Regulated independent expression of 3' untranslated regions in mammals

Eukaryotic mRNA localization, translation and stability are regulated by 3' untranslated regions (3'UTRs). 3'UTRs control mRNA expression in cis, via regulatory elements that are recognized by trans-acting factors, including RNA-binding proteins and microRNAs. However, a recent analysis of transcription start sites in mouse suggested that 3'UTRs may also be the source of independent transcripts, but there have been no in vivo analyses to confirm this suggestion. Here we report that a large number of 3'UTRs are not only linked to but are also expressed separately from their associated protein-coding sequences. We identify ~14,000 mouse genes exhibiting independent expression of 3'UTRs, of which 1,385 were supported by two distinct experimental approaches, and ~100 confirmed by microarray expression profiles. In situ hybridization demonstrated that 3'UTR-associated transcripts (uaRNA) can be expressed as part of mRNAs or discordantly in a developmentally-regulated and cell-specific manner, in some cases localizing to the nucleus. We also provide evidence that chromatin remodelling and transcription factor networks are involved in regulating uaRNA expression. These observations suggest that 3'UTRs not only function in cis to regulate protein expression but also in trans as noncoding RNAs, a conclusion supported by genetic studies dating back over a decade. Our findings prompt a re-evaluation of 3'UTR biology and the complexity of genome architecture in mammals.