Genome-Wide Assessment of AU-Rich Elements by the AREScore Algorithm

Abstract

In mammalian cells, AU-rich elements (AREs) are well known regulatory sequences located in the 3′ untranslated region (UTR) of many short-lived mRNAs. AREs cause mRNAs to be degraded rapidly and thereby suppress gene expression at the posttranscriptional level. Based on the number of AUUUA pentamers, their proximity, and surrounding AU-rich regions, we generated an algorithm termed AREScore that identifies AREs and provides a numerical assessment of their strength. By analyzing the AREScore distribution in the transcriptomes of 14 metazoan species, we provide evidence that AREs were selected for in several vertebrates and Drosophila melanogaster. We then measured mRNA expression levels genome-wide to address the importance of AREs in SL2 cells derived from D. melanogaster hemocytes. Tis11, a zinc finger RNA–binding protein homologous to mammalian tristetraprolin, was found to target ARE–containing reporter mRNAs for rapid degradation in SL2 cells. Drosophila mRNAs whose expression is elevated upon knock down of Tis11 were found to have higher AREScores. Moreover high AREScores correlate with reduced mRNA expression levels on a genome-wide scale. The precise measurement of degradation rates for 26 Drosophila mRNAs revealed that the AREScore is a very good predictor of short-lived mRNAs. Taken together, this study introduces AREScore as a simple tool to identify ARE–containing mRNAs and provides compelling evidence that AREs are widespread regulatory elements in Drosophila.

TORn about SASP regulation

“…To investigate if the effect of ZFP36L1 was linked to the presence of AREs, we used an algorithm termed AREScore that identifies AREs and provides a numerical assessment of their strength. 6 We observed a very consistent correlation between AREscore and sensitivity to ZFP36L1 that suggest that AREscores can be used as a predictor of ZFP36L1 function. Our findings open up many interesting prospects regarding the therapeutic potential of ZFP36L1 within a wide range of pathologies such as fibrosis or cancer.…”

A GC-rich sequence feature in the 3′ UTR directs UPF1-dependent mRNA decay in mammalian cells

“…Specific RNA-binding proteins bind to AREs, resulting in the regulation of stability of mRNAs containing AREs. The presence of a high AU-content surrounding an ARE is important for ARE-mediated mRNA decay (Spasic et al 2011). A previous study found that UPF1 preferentially binds G-rich sequences in 3 ′ UTRs in mESCs (Hurt et al 2013).…”

dTIS11 Protein-dependent Polysomal Deadenylation Is the Key Step in AU-rich Element-mediated mRNA Decay in Drosophila Cells

“…Recently, we and others have shown that AMD is conserved in Drosophila. In this organism, dTIS11 regulates the stability of ARE-containing mRNAs including messenger RNAs involved in the immune response, such as antimicrobial peptide-coding mRNAs (23)(24)(25). We have observed that AMD requires the CAF1 protein in Drosophila.…”