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The stability of mRNA influences the temporal order of the induction of genes encoding inflammatory molecules

Abstract

The inflammatory response plays out over time in a reproducible and organized way after an initiating stimulus. Here we show that genes activated in cultured mouse fibroblasts in response to the cytokine tumor necrosis factor could be categorized into roughly three groups, each with different induction kinetics. Although differences in transcription were important in determining the grouping of these genes, differences in mRNA stability also exerted a strong influence on the temporal order of gene expression, in some cases overriding that of transcriptional control elements. Transcripts of mRNA expressed early had abundant AU-rich elements in their 3′ untranslated regions, whereas those expressed later had fewer. Thus, mRNA stability and transcriptional control, two intrinsic characteristics of genes, control the kinetics of gene expression induced by proinflammatory cytokines.

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Figure 1: TNF-activated genes can be categorized into three kinetically different groups.
Figure 2: Gene expression after TNF withdrawal.
Figure 3: Stability of mRNA encoded by genes in groups I, II and III.
Figure 4: Kinetic patterns of gene expression in macrophages.
Figure 5: Gene-expression patterns are determined by the 3′ UTR of a gene.

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Gene Expression Omnibus

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Acknowledgements

We thank M. Boldin, R. O'Connell, X. Luo and K. Taganov for comments on the manuscript, and A. Balazs (California Institute of Technology) for the plasmid pHAGE2-CMV-eGFP-W. Supported by the National Institutes of Health (2R01GM039458 to D.B.) and the Millard and Muriel Jacobs Genetics and Genomics Laboratory at California Institute of Technology (microarray analysis).

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S.H. designed, did and analyzed the experiments; S.H. and D.B. wrote the manuscript.

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Correspondence to David Baltimore.

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Hao, S., Baltimore, D. The stability of mRNA influences the temporal order of the induction of genes encoding inflammatory molecules. Nat Immunol 10, 281–288 (2009). https://doi.org/10.1038/ni.1699

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