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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.

SUBMITTER: Hong NA

PROVIDER: S-EPMC232063 | biostudies-other | 1997 Apr

REPOSITORIES: biostudies-other

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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.

Hong N A NA Cado D D Mitchell J J Ortiz B D BD Hsieh S N SN Winoto A A

Molecular and cellular biology 19970401 4

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 TC ...[more]

PMID: 9121464

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Project description:BACKGROUND:In mammals, T cells develop along two discrete pathways characterized by expression of either the ?? or the ?? T cell receptors. Human and mouse display a low peripheral blood ?? T cell percentage ("?? low species") while sheep, bovine and pig accounts for a high proportion of ?? T lymphocytes ("?? high species"). While the T cell receptor alpha (TRA) and delta (TRD) genes and the genomic organization of the TRA/TRD locus has been determined in human and mouse, this information is still poorly known in artiodactyl species, such as sheep. RESULTS:The analysis of the current Ovis aries whole genome assembly, Oar_v3.1, revealed that, as in the other mammalian species, the sheep TRD locus is nested within the TRA locus. In the most 5' part the TRA/TRD locus contains TRAV genes which are intermingled with TRDV genes, then TRD genes which include seven TRDD, four TRDJ genes, one TRDC and a single TRDV gene with an inverted transcriptional orientation, and finally in the most 3' part, the TRA locus is completed by 61 TRAJ genes and one TRAC gene. Comparative sequence and analysis and annotation led to the identification of 66 TRAV genes assigned to 34 TRAV subgroups and 25 TRDV genes belonging to the TRDV1 subgroup, while one gene was found for each TRDV2, TRDV3 and TRDV4 subgroups. Multiple duplication events within several TRAV subgroups have generated the sheep TRAV germline repertoire, which is substantially larger than the human one. A significant proportion of these TRAV gene duplications seems to have occurred simultaneously with the amplification of the TRDV1 subgroup genes. This dynamic of expansion has also generated novel multigene subgroups, which are species-specific. Ovis aries TRA and TRD genes identified in this study were assigned IMGT definitive or temporary names and were approved by the IMGT/WHO-IUIS nomenclature committee. The completeness of the genome assembly in the 3' part of the locus has allowed us to interpret rearranged CDR3 of cDNA from both TRA and TRD chain repertoires. The involvement of one up to four TRDD genes into a single transcript makes the potential sheep TRD chain much larger than any known TR chain repertoire. CONCLUSIONS:The sheep genome, as the bovine genome, contains a large and diverse repertoire of TRA and TRD genes when compared to the "?? T cell low" species genomes. The composition and length of the rearranged CDR3 in TRD V-delta domains influence the three-dimensional configuration of the antigen-combining site thus suggesting that in ruminants, ?? T cells play a more important and specific role in immune recognition.

Dataset Information

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.

Publications

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.

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