title: 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.
abstract: 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.
authors.affiliation: Department of Molecular and Cell Biology, University of California at Berkeley, 94720-3200, USA.
authors.forename: N A
authors.initials: NA
authors.lastname: Hong
authors.forename: D
authors.initials: D
authors.lastname: Cado
authors.forename: J
authors.initials: J
authors.lastname: Mitchell
authors.forename: B D
authors.initials: BD
authors.lastname: Ortiz
authors.forename: S N
authors.initials: SN
authors.lastname: Hsieh
authors.forename: A
authors.initials: A
authors.lastname: Winoto
mesh_terms: D000483:Alleles; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins; D004247:DNA / Q000235:genetics; D003850:Deoxyribonuclease I; D004742:Enhancer Elements, Genetic; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D005809:Genes, Regulator; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D011506:Proteins / Q000235:genetics*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics*; D012260:Ribonucleases; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
chemical_list: D051017:Apoptosis Regulatory Proteins; C489987:Dad1 protein, mouse; D008565:Membrane Proteins; D011506:Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D004247:DNA; D012260:Ribonucleases; D003850:Deoxyribonuclease I