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Molecular and Cellular Biology, January 2000, p. 42-53, Vol. 20, No. 1
0270-7306/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Definition of a T-Cell Receptor beta  Gene Core Enhancer of V(D)J Recombination by Transgenic Mapping

Raj Kamal Tripathi,1 Noëlle Mathieu,1 Salvatore Spicuglia,1 Dominique Payet,1 Christophe Verthuy,1 Gaëlle Bouvier,1 Danielle Depetris,2 Marie-Geneviève Mattei,2 William M. HempeL,1 and Pierre Ferrier1,*

Centre d'Immunologie de Marseille-Luminy, Institut National de la Santé et de la Recherche Médicale-Centre National de la Recherche Scientifique, 13288 Marseille,1 and Laboratoire de Génétique Médicale et Développement, Faculté de Médecine, Institut National de la Santé et de la Recherche Médicale, 13385 Marseille,2 France

Received 9 July 1999/Returned for modification 3 August 1999/Accepted 23 September 1999

V(D)J recombination in differentiating lymphocytes is a highly regulated process in terms of both cell lineage and the stage of cell development. Transgenic and knockout mouse studies have demonstrated that transcriptional enhancers from antigen receptor genes play an important role in this regulation by activating cis-recombination events. A striking example is the T-cell receptor beta -chain (TCRbeta ) gene enhancer (Ebeta ), which in the mouse consists of at least seven nuclear factor binding motifs (beta E1 to beta E7). Here, using a well-characterized transgenic recombination substrate approach, we define the sequences within Ebeta required for recombination enhancer activity. The Ebeta core is comprised of a limited set of motifs (beta E3 and beta E4) and an additional previously uncharacterized 20-bp sequence 3' of the beta E4 motif. This core element confers cell lineage- and stage-specific recombination within the transgenic substrates, although it cannot bypass the suppressive effects resulting from transgene integration in heterochromatic centromeres. Strikingly, the core enhancer is heavily occupied by nuclear factors in immature thymocytes, as shown by in vivo footprinting analyses. A larger enhancer fragment including the beta E1 through beta E4 motifs but not the 3' sequences, although active in inducing germ line transcription within the transgenic array, did not retain the Ebeta recombinational activity. Our results emphasize the multifunctionality of the TCRbeta enhancer and shed some light on the molecular mechanisms by which transcriptional enhancers and associated nuclear factors may impact on cis recombination, gene expression, and lymphoid cell differentiation.

* Corresponding author. Mailing address: Centre d'Immunologie INSERM-CNRS de Marseille-Luminy, Case 906, 13288 Marseille Cedex 9, France. Phone: (33) 491-269435. Fax: (33) 491-269430. E-mail: ferrier{at}ciml.univ-mrs.fr.

Molecular and Cellular Biology, January 2000, p. 42-53, Vol. 20, No. 1
0270-7306/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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