Genome-wide Analysis Identifies Interleukin-10 mRNA as Target of Tristetraprolin

• Published in: The Journal of biological chemistry 2008-04, Vol.283 (17), p.11689-11699
• Main Authors: Stoecklin, Georg, Tenenbaum, Scott A., Mayo, Thomas, Chittur, Sridar V., George, Ajish D., Baroni, Timothy E., Blackshear, Perry J., Anderson, Paul
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions; Animals; Cell Line; Gene Expression Regulation; Genome; Inflammation; Interleukin-10 - metabolism; Macrophages - metabolism; Mice; Models, Biological; Oligonucleotide Array Sequence Analysis; Protein Structure, Tertiary; RNA Stability; RNA, Messenger - metabolism; Tristetraprolin - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M709657200

Tristetraprolin (TTP) is an RNA-binding protein required for the rapid degradation of mRNAs containing AU-rich elements. Targets regulated by TTP include the mRNAs encoding tumor necrosis factor-α, granulocyte-macrophage colony-stimulating factor, interleukin-2 (IL-2), and immediate early response 3. To identify novel target mRNAs of TTP in macrophages, we used a genome-wide approach that combines RNA immunoprecipitation and microarray analysis. A list was compiled of 137 mRNAs that are associated with TTP with an estimated accuracy on the order of 90%. Sequence analysis revealed a highly significant enrichment of AU-rich element motifs, with AUUUA pentamers present in 96% and UUAUUUAUU nonamers present in 44% of TTP-associated mRNAs. We further show that IL-10 is a novel target regulated by TTP. IL-10 mRNA levels were found to be elevated because of a reduced decay rate in primary macrophages from TTP-/- mice. Our study demonstrates the importance of experimental approaches for identifying targets of RNA-binding proteins.