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Original Article |
Correspondence to: Pierre Ferrier, CIML, Case 906, 13288 Marseille Cedex 9, France. Tel:33-491-269435 Fax:33-491-269430 E-mail:ferrier{at}ciml.univ-mrs.fr.
Gene targeting studies have shown that T cell receptor (TCR)-ß gene expression and recombination are inhibited after deletion of an enhancer (Eß) located at the 3' end of the 
500-kb TCR-ß locus. Using knockout mouse models, we have measured, at different regions throughout the TCR-ß locus, the effects of Eß deletion on molecular parameters believed to reflect epigenetic changes associated with the control of gene activation, including restriction endonuclease access to chromosomal DNA, germline transcription, DNA methylation, and histone H3 acetylation. Our results demonstrate that, in early developing thymocytes, Eß contributes to major chromatin remodeling directed to an 25-kb upstream domain comprised of the Dß-Jß locus regions. Accordingly, treatment of Eß-deleted thymocytes with the histone deacetylase inhibitor trichostatin A relieved the block in TCR-ß gene expression and promoted recombination within the Dß-Jß loci. Unexpectedly, however, epigenetic processes at distal Vß genes on the 5' side of the locus and at the 3' proximal Vß14 gene appear to be less dependent on Eß, suggesting that Eß activity is confined to a discrete region of the TCR-ß locus. These findings have implications with respect to the developmental control of TCR-ß gene recombination, and the process of allelic exclusion at this locus.
Key Words: T cell receptor, thymus, lymphocyte differentiation, chromatin, T cell receptor rearrangement
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