In silico motif analysis suggests an interplay of transcriptional and translational control in mTOR response

Abstract

The short 5'-terminal oligopyrimidine tract (TOP) of 5' UTRs is a well-known regulatory sequence motif of mRNAs that are subject to growth-dependent translation. Specifically, translation of TOP mRNAs is regulated by the mTOR signaling pathway that is involved in cell proliferation, cancer development and aging. High throughput data permit detailed study of specific features of the mRNA TOP motif and its DNA origins at transcription start sites (TSS). Recently, ribosome profiling was used to identify mRNA targets of the mTOR pathway in PC3 cells. A novel pyrimidine-rich translational element (PRTE) was reported to play a key role without positional preferences within the 5' UTRs, unlike 5' TOP, which are strictly located at the 5' ends. In this study, we couple recently reported ribosome profiling data on the mTOR mRNA targets with the annotation of TSS obtained by HeliScopeCAGE. We confirm the canonical TOP and strong positional preferences of respective oligopyrimidine tracts (OP) straddling the experimentally validated TSS regions at the DNA level. Such OP localization ensures that transcription from OP segments creates the 5'-terminal TOP in the corresponding mRNAs. We demonstrate that OP are not overrepresented in downstream regions of 5' UTRs of mTOR targets. Finally, we highlight several mTOR target genes with broad and multimodal TSS spanning dozens of nucleotides that are only partically covered with an OP. Therefore, in such cases only a fraction of all produced mRNAs carry a TOP regulatory motif and, thus, respond to mTOR via TOP mechanism. We hypothesize that the interplay between transcription and translation may play a crucial role in the regulation of the mTOR response.