title: 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.
authors.affiliation: Helmholtz Junior Research Group Posttranscriptional Control of Gene Expression, German Cancer Research Center, DKFZ-ZMBH Alliance, Heidelberg, Germany.
authors.forename: Milan
authors.initials: M
authors.lastname: Spasic
authors.forename: Caroline C
authors.initials: CC
authors.lastname: Friedel
authors.forename: Johanna
authors.initials: J
authors.lastname: Schott
authors.forename: Jochen
authors.initials: J
authors.lastname: Kreth
authors.forename: Kathrin
authors.initials: K
authors.lastname: Leppek
authors.forename: Sarah
authors.initials: S
authors.lastname: Hofmann
authors.forename: Sevim
authors.initials: S
authors.lastname: Ozgur
authors.forename: Georg
authors.initials: G
authors.lastname: Stoecklin
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D019295:Computational Biology / Q000379:methods; D016384:Consensus Sequence; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism*; D019143:Evolution, Molecular; D005786:Gene Expression Regulation; D016678:Genome; D055106:Genome-Wide Association Study; D020871:RNA Stability / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D038621:Regulatory Sequences, Ribonucleic Acid / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D012984:Software; D059467:Transcriptome / Q000235:genetics*; D051816:Tristetraprolin / Q000235:genetics* / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D029721:Drosophila Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D038621:Regulatory Sequences, Ribonucleic Acid; C572932:Tis11 protein, Drosophila; D051816:Tristetraprolin