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Molecular and Cellular Biology, March 1999, p. 1901-1909, Vol. 19, No. 3
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

A New Element within the T-Cell Receptor alpha  Locus Required for Tissue-Specific Locus Control Region Activity

Benjamin D. Ortiz, Dragana Cado, and Astar Winoto*

Department of Molecular and Cell Biology, Cancer Research Laboratory and Division of Immunology, University of California, Berkeley, California 94720-3200

Received 25 August 1998/Returned for modification 14 October 1998/Accepted 9 December 1998

Locus control regions (LCRs) are cis-acting regulatory elements thought to provide a tissue-specific open chromatin domain for genes to which they are linked. The gene for T-cell receptor alpha  chain (TCRalpha ) is exclusively expressed in T cells, and the chromatin at its locus displays differentially open configurations in expressing and nonexpressing tissues. Mouse TCRalpha exists in a complex locus containing three differentially regulated genes. We previously described an LCR in this locus that confers T-lineage-specific expression upon linked transgenes. The 3' portion of this LCR contains an unrestricted chromatin opening activity while the 5' portion contains elements restricting this activity to T cells. This tissue-specificity region contains four known DNase I hypersensitive sites, two located near transcriptional silencers, one at the TCRalpha enhancer, and another located 3' of the enhancer in a 1-kb region of unknown function. Analysis of this region using transgenic mice reveals that the silencer regions contribute negligibly to LCR activity. While the enhancer is required for complete LCR function, its removal has surprisingly little effect on chromatin structure or expression outside the thymus. Rather, the region 3' of the enhancer appears responsible for the tissue-differential chromatin configurations observed at the TCRalpha locus. This region, herein termed the "HS1' element," also increases lymphoid transgene expression while suppressing ectopic transgene activity. Thus, this previously undescribed element is an integral part of the TCRalpha LCR, which influences tissue-specific chromatin structure and gene expression.

* Corresponding author. Mailing address: Department of Molecular and Cell Biology, Cancer Research Laboratory and Division of Immunology, University of California, Berkeley, CA 94720-3200. Phone: (510) 642-0217. Fax: (510) 642-0468. E-mail: winoto{at}uclink4.berkeley.edu.

Molecular and Cellular Biology, March 1999, p. 1901-1909, Vol. 19, No. 3
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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