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.
journal_name
Mol Cell Bioljournal_title
Molecular and cellular biologyauthors
Patial S,Stumpo DJ,Young WS 3rd,Ward JM,Flake GP,Blackshear PJdoi
10.1128/MCB.01068-15subject
Has Abstractpub_date
2016-04-15 00:00:00pages
1395-411issue
9eissn
0270-7306issn
1098-5549pii
MCB.01068-15journal_volume
36pub_type
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