A new element within the T-cell receptor or locus required for tissue-specific locus control region activity

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 (TCR alpha) is exclusivel y expressed in T cells, and the chromatin at its locus displays differentia lly open configurations in expressing and nonexpressing tissues. Mouse TCR alpha exists in a complex locus containing three differentially regulated g enes. We previously described an LCR in this locus that confers T-lineage-s pecific expression upon linked transgenes. The 3' portion of this LCR conta ins an unrestricted chromatin opening activity while the 5' portion contain s elements restricting this activity to T cells. This tissue-specificity re gion contains four known DNase I hypersensitive sites, two located near tra nscriptional silencers, one at the TCR alpha enhancer, and another located 3' of the enhancer in a 1-kb region of unknown function. Analysis of this r egion using transgenic mice reveals that the silencer regions contribute ne gligibly to LCR activity. While the enhancer is required for complete LCR f unction, its removal has surprisingly little effect on chromatin structure or expression outside the thymus. Rather, the region 3' of the enhancer app ears responsible for the tissue-differential chromatin configurations obser ved at the TCR alpha locus. This region, herein termed the "HS1' element," also increases lymphoid transgene expression while suppressing ectopic tran sgene activity. Thus, this previously undescribed element is an integral pa rt of the TCR alpha LCR, which influences tissue-specific chromatin structu re and gene expression.