A TARGETED MUTATION AT THE T-CELL RECEPTOR ALPHA DELTA LOCUS IMPAIRS T-CELL DEVELOPMENT AND REVEALS THE PRESENCE OF THE NEARBY ANTIAPOPTOSIS GENE DAD1/

Locus control regions are cis gene regulatory elements comprised of DN ase I-hypersensitive sites. These regions usually do not stimulate tra nscription outside of a chromosomal context, and therefore their abili ty to regulate the expression of genes is thought to occur through the modification of chromatin accessibility. A locus control region is lo cated downstream of the T-cell receptor (TCR) alpha/delta locus on mou se chromosome 14. This locus control region is known. to drive T-cell- specific TCR alpha transcription in transgenic mice. In this report, w e describe a targeted deletion of this locus control region and show t hat this mutation acts at a critical checkpoint in alpha beta T-cell d evelopment, between the TCR-intermediate and TCR-high stages. Our anal ysis further reveals that the antiapoptosis gene Dad1 is at the 3' end of the TCR alpha/delta locus and that Dad1 is required for embryogene sis. We show that mouse Dad1 has a broader expression pattern than the TCR genes, in terms of both tissue and temporal specificity. Finally, we report that the chromatin between TCR alpha and Dad1 is DNase I hy persensitive in a variety of cell types, thus correlating with Dad1 ex pression and raising the possibility that Dad1 regulatory sequences re side in this region.