Beyond the Identification of Transcribed Sequences:
Functional, Evolutionary and Expression Analysis
12th International Workshop
October 25-28, 2002
Washington, DC

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Global Analysis of mRNA Decay in T Cells

Arvind Raghavan and Paul R. Bohjanen
University of Minnesota, Minneapolis, MN 55455 USA
Telephone: 612-624-0469
Fax: 612-623-0623

Regulation of gene expression at the level of mRNA stability facilitates rapid, selective and temporally precise responses to activation stimuli. For example, rapid decay of cytokine and proto- oncogene transcripts induced by T cell receptor (CD3) and co-receptor (CD28) stimulation is essential for the normal differentiation and proliferation of activated T cells. We have used Affymetrix oligonucleotide arrays to profile mRNA decay rates of transcripts in purified human T cells that were either unstimulated or were stimulated for 3 hours with anti-CD3 and/or anti- CD28 monoclonal antibodies. By arresting transcription with Actinomycin D, we derived mRNA decay curves for each of approximately 6,000 transcripts expressed in T cells under conditions of rest and activation. While the majority of transcripts in resting T cells were stable (t1/2 > 360 min.), we identified many short-lived transcripts (t1/2 < 60 min.) that encoded important regulators of cell-surface signaling, transcription, and apoptosis. Also, T cell stimulation led to dramatic changes in transcript decay rates. For example, hundreds of transcripts were repressed and destabilized following T lymphocyte activation. We also identified transcripts, including cytokine transcripts, that showed CD28 co-stimulation-dependent stabilization, in accordance with previously published results. Although numerous transcripts with rapid decay rates were found to contain AU-rich element (ARE)- like sequences, many transcripts that are regulated at the level of mRNA stability contain no previously characterized stability determinants. We found that many transcripts encoding critical components of T cell receptor signaling pathways are coordinately destabilized and downregulated following T cell activation, suggesting that mRNA decay may provide a mechanism for coordinate regulation of gene expression.

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