Mining microarray data to identify transcription factors expressed in naïve resting but not activated T lymphocytes

Transcriptional repressors controlling the expression of cytokine genes have been implicated in a variety of physiological and pathological phenomena. An unknown repressor that binds to the distal NFAT element of the interleukin-2 (IL-2) gene promoter in naive T-helper lymphocytes has been implicate...

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Veröffentlicht in:Genes and immunity 2004-01, Vol.5 (1), p.16-25
Hauptverfasser: Argyropoulos, C, Nikiforidis, G C, Theodoropoulou, M, Adamopoulos, P, Boubali, S, Georgakopoulos, T N, Paliogianni, F, Papavassiliou, A G, Mouzaki, A
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Sprache:eng
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Zusammenfassung:Transcriptional repressors controlling the expression of cytokine genes have been implicated in a variety of physiological and pathological phenomena. An unknown repressor that binds to the distal NFAT element of the interleukin-2 (IL-2) gene promoter in naive T-helper lymphocytes has been implicated in autoimmune phenomena and has emerged as a potentially important factor controlling the latency of HIV-1. The aim of this paper was the identification of this repressor. We resorted to public microarray databases looking for DNA-binding proteins that are present in naïve resting T cells but are downregulated when the cells are activated. A Bayesian data mining statistical analysis uncovered 25 candidate factors. Of the 25, NFAT4 and the oncogene ets-2 bind to the common motif AAGGAG found in the HIV-1 LTR and IL-2 probes. Ets-2 binding site contains the three G's that have been shown to be important for binding of the unknown factor; hence, we considered it the likeliest candidate. Electrophoretic mobility shift assays confirmed cross-reactivity between the unknown repressor and anti-ets-2 antibodies, and cotransfection experiments demonstrated the direct involvement of Ets-2 in silencing the IL-2 promoter. Designing experiments for transcription factor analysis using microarrays and Bayesian statistical methodologies provides a novel way toward elucidation of gene control networks.
ISSN:1466-4879
1476-5470
DOI:10.1038/sj.gene.6364034