Effects of Combined Tristetraprolin/Tumor Necrosis Factor Receptor Deficiency on the Splenic Transcriptome

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 expressi...

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Published in:Molecular and cellular biology 2016-05, Vol.36 (9), p.1395-1411
Main Authors: Patial, Sonika, Stumpo, Deborah J., Young, W. Scott, Ward, James M., Flake, Gordon P., Blackshear, Perry J.
Format: Article
Language:English
Subjects:
Animals
Binding Sites
Exons
Gene Expression Regulation
Introns
Male
Mice, Knockout
Receptors, Transferrin - genetics
Receptors, Tumor Necrosis Factor, Type I - genetics
Receptors, Tumor Necrosis Factor, Type I - metabolism
Receptors, Tumor Necrosis Factor, Type II - genetics
Receptors, Tumor Necrosis Factor, Type II - metabolism
RNA, Messenger
Sequence Analysis, RNA
Spleen - immunology
Spleen - physiology
Spotlight
Transcriptome
Tristetraprolin - genetics
Tristetraprolin - metabolism
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Summary: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.
ISSN:1098-5549
0270-7306
1098-5549
DOI:10.1128/MCB.01068-15