, 77–80 (1988).

    Article  CAS  PubMed  Google Scholar 

  29. Dynlacht, B.D., Hoey, H. & Tjian, R. Isolation of coactivators associated with the TATA-binding protein that mediate transcriptional activation. Cell 66, 563–576 (1991).

    Article  CAS  PubMed  Google Scholar 

  30. Brou, C. et al. Distinct TFIID complexes mediate the effect of different transcriptional activators. EMBO J. 12, 489–499 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Jacq, X. et al. Human TAFII30 is present in a distinct TFIID complex and is required for transcriptional activation by the estrogen receptor. Cell 79, 107–117 (1994).

    Article  CAS  PubMed  Google Scholar 

  32. Mengus, G., May, M., Carré, L., Chambon, P. & Davidson, I. Human TAFII135 potentiates transcriptional activation by the AF-2s of the retinoic acid, vitamin D3, and thyroid hormone receptors in mammalian cells. Genes Dev. 11, 1381–1395 (1997).

    Article  CAS  PubMed  Google Scholar 

  33. Hen, R., Sassone-Corsi, P., Corden, J., Gaub, M.P. & Chambon, P. Sequences upstream from the TATA box are required in vivo and in vitro for efficient transcription from the Adenovirus-2 major late promoter. Cell 43, 165–175 (1985).

    Article  Google Scholar 

  34. Sawadogo, M. & Roeder, R.G. Interaction of a gene-specific transcription factor with the adenovirus major late promoter upstream of the TATA box region. Cell 43, 165–175 (1985).

    Article  CAS  PubMed  Google Scholar 

  35. Miyamoto, N.G., Moncollin, V., Egly, J.M. & Chambon, P. Specific interaction between a transcription factor and the upstream element of the Adenovirus-2 major late promoter. EMBO J. 4, 3563–3570 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Dynan, W.S. & Tjian, R. The promoter specific transcription factor Sp1 binds to upstream sequences in the SV40 early promoter. Cell 35, 79–87 (1983).

    Article  CAS  PubMed  Google Scholar 

  37. Everett, R.D., Baty, D. & Chambon, P. The repeated GC-rich motifs upstream from the TATA box are important elements of the SV40 early promoter. Nucleic Acids Res. 11, 2447–2464 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Barrera-Saldana, H. et al. All six GC-motifs of the SV40 early upstream element contribute to promoter activity in vivo and in vitro. EMBO J. 4, 3839–3849 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Gidoni, D. et al. Bidirectional SV40 transcription mediated by tandem Sp1 binding interactions. Science 230, 511–517 (1985).

    Article  CAS  PubMed  Google Scholar 

  40. Kadonaga, J.T., Carner, K.R., Masiarz, F.R. & Tjian, R. Isolation of cDNA encoding transcription factor Sp1 and functional analysis of the DNA binding domain. Cell 51, 1079–1090 (1987).

    Article  CAS  PubMed  Google Scholar 

  41. Benoist, C. & Chambon, P. Deletions covering the putative promoter region of early mRNAs of simian virus 40 do not abolish T-antigen expression. Proc. Natl Acad. Sci. USA 77, 3865–3869 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Benoist, C. & Chambon, P. In vivo sequence requirements of the SV40 early promoter region. Nature 290, 304–310 (1981).

    Article  CAS  PubMed  Google Scholar 

  43. Mathis, D. & Chambon, P. The SV40 early region TATA box, but not the upstream sequences, is required for accurate in vitro initiation of transcription. Nature 290, 310–316 (1981).

    Article  CAS  PubMed  Google Scholar 

  44. Moreau, P. et al. The SV40 72 base pair repeat has a striking effect on gene expression both in SV40 and other chimeric recombinants. Nucleic Acids Res. 9, 6047–6068 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wasylyk, B., Wasylyk, C., Augereau, P. & Chambon, P. The SV40 72bp repeat preferentially potentiates transcription starting from proximal natural or substitute promoter elements. Cell 32, 503–514 (1983).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  47. Banerji, J., Olson, L. & Schaffner, W. A lymphocyte-specific cellular enhancer is located downstream of the joining region in immunoglublin heavy chain genes. Cell 33, 729–740 (1983).

    Article  CAS  PubMed  Google Scholar 

  48. Gillies, S.D., Morrison, S.L., Oi, V.T. & Tonegawa, S. A tissue specific transcription enhancer element is located in the major intron of a rearranged immunoglobulin heavy chain gene. Cell 33, 717–728 (1983).

    Article  CAS  PubMed  Google Scholar 

  49. Zenke, M. et al. Multiple sequence motifs are involved in SV40 enhancer function. EMBO J. 5, 387–397 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Nomiyama, H., Fromental, C., Xiao, J.H. & Chambon, P. Cell-specific activity of the constituent elements of the SV40 enhancer. Proc. Natl Acad. Sci. USA 84, 7881–7885 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Wildeman, A. et al. Specific protein binding to the SV40 enhancer in vitro. Mol. Cell. Biol. 6, 2098–2105 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Davidson, I. et al. Cell-type specific protein binding to the enhancer of simian virus 40 in nuclear extracts. Nature 323, 544–548 (1986).

    Article  CAS  PubMed  Google Scholar 

  53. Scheidereit, C., Geisse, S., Westphal, H.M. & Beato, M. The glucocorticoid receptor binds to defined nucleotide sequences near the promoter of mouse mammary tumour virus. Nature 304, 749–752 (1983).

    Article  CAS  PubMed  Google Scholar 

  54. Yamamoto, K. Steroid Receptor regulated transcription of specific genes and gene networks. Annu. Rev. Genet. 19, 209–252 (1985).

    Article  CAS  PubMed  Google Scholar 

  55. Chandler, V.L., Maler, B.A. & Yamamoto, K.R. DNA sequences bound specifically by glucocorticoid receptor in vitro render a heterologous promoter hormone responsive in vivo. Cell 33, 489–499 (1983).

    Article  CAS  PubMed  Google Scholar 

  56. Walter, P. et al. Cloning of the human estrogen receptor cDNA. Proc. Natl Acad. Sci. USA 82, 7889–7893 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Green, S. et al. The human oestrogen cDNA: sequence, expression and homology to v-erbA. Nature 320, 134–139 (1986).

    Article  CAS  PubMed  Google Scholar 

  58. Greene, G.L. et al. Sequence and expression of human estrogen receptor complementary DNA. Science 231, 1150–1154 (1986).

    Article  CAS  PubMed  Google Scholar 

  59. Krust, A. et al. The chicken oestrogen receptor sequence: homology with v-erbA and the human oestrogen and glucocorticoid receptors. EMBO J. 5, 891–897 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kumar, V., Green, S., Staub, A. & Chambon, P. Localisation of the oestradiol-binding and putative DNA-binding domains of the human oestrogen receptor. EMBO J. 5, 2231–2236 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Kumar, V. et al. Functional domains of the human estrogen receptor. Cell 51, 941–951 (1987).

    Article  CAS  PubMed  Google Scholar 

  62. Green, S. & Chambon, P. Oestradiol induction of a glucocorticoid-responsive gene by a chimeric receptor. Nature 325, 75–78 (1987).

    Article  CAS  PubMed  Google Scholar 

  63. Kumar, V. et al. Functional domains of the human estrogen receptor. Cell 51, 941–951 (1987).

    Article  CAS  PubMed  Google Scholar 

  64. Petkovich, M., Brand, N.J., Krust, A. & Chambon, P. A human retinoic acid receptor which belongs to the family of nuclear receptors. Nature 330, 444–450 (1987).

    Article  CAS  PubMed  Google Scholar 

  65. Giguère, V., Ong, E.S., Segui, P. & Evans, R.M. Identification of a receptor for the morphogen retinoic acid. Nature 330, 624–629 (1987).

    Article  PubMed  Google Scholar 

  66. Laudet, V. & Gronemeyer, H. The Nuclear Receptor Facts Book (Academic, London, 2002).

    Google Scholar 

  67. Tora, L. et al. The human estrogen receptor has two independent nonacidic transcriptional activation functions. Cell 59, 477–487 (1989).

    Article  CAS  PubMed  Google Scholar 

  68. Tasset, D., Tora, L., Fromental, C., Scheer, E. & Chambon, P. Distinct classes of transcriptional activating domains function by different mechanisms. Cell 62, 1177–1187 (1990).

    Article  CAS  PubMed  Google Scholar 

  69. Onate, S.A., Tsai, S.Y., Tsai, M.J. & O'Malley, B. Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science 270, 1354–1357 (1995).

    Article  CAS  PubMed  Google Scholar 

  70. Voegel, J.J., Heine, M.J.S., Zechel, C., Chambon, P. & Gronemeyer, H. TIF2, a 160-kDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors. EMBO J. 15, 3667–3675 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Bourguet, W., Ruff, M., Chambon, P., Gronemeyer, H. & Moras, D. Crystal structure of the ligand binding domain of the human nuclear receptor RXRα. Nature 375, 377–382 (1995).

    Article  CAS  PubMed  Google Scholar 

  72. Renaud, J-P. et al. Crystal structure of the RAR-γ ligand-binding domain bound to all-trans retinoic acid. Nature 378, 681–689 (1995).

    Article  CAS  PubMed  Google Scholar 

  73. Wurtz, J-M. et al. A canonical structure for the ligand-binding domain of nuclear receptors. Nat. Struct. Biol. 3, 87–94 (1996).

    Article  CAS  PubMed  Google Scholar 

  74. Egea, P.F. et al. Crystal structure of the human RXRα ligand-binding domain bound to its natural ligand: 9-cis retinoic acid. EMBO J. 19, 2592–2601 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Chambon, P. A decade of molecular biology of retinoic acid receptors. FASEB J. 10, 940–954 (1996).

    Article  CAS  PubMed  Google Scholar 

  76. Kato, S. et al. Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science 270, 1491–1494 (1995).

    Article  CAS  PubMed  Google Scholar 

  77. Rochette-Egly, C. & Chambon, P. F9 Embryocarcinoma cells: a cell autonomous model to study the functional selectivity of RARs and RXRs in retinoid signaling. Histol. Histopathol. 16, 909–922 (2001).

    CAS  PubMed  Google Scholar 

  78. Leid, M., Kastner, P. & Chambon, P. Multiplicity generates diversity in the retinoic acid signalling pathways. Trends Biochem. Sci. 17, 427–433 (1992).

    Article  CAS  PubMed  Google Scholar 

  79. Dilworth, F.J., Fromental-Ramain, C., Yamamoto, K. & Chambon, P. ATP-driven chromatin remodeling activity and histone acetyltransferases act sequentially during transactivation by RAR/RXR in vitro. Mol. Cell 6, 1049–1058 (2000).

    Article  CAS  PubMed  Google Scholar 

  80. Dilworth, F.J. & Chambon, P. Nuclear receptors coordinate the activities of chromatin remodeling complexes and coactivators to facilitate initiation of transcription. Oncogene Rev. 20, 3047–3054 (2001).

    Article  CAS  Google Scholar 

  81. Kastner, P., Mark, M. & Chambon, P. Nonsteroid nuclear receptors: what are genetic studies telling us about their role in real life? Cell 83, 859–869 (1995).

    Article  CAS  PubMed  Google Scholar 

  82. Mark, M. & Chambon, P. Functions of RARs and RXRs in vivo: Genetic dissection of the retinoid signaling pathway. Pure Appl. Chem. 75, 1709–1732 (2003).

    Article  CAS  Google Scholar 

  83. Chapellier, B. et al. Physiological and retinoid-induced proliferations of epidermal basal keratinocytes are differently controlled. EMBO J. 21, 3402–3413 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Thomas, K.R. & Capecchi, M.R. Targeted disruption of the murine int-1 proto-oncogene resulting in severe abnormalities in the midbrain and cerebellar development. Nature 346, 847–850 (1990).

    Article  CAS  PubMed  Google Scholar 

  85. Metzger, D., White, J.H. & Chambon, P. The human oestrogen receptor functions in yeast. Nature 334, 31–36 (1988).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

I thank my students, my postdocs and all of my collaborators for their enthusiastic contributions over all these years, G. Richards for a critical reading of the manuscript, and the French and foreign institutions that have supported my laboratory. Last, but not least, I am grateful to all members of my own family who have always been “super” over all these years.

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  1. Institut de Génétique et de Biologie Moléculaire et Cellulaire (CNRS, INSERM, ULP, Collège de France) and the Institut Clinique de la Souris, B.P.10142, Illkirch, 67404, Strasbourg, France

    Pierre Chambon

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Chambon, P. How I became one of the fathers of a superfamily. Nat Med 10, 1027–1031 (2004). https://doi.org/10.1038/nm1004-1027

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