Global assessment of GU-rich regulatory content and function in the human transcriptome

Unlike AU-rich elements (AREs) that are largely present in the 3'UTRs of many unstable mammalian mRNAs, the function and abundance of GU-rich elements (GREs) are poorly understood. We performed a genome-wide analysis and found that at least 5% of human genes contain GREs in their 3'UTRs with functional over-representation in genes involved in transcription, nucleic acid metabolism, developmental processes, and neurogenesis. GREs have similar sequence clustering patterns with AREs such as overlapping GUUUG pentamers and enrichment in 3'UTRs. Functional analysis using T-cell mRNA expression microarray data confirms correlation with mRNA destabilization. Reporter assays show that compared to AREs the ability of GREs to destabilize mRNA is modest and does not increase with the increasing number of overlapping pentamers. Naturally occurring GREs within U-rich contexts were more potent in destabilizing GFP reporter mRNAs than synthetic GREs with perfectly overlapping pentamers. Overall, we find that GREs bear a resemblance to AREs in sequence patterns but they regulate a different repertoire of genes and have different dynamics of mRNA decay. A dedicated resource on all GRE-containing genes of the human, mouse and rat genomes can be found at brp.kfshrc.edu.sa/GredOrg.