Open AccessA Targeted Mutation at the T-Cell Receptor α/δ Locus Impairs T-Cell Development and Reveals the Presence of the Nearby Antiapoptosis Gene Dad1
Author(s) -
Nam-Doo Hong,
Dragana Cado,
James R. Mitchell,
Benjamin Ortiz,
Shu-Ching Hsieh,
Astar Winoto
Publication year - 1997
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.17.4.2151
Subject(s) - biology , t cell receptor , locus (genetics) , hypersensitive site , chromatin , gene , locus control region , genetics , microbiology and biotechnology , gene targeting , gene expression , t cell , promoter , immune system
Locus control regions are cis gene regulatory elements comprised of DNase I-hypersensitive sites. These regions usually do not stimulate transcription outside of a chromosomal context, and therefore their ability to regulate the expression of genes is thought to occur through the modification of chromatin accessibility. A locus control region is located downstream of the T-cell receptor (TCR) alpha/delta locus on mouse chromosome 14. This locus control region is known to drive T-cell-specific TCR alpha transcription in transgenic mice. In this report, we describe a targeted deletion of this locus control region and show that this mutation acts at a critical checkpoint in alphabeta T-cell development, between the TCR-intermediate and TCR-high stages. Our analysis further reveals that the antiapoptosis gene Dad1 is at the 3' end of the TCR alpha/delta locus and that Dad1 is required for embryogenesis. 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 hypersensitive in a variety of cell types, thus correlating with Dad1 expression and raising the possibility that Dad1 regulatory sequences reside in this region.