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Identification of stage-specific gene modulation during early thymocyte development by whole-genome profiling analysis after aryl hydrocarbon receptor activation.
- Source :
-
Molecular pharmacology [Mol Pharmacol] 2010 May; Vol. 77 (5), pp. 773-83. Date of Electronic Publication: 2010 Feb 16. - Publication Year :
- 2010
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Abstract
- The aryl hydrocarbon receptor (AHR) is a basic helix-loop-helix transcription factor, implicated as an important modulator of the immune system and of early thymocyte development. We have shown previously that AHR activation by the environmental contaminant and potent AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) leads to a significant decline in the percentage of S-phase cells in the CD3(-)CD4(-)CD8(-) triple-negative stage (TN) 3 and TN4 T-cell committed thymocytes 9 to 12 h after exposure. In the more immature TN1- or TN2-stage cells, no effect on cell cycle was observed. To identify early molecular targets, which could provide insight into how the AHR acts as a modulator of thymocyte development and cell cycle regulation, we performed gene-profiling experiments using RNA isolated from four intrathymic progenitor populations in which the AHR was activated for 6 or 12 h. This microarray analysis of AHR activation identified 108 distinct gene probes that were significantly modulated in the TN1-4 thymocyte progenitor stages. Although most of the genes identified have specific AHR recognition sequences, only seven genes were altered exclusively in the two T-cell committed stages of early thymocyte development (TN3 and TN4) in which the decline of S-phase cells is seen. Moreover, all seven of these genes were reduced in expression, and five of the seven are associated with cell cycle regulatory processes. These seven genes are novel targets for modulation by the TCDD-activated AHR and may be involved in the observed cell-cycle arrest and suppression of early thymocyte development.
- Subjects :
- Animals
CD3 Complex genetics
CD4 Antigens genetics
CD8 Antigens genetics
Injections, Intraperitoneal
Mice
Mice, Inbred C57BL
Oligonucleotide Array Sequence Analysis
Polychlorinated Dibenzodioxins administration & dosage
RNA genetics
RNA, Messenger genetics
Reverse Transcriptase Polymerase Chain Reaction
Thymus Gland drug effects
Thymus Gland growth & development
Gene Expression Profiling
Gene Expression Regulation, Developmental drug effects
Polychlorinated Dibenzodioxins pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1521-0111
- Volume :
- 77
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Molecular pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 20159946
- Full Text :
- https://doi.org/10.1124/mol.109.062497