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Abstract
Tristetraprolin (TTP) acts by binding to AU-rich elements in certain mRNAs, such as tumor necrosis factor (TNF) mRNA, and increasing their decay rates. TTP knockout mice exhibit a profound inflammatory syndrome that is largely due to increased TNF levels. Although TTP's effects on gene expression have been well studied in cultured cells, little is known about its functions in intact tissues. We performed deep RNA sequencing on spleens from TTP knockout mice that were also deficient in both TNF receptors (“triple knockout” mice) to remove the secondary effects of excess TNF activity. To help identify posttranscriptionally regulated transcripts, we also compared changes in mature mRNA levels to levels of transiently expressed pre-mRNA. In the triple knockout spleens, levels of 3,014 transcripts were significantly affected by 1.5-fold or more, but only a small fraction exhibited differential mRNA/pre-mRNA changes suggestive of increased mRNA stability. Transferrin receptor mRNA, which contains two highly conserved potential TTP binding sites, was significantly upregulated relative to its pre-mRNA. This was reflected in increased transferrin receptor expression and increased splenic iron/hemosiderin deposition. Our results suggest that TTP deficiency has profound effects on the splenic transcriptome, even in the absence of secondary increases in TNF activity.
Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.01068-15.
ACKNOWLEDGMENTS
We are very grateful to the NIH Intramural Sequencing Center for the RNA-Seq data. We thank Norris Flagler for digital quantitation of slides and the Histology and the Immunohistochemistry cores for technical support. We also thank Mike Fessler and Don Cook for critical comments on the manuscript.
This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences and National Institute of Mental Health.